Japan Guideline

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.
jp
JCS GUIDELINES
Guidelines for Diagnosis and Management of Cardiovascular Sequelae in Kawasaki Disease (JCS 2008)
Digest Version
JCS Joint Working Group
Table of Contents
Introduction of the Revised Guidelines 1990 I Current Epidemiology of Kawasaki Disease, and Advancement in and Topics Related to Acute Phase Treatment 1991 1.CurrentEpidemiologyofKawasakiDisease 1991 2.MortalityandPrognosisofPatientsWith KawasakiDisease 1991 3.AdvancementinIntravenousImmunoglobulin (IVIG)Therapy 1992 4.ChangesOverTimeintheIncidenceof CoronaryArteryLesion 1992 5.AdvancementinTreatmentforPatients NotRespondingtoIVIGTherapy 1992 6.ProblemsWithIncomplete(Atypical) KawasakiDisease 1992 II Pathology, Pathophysiology, and Natural History of Cardiac Sequelae in Kawasaki Disease 1992 1.CoronaryArteryLesions 1992 2.MyocardialInjury 1993 3.ValvularDisease 1994 4.Arteriosclerosis(EspeciallyProgression toAtherosclerosis) 1994 5.Non-CoronaryVesselDisorders 1994 6.SummaryofPathology,Pathophysiology, andNaturalHistoryofCardiacSequelae 1994 7.GeneticBackground 1996 III Examinations 1996 1.BloodTests 1996 2.PhysiologicalExaminations(ECG) 1996 3.DiagnosticImaging 1998 4.SummaryofExaminations 2002 IV Treatment Methods 2004 1.Pharmacotherapy 2004 2.Non-PharmacologicalTreatment 2004 3.Initial(Medical)TreatmentforAMI 2008 4.GuidanceonActivitiesofDailyLifeand Exercise(IncludingtheSchoolActivity ManagementTable) 2009
V Follow-up Evaluation 2012 1.ClassificationofSeverityofCoronaryArtery LesionsBasedonEchocardiographicFindings 2012 2.RelationshipBetweenEchocardiography BasedSeverityClassificationandthe SeverityClassificationofCardiovascular LesionsinKawasakiDisease 2012 3.Follow-upEvaluationAccordingtothe Echocardiography-BasedSeverity Classification 2012 4.AcutePhaseKawasakiDiseaseinSummary (SupervisedbytheJapanKawasakiDisease ResearchSociety) 2013 VI Management of Adults With a History of Kawasaki Disease and Cooperation With Cardiovascular Internists 2013 1.Diagnosis 2013 2.Treatment 2014 3.ManagementofDailyLifeandExercise 2014 4.UnderstandingofKawasakiDisease byInternists 2014 5.CoronaryAneurysmsandMyocardial InfarctioninYoungPatientsand KawasakiDisease 2014 6.ComparisonWithAdult-TypeMyocardial Infarction 2014 VII Summarized Guidelines 2015 References 2016 (Circ J 2010;74:19892020)
Released online August 18, 2010 Mailing address: Scientific Committee of the Japanese Circulation Society, 8th Floor CUBE OIKE Bldg., 599 Bano-cho, Karasuma Aneyakoji, Nakagyo-ku, Kyoto 604-8172, Japan. E-mail: meeting@j-circ.or.jp This English language document is a revised digest version of Guidelines for Diagnosis and Management of Cardiovascular Sequelae in Kawasaki Disease reported at the Japanese Circulation Society Joint Working Groups performed in 2007. (website http://www.j-circ. or.jp/guideline/pdf/JCS2008_ogawasy_d.pdf) Joint Working Groups: The Japanese Circulation Society, The Japanese Association for Thoracic Surgery, The Japan Pediatric Society, The Japanese Society of Pediatric Cardiology and Cardiac Surgery, The Japanese College of Cardiology ISSN-1346-9843 doi: 10.1253/circj.CJ-10-74-0903 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
Circulation Journal Vol.74, September 2010
1990
Introduction of the Revised Guidelines

More than forty years have passed since 1967, when the first case series of Kawasaki disease was reported.1 Currently, more than half of the patients diagnosed with Kawasaki disease are 16 years of age or older. In Japan, Kawasaki disease is now managed not only by pediatricians but also by internists. As this timeline suggests, it is expected that more than half of the patients with cardiovascular sequelae of Kawasaki disease have reached adulthood. However, since Kawasaki disease develops most frequently by around 1 year of age, many internists are still not familiar with it (Table 1). The main cardiovascular disease caused by Kawasaki disease is vasculitis, and in this respect patients with this disease differ significantly from other adult patients with arteriosclerosis and/or hypertension. Since the number of adult patients with a history of Kawasaki disease will increase over time, pediatric cardiologists need to accurately provide their findings on Kawasaki disease to cardiovascular internists. Reliable means are needed to ensure appropriate diagnosis, treatment, and determination of the prognosis of patients with cardiovascular sequelae in Kawasaki disease. We hope the present guidelines will help healthcare professionals diagnose and treat their patients with Kawasaki disease. No major additions or corrections of the revised guidelines presented here have been made. The present guidelines basically follow the previous version of the guidelines. However, since the number of adult patients with coronary artery lesions and a history of Kawasaki disease is growing increasingly larger over time, in the present guidelines additional descriptions are included of the risk of development of arteriosclerosis, mechanism of development of arteriosclerosis, and prevention and treatment of arteriosclerosis in patients with a history of Kawasaki disease, particularly those with coronary artery lesions. The recent advancement of diagnostic imaging techniques has been impressive, and there are many techniques useful in the diagnosis and treatment of coronary artery lesions due to Kawasaki disease. The present
Table 1. Diagnostic Guidelines of Kawasaki Disease (MCLS: Infantile Acute Febrile Mucocutaneous Lymph Node Syndrome) Thisisadiseaseofunknownetiologyaffectingmostfrequentlyinfantsandyoungchildrenunder5yearsofage.Thesymptomscanbeclassifiedintotwocategories,principalsymptomsandothersignificantsymptomsorfindings. A. Principal symptoms 1. Feverpersisting5daysormore(inclusiveofthosecasesinwhomthefeverhassubsidedbeforethe5thdayinresponsetotherapy) 2. Bilateralconjunctivalcongestion 3. Changesoflipsandoralcavity:Reddingoflips,strawberrytongue,diffuseinjectionoforalandpharyngealmucosa 4. Polymorphousexanthema 5. Changesofperipheralextremities: (Acutephase):Reddingofpalmsandsoles,Indurativeedema (Convalescentphase):Membranousdesquamationfromfingertips
6. Acutenonpurulentcervicallymphadenopathy Atleastfiveitemsof1to6shouldbesatisfiedfordiagnosisofKawasakidisease. However,patientswithfouritemsoftheprincipalsymptomscanbediagnosedasKawasakidiseasewhencoronaryaneurysmordilatationis recognizedbytwo-dimensional(2D)echocardiographyorcoronaryangiography. B. Other significant symptoms of findings Thefollowingsymptomsandfindingsshouldbeconsideredintheclinicalevaluationofsuspectedpatients. 1. Cardiovascular:Auscultation(heartmurmur,galloprhythm,distantheartsounds),ECGchanges(prolongedPR/QTintervals,abnormalQwave,low-voltageQRScomplexes,ST-Tchanges,arrhythmias),chestX-rayfindings(cardiomegaly),2Dechofindings(pericardialeffusion,coronaryaneurysms),aneurysmofperipheralarteriesotherthancoronary(axillary,etc.),anginapectorisormyocardial infarction 2. Gastrointestinal(GI)tract:Diarrhea,vomiting,abdominalpain,hydropsofgallbladder,paralyticileus,mildjaundice,slightincreaseof serumtransaminase 3. Blood:Leukocytosiswithshifttotheleft,thrombocytosis,increasederythrocytesedimentationrate(ESR),positiveC-reactiveprotein (CRP),hypoalbuminemia,increased2-globulin,slightdecreaseinerythrocyteandhemoglobinlevels 4. Urine:Proteinuria,increaseofleukocytesinurinesediment 5. Skin:RednessandcrustatthesiteofBCGinoculation,smallpustules,transversefurrowsofthefingernails 6. Respiratory:Cough,rhinorrhea,abnormalshadowonchestX-ray 7. Joint:Pain,swelling 8. Neurological:Cerebrospinalfluid(CSF)pleocytosis,convulsion,unconsciousness,facialpalsy,paralysisoftheextremities Remarks 1. Foritem5underprincipalsymptoms,theconvalescentphaseisconsideredimportant. 2. Nonpurulentcervicallymphadenopathyislessfrequentlyencountered(approximately65%)thanotherprincipalsymptomsduringthe acutephase. 3. Male:Femaleratio:1.3to1.5:1,patientsunder5yearsofage:80to85%,fatalityrate:0.1% 4. Recurrencerate:2to3%,proportionofsiblingscases:1to2% 5. Approximately10%ofthetotalcasesdonotfulfillfiveofthesixprincipalsymptoms,inwhichotherdiseasescanbeexcludedand Kawasakidiseaseissuspected.Insomeofthesepatientscoronaryaneurysms(includingso-calledcoronaryarteryectasia)havebeen confirmed. PreparedbytheKawasakiDiseaseResearchGroupoftheMinistryofHealth,Labor,andWelfare,5threvisededition.
JCS Guidelines for Kawasaki Disease
1991
Table 2. Classification of Severity of Cardiovascular Lesions in Kawasaki Disease (a) Classification of coronary aneurysms during the acute phase Smallaneurysms(ANs)ordilatation(Dil):localizeddilatationwith<4mminternaldiameter Inchildren>5yearsofage,theinternaldiameterofasegmentmeasures<1.5timesthatofanadjacentsegment Mediumaneurysms(ANm):aneurysmswithaninternaldiameterfrom>4mmto<8mm Inchildren>5yearsofage,theinternaldiameterofasegmentmeasures1.5to4timesthatofanadjacentsegment Giantaneurysms(ANl):aneurysmswithaninternaldiameterof>8mm Inchildren>5yearsofage,theinternaldiameterofasegmentmeasures>4timesthatofanadjacentsegment TheseverityofKawasakidiseaseisclassifiedintothefollowing5gradesonthebasisoffindingsofechocardiographyandselectivecoronaryangiographyorothermethods: I. Nocoronarydilatation:patientswithnocoronarydilatationincludingthoseintheacutephase II. Transientcoronarydilatationduringtheacutephase:patientswithslightandtransientcoronarydilatationwhichtypicallysubsides within30daysafteronset III. Regression:patientswhostillexhibitcoronaryaneurysmsmeetingthecriteriafordilatationormoreseverechangeonday30after onset,despitecompletedisappearanceofchangesinthebilateralcoronaryarterysystemsduringthefirstyearafteronset,and whodonotmeetthecriteriaforGroupV IV. Remainingcoronaryaneurysm:patientsinwhomunilateralorbilateralcoronaryaneurysmsaredetectedbycoronaryangiography inthesecondyearorlaterandwhodonotmeetthecriteriaforGroupV V. Coronarystenoticlesions:patientswithcoronarystenoticlesionsdetectedbycoronaryangiography (a) atientswithoutischemicfindings:patientswithoutischemicsigns/symptomsdetectablebylaboratorytestsorotherexaminaP tions (b) Patientswithischemicfindings:patientswithischemicsigns/symptomsdetectablebylaboratorytestsorotherexaminations
(b) Severity classification
Otherclinicalsymptomsoffindings: henpatientshavemoderateorseverevalvulardisease,heartfailure,severearrhythmia,orother W cardiacdisease,suchconditionsshouldbedescribedinadditiontotheseverityofKawasakidisease.
guidelines thus describe in detail current knowledge on diagnostic imaging techniques used to evaluate coronary artery lesions. We also discuss the genetic background of Kawasaki disease, although findings regarding this still limited. We previously discussed the classification of coronary artery lesions during the acute phase of Kawasaki disease. Although the criteria for small aneurysms and giant aneurysms were slightly questioned, we decided that no modifications of the criteria needed to be made, based on the opinions of members and collaborators such as that no new evidence have been provided on this matter, and that the classification may not be revised in the present guidelines because it will not affect the contents of the present guidelines for the diagnosis and treatment of cardiovascular sequelae in Kawasaki disease. We used the conventional classification to prepare the present guidelines (Table 2). Although the present guidelines are based in principle on available evidence, the diagnosis and treatment of sequelae in Kawasaki disease are often based on case reports.
Table 3. Levels of Recommendations Class I Conditionsforwhichthereisevidenceforand/or generalagreementthattheprocedureortreatmentis usefulandeffective. Conditionsforwhichthereisconflictingevidenceand/ oradivergenceofopinionregardingtheusefulness/ efficacyofaprocedureortreatment.
Class II
Class III Conditionsforwhichthereisevidenceand/orgeneral agreementthattheprocedureortreatmentisnot useful/effectiveandmayinsomecasesbeharmful.
Emphasis was therefore placed on case reports in the present guidelines as well. Table 3 lists the criteria for levels of recommendations on the procedure and treatment of cardiovascular sequelae in Kawasaki disease.
I Current Epidemiology of Kawasaki Disease, and Advancement in and Topics Related to Acute Phase Treatment
1. Current Epidemiology of Kawasaki Disease
According to the 19th national survey on Kawasaki disease (2005 to 2006),2 the number of patients diagnosed was 10,041 in 2005 and 10,434 in 2006, yielding a total of 20,475 patients. The mean prevalence during the 2-year survey period was 184.6 patients/100,000 children 0 to 4 years of age (male 209.3, female 158.6). The total number of patients with Kawasaki disease including those patients reported in the 19th national survey is 225,682 (male 130,827, female 94,855) as of December 31, 2006. About 90,000 patients were 20 years of age as of January 2006.3
2. Mortality and Prognosis of Patients With Kawasaki Disease

The mortality of patients with Kawasaki disease has gradually decreased, from 0.13% in 1989 to 0.01% in the latest survey. In a cohort study of 6,576 patients followed for about 20
1992 years,4 the standardized mortality ratio (SMR) was 1.14 overall and 0.71 in patients after the acute phase. The mortality rate in male patients with cardiac sequelae in Kawasaki disease was 2.55, and significantly higher than the overall rate.
JCS Joint Working Group dilatation 2.8%, aneurysm 1.3%, giant aneurysm 0.33%), and 3.7% in the 19th survey (coronary dilatation 2.3%, aneurysm 1.0%, giant aneurysm 0.35%). The improvement of clinical results may be explained by the increase in frequency of use of single-dose treatment with immunogloblin 2 g/kg from 8% to 68%.
3. Advancement in Intravenous Immunoglobulin (IVIG) Therapy

During the acute phase, about 86% of patients received IVIG therapy in the 19th national survey.2 Among patients undergoing initial IVIG therapy, 16.2% received an additional IVIG therapy after the initial therapy, and 4.5% of patients received steroids (including patients receiving additional IVIG therapy and those receiving a combination of IVIG and steroids). Pulse steroid therapy was performed in 3.0% of patients and non-pulse steroid therapy in 2.5% (including patients undergoing both pulse therapy and non-pulse therapy).
5. Advancement in Treatment for Patients Not Responding to IVIG Therapy

It is important to treat patients not responding to initial IVIG therapy, who account for about 15% of children with Kawasaki disease, and additional treatments with IVIG, steroid, ulinastatin, and plasmapheresis has been performed for them. Although immunosuppressive agents, such as cyclosporine and infliximab are also used currently, the efficacy and safety of these drugs in the treatment of Kawasaki disease have yet to be established.
4. Changes Over Time in the Incidence of Coronary Artery Lesion

The prevalence of coronary artery lesion during the acute phase has decreased over time: 18.1% in 1997 to 2000 (coronary dilatation 14.7%, aneurysm 2.9%, giant aneurysm 0.50%), 14.8% in 2001 to 2004 (coronary dilatation 11.6%, aneurysm 1.9%, giant aneurysm 0.36%),5 and 11.9% in the 19th survey (coronary dilatation 10.1%, aneurysm 1.5%, giant aneurysm 0.35%).2 The prevalence of coronary artery lesion observed as sequelae in Kawasaki disease has also decreased, from 6.2% in 1997 to 2000 (coronary dilatation 3.9%, aneurysm 1.9%, giant aneurysm 0.46%), to 4.5% in 2001 to 2004 (coronary
6. Problems With Incomplete (Atypical) Kawasaki Disease

The incidence of coronary artery lesions in patients exhibiting 4 principal symptoms of Kawasaki disease is slightly higher than that in patients with 5 to 6 principal symptoms.6 Presentation of a small number of principal symptoms does not necessarily indicate mild disease. Patients with at least 4 principal symptoms require treatment identical to that for patients with complete (typical) Kawasaki disease, and patients with 3 principal symptoms should be treated similarly to those with complete Kawasaki disease.
II Pathology, Pathophysiology, and Natural History of Cardiac Sequelae in Kawasaki Disease

1. Coronary Artery Lesions
The incidence of coronary aneurysm as a sequelae of Kawasaki disease was 16.7% in 1983, when aspirin was the main component of acute phase treatment, but decreased to 3.8% in 2007 as the use of high-dose gamma globulin therapy increased.2 The mortality rate of children with Kawasaki disease was above 1% by 1974, but decreased to around 0.1% in 1990s and is currently 0.01%.2 1 DevelopmentofCoronaryAneurysms Coronary artery lesions are observed during the initial acute phase of Kawasaki disease by echocardiography in all patients as increased echo intensity of the coronary artery wall an average of 5.4 days after onset.7 Coronary dilatation subsides during the initial acute phase, ie, within 30 days after onset, and is referred to as transient coronary dilatation,7 while coronary aneurysms persisting during the convalescence phase or later are considered sequelae of Kawasaki disease. The incidences of coronary sequelae have decreased to 10.09%, 1.49%, and 0.35% in the case of coronary dilatation, aneurysms, and giant aneurysms, respectively.2 It is important to examine for persistent aneurysms using echocardiography during the early stage and about 30 days after the onset of Kawasaki disease. 2 Prognosis(Table 2andTable 4) (1) Reduction and Regression of Aneurysms Coronary aneurysms remaining 30 days after the onset of Kawasaki disease typically decrease in size during the convalescence phase or later. Regression of coronary aneurysms, ie, disappearance of abnormal findings on coronary angiography (CAG), often occurs within 1 to 2 years after onset and typically occurs in the case of small or medium aneurysms.8 This regression has been reported to occur in 329 to 50%10 of patients. It has been reported that patients may develop stenosis of vessels11 that have exhibited regression, decrease in coronary diastolic function,12 abnormal vascular endothelial function, and substantial intimal hyperplasia,1214 which have been suggested to lead to juvenile arteriosclerosis. Patients should thus be followed up even after regression of coronary aneurysms.15 (2) Occlusion of Aneurysms Medium and giant aneurysms are often associated with thrombotic occlusion in the relatively early stage of Kawasaki
1993
Table 4. Classification of Coronary Artery Lesions by Angiographic Findings Dilatationlesions:DL(ANl,ANm,ANs,orDil,asdefinedin echocardiography-basedclassification[Table 2]) Stenoticlesions:SL Occlusion:OC,100%SL Segmentalstenosis:SS[recanalizedvessel](SeeFigure 1) A. raid-likelesion:multipleregionsofneovascularizations B withinthethromboticocclusion B. ridginglesion:developmentofnutrientarteriesdistalto B anoccludedaneurysm C. ericoronaryarterycommunication:anterogradeblood P flowwithacommunicationoftwopointsinonecoronary arteryviaanexistingvessel Localstenosis:LS Subcommittee on Standardization of Coronary Artery Lesions due to Kawasaki Disease, the Kawasaki Disease Research Group,MinistryofHealthandWelfare,1983.
Figure 1. Subtypesofsegmentalstenosis.
Table 5. Characteristics of Myocarditis During the Acute Phase of Kawasaki Disease MyocarditisduringtheacutephaseofKawasakidisease isoftentransient isoftenassociatedwithaslightdecreaseinleftventricularejectionfraction isoftenassociatedwithtransientpericardialeffusion isassociatedwithtransientabnormalitiesofallvalves,among whichslightmitralinsufficiencyandaorticinsufficiencymay persist israrelyassociatedwithseveremyocarditis.
disease. While coronary occlusions are associated with myocardial infarction and sudden death, approximately two-thirds patients with them are asymptomatic.16 It is typical of Kawasaki disease that coronary occlusion is followed by the development of recanalized vessels and collateral flows which significantly improve findings of myocardial ischemia.17 However, patients may often suffer symptoms of myocardial ischemia during adolescence, and may require bypass surgery or develop heart failure and arrhythmias. (3) Recanalization (Segmental Stenosis) Neovascularization considered to represent recanalization after occlusion is referred to as segmental stenosis. Segmental stenosis is observed in 15% of patients with coronary artery lesions due to Kawasaki disease, and occurs in the right coronary artery in 90% of such patients16; occlusion and recanalization in the right coronary artery are considered more common. Angiographic findings of segmental stenosis are classified into three types according to their pathophysiology, time of onset, and prognosis17 (Figure 1). (4) Localized Stenosis During the period up to 10 to 21 years after onset, localized stenoses of 75% vessel diameter develop in 4.7 to 12% of patients with coronary artery lesions, and often occur in the proximal segment or the main trunk of the left anterior descending artery.18 Although progression to stenosis is more common in the case of giant aneurysms, it has been suggested that even small aneurysms with a diameter of 5 to 6 mm on angiography may progress to stenosis during longterm follow-up.9 Evaluation with intravascular ultrasound (IVUS) has revealed intimal hyperplasia in aneurysms with an internal diameter of >4 mm, which may progress to stenosis.19 (5) Coronary Arteries Without Aneurysm Formation Slight or moderate intimal hyperplasia in coronary arteries without aneurysm formation has been reported in patients with Kawasaki disease,12,14 and whether a history of Kawasaki disease is a risk factor for development of atherosclerotic lesions has been discussed.
2. Myocardial Injury
Myocardial injury is classified mainly into two types: inflammatory myocardial injury associated with myocarditis or valvulitis during the acute phase, and ischemic myocardial injury secondary to coronary aneurysms or microcirculation disorder due to coronary arteritis. 1 InflammatoryLesions Interstitial myocarditis and pericarditis are major inflammatory heart diseases associated with Kawasaki disease. The presence of myocarditis during the acute phase has been detected with gallium (Ga)-67 myocardial scintigraphy.20 Cell infiltration mainly by monocytes is a main pathological finding, while degeneration and necrosis of myocytes are rare. Table 5 lists the characteristics of myocarditis in Kawasaki disease. 2 IschemicLesions Acute myocardial infarction (AMI) due to stenotic lesions adjacent to coronary aneurysms caused by severe coronary arteritis tends to develop during the second week after onset or later. Progression of coronary aneurysms to stenotic lesions is more prevalent in aneurysms with an internal diameter of 6 mm, and is especially prevalent in giant aneurysms with a diameter of 8 mm. Chronic myocardial infarction is observed more often after the first 7 weeks of disease, following the acute phase. 3 LesionsintheConductingSystem During the acute phase, inflammation of the conducting system is observed, and transient atrioventricular block, premature ventricular contraction, supraventricular tachycardia, or ventricular tachycardia may develop as clinical manifestations of injury to the conducting system.
1994
3. Valvular Disease
Slight and transient mitral, tricuspid, or pulmonary valve insufficiency is often observed by Doppler echocardiography during the acute phase of Kawasaki disease, and aortic valve insufficiency is also observed in rare cases.21 In addition to regurgitation due to myocarditis and valvulitis during the acute phase, regurgitation may also develop during the remote phase due to thickness or deformation of valves with fibrosis after valvulitis, or to papillary muscle dysfunction caused by ischemia2224 (Figure 2). The incidence of valvular disease is reported to be 1.88% during the acute phase and 0.41% or later.2
5. Non-Coronary Vessel Disorders

Aneurysms of the axillary arteries, femoral arteries, iliac arteries, renal arteries, abdominal aorta, and internal mammary arteries have been observed in rare cases (0.633 to 2%34), and all patients with peripheral aneurysms in these arteries have large coronary aneurysms. Cases of necrotic lesions of the fingers, cerebral infarction due to cerebrovascular disorders, renovascular hypertension, shock due to rupture of femoral arteries, replacement of large abdominal aneurysms with vascular prostheses, and coating of aneurysms have been reported in patients with a history of Kawasaki disease. Although in many cases aneurysms in the axillary arteries and other vessels regress within 1 to 2 years, a case of abrupt occlusion after 35 years has been reported.35 Patients with aneurysms of the peripheral arteries should thus be followed for a long period of time.
4. Arteriosclerosis (Especially Progression to Atherosclerosis)

The progression of vessel disorders due to Kawasaki disease, and especially that of coronary artery lesions to sclerotic lesions, has been described in detail.14,2529 Recent clinical studies have revealed that abnormal diastolic function of peripheral vessels and changes in endothelial cell biomarkers of vascular endothelial dysfunction are present during the remote phase regardless of the presence or absence of coronary artery lesions.3032 However, there is no clinical evidence clearly indicating whether the incidence of atherosclerosis, a finding of lifestyle-related diseases commonly observed in adults, is higher in individuals with a history of Kawasaki disease. Long-term, large-scale, continuous clinical studies will be needed to answer this question. Careful and detailed investigations of the development and progression of arteriosclerotic lesions after Kawasaki disease are needed to clarify the mechanisms underlying them and determine how to prevent the development/progression of such lesions, in ensuring appropriate long-term management of patients.
6. Summary of Pathology, Pathophysiology, and Natural History of Cardiac Sequelae

1 CoronaryArteryLesions Although significant infiltration of inflammatory cells in the coronary arteries during the acute phase of Kawasaki disease regresses over time, a large number of inflammatory cells may remain in the intima, and endarteritis may persist for a long period of time even after remission of clinical symptoms.36,37 During the remote phase, vascular smooth muscle cells continue to multiply actively at the inlet and outlet of the aneurysm,29 and concentric intimal hyperplasia may induce stenosis or occlusion. When an aneurysm becomes clogged by a clot, a new artery with multiple lumens is often formed through the clot. The prognosis in such cases of myocardial ischemia is thus often fair.17 However, such spontaneous recanalization develops only when sudden death or severe myocardial infarction does not occur at the time of occlusion. Patients with medium or giant aneurysms and those with progressive localized stenosis are continuously at risk of sudden death and/or myocardial infarction. It is therefore believed
Acute phase
Myocarditis
Endocarditis
Coronary aneurysms
Ring dilatation Papillary muscle dysfunction
Valvulitis Atrioventricular valve Aortic valve
Convalescence phase
Transient atrioventricular valvular regurgitation
Disappearance of regurgitation
Improvement/ disappearance of regurgitation Cusp deformation, Fibrous degeneration Atrioventricular chordal rupture Development/aggravation of regurgitation Coronary occlusion Ischemic papillary muscle dysfunction
Remote phase Heart failure Figure 2. Mechanismofdevelopmentofvalvulardiseases.
JCS Guidelines for Kawasaki Disease that such patients be followed for life with frequent selective CAG, magnetic resonance imaging (MRI),36 and/or multi-row detector computed tomography (MDCT)38 to monitor changes in the morphology of coronary arteries.
1995 2 Myocarditis,Endocarditis,Valvulitis,andPericarditis These inflammatory cardiac diseases, which are often asymptomatic, are quite prevalent during the acute phase.39 They are often mild in severity throughout the course of disease, though heart failure, cardiac tamponade, and death due to arrhythmia induced by inflammation of atrioventricular and/or
Table 6. Major Reports of Studies of Gene Polymorphism Associated With Kawasaki Disease Analysis *Susceptibility toKD SNP No. of patients 78KDsibling pairs Ethnic group Japanese Results LinkageanalysisofsiblingsofKDpatients. Highlinkagedisequilibriumwasnotedin 12q24,4q35,5q34,6q27,7q15,8q24,18q23, 19q13,Xp22,andXq27. LinkageanalysisofsiblingsofKDpatients. 1,222SNPsin19q13.2-13.3withlinkage disequilibrium3SNPs,fromwhichITPKC wasselected.ITPKCplaysaroleinthenegativecontrolofIL-2expression.Expressionof ITPKCwaslowinCallele,andexpressionof IL-2wasincreased.InJapaneseparticipants, theincidenceofcoronaryarterydisorderwas 2.05-foldhigherwiththeCallele. CD40Lgenewasscreenedtodetect22SNP. IVS4+121A>Ginintron4.Gallelewashigh inKD. TwohaplotypesoftheCCR3-CCR2-CCR5 geneclusterappeartobeatriskforKD,and onetobeaprotectivehaplotype. Aninverserelationshipbetweentheworldwide distributionofCCR532alleleandtheincidenceofKDwasobserved.HHG*2,theCCR5 32-containinghaplotypeofCCR5,wasassociatedwithdecreasedsusceptibilitytoKD.AnalysisofCCR5ligandsandCCL3L1genedose stratumrevealedthatIndividualswho possessedbothHHG*2and2copiesof CCL3L1hadanearly80%lowerriskofdevelopingKD. TheVEGFhaplotypeCGCC(-259A/C, Ex1+405G/C,Ex1-73C/T,236bp3STPCC) wascorrelatedwithsusceptibilitytoKD. TDanalysiswasperformedfor98SNPsof58 genesinacohortof209KDfamilies(trio). PON1,GPRK2L,IL-4,TGF-beta,andGCwere screened.OnlyIL-4wassignificantinanother cohort.HaplotypeanalysisofgenesnearIL-4 didnotrevealanycorrelationsstrongerthanfor IL-4.NocorrelationwithCALwasnoted.TheC alleleoftheIL-4C-589Gwascorrelatedwith susceptibilitytoKD. ExpressionofTIMP-2inPBMCswashighinthe CALgroup.Analysisof5SNPinthe5flanking regionrevealedsignificantlyhigherexpressions of-806T>C,-417G>C,-177C>GintheCAL groupforbothgenotypeandalleletype.Inthe CCCAThaplotype,asignificantdecreasein expressionofTIMP-2wasconfirmed.CCCAT haplotypewassignificantlylowerintheCAL group. ThepresenceoftheACEI/DDalleleandAT1R 1166A/CCalleleincreasedtheincidenceof coronarystenosis2.71-fold. TheG/GalleleoftheMCP-1-2518C/Gwas associatedwithlongdurationoffever,and tendedtobeintractabletoimmunoglobulin therapy. Reported by OnouchiY,etal41
*Susceptibility toKD RiskforCAL
ITPKC
78KDsibling pairs Casecontrol studyin 276KDpatients and282controls
Japanese Americans
OnouchiY,etal42
Susceptibility toKD Susceptibility toKD
CD40L
427KDpatients 476controls 170KDpatients 300controls
Japanese
OnouchiY,etal43
CCR3CCR2CCR5 cluster CCR5 CCL3L1
German Caucasians
BreunisWB,etal44
Susceptibility toKD
160KDfamilies
Americans
BurnsJC,etal45
Susceptibility toKD Susceptibility toKD
VEGF
170KDpatients 300controls 220KD families(trio)
German Caucasians Americans Canadians
BreunisWB,etal46
IL-4
BurnsJC,etal47
RiskforCAL
TIMP-2
208KDpatients 184controls
Japanese
FurunoK,etal48
RiskforCAL
ACE
246KDpatients 147controls 184KDpatients
Japanese
FukazawaR,etal49
Disease severity
MCP-1, CCR2
Japanese
FukazawaR,etal50
*Comprehensivegeneexpressionanalysis. KD, Kawasaki disease; CAL, coronary artery lesion; SNP, single nucleotide polymorphism; ITPKC, inositol 1,4,5-triphosphate 3-kinase C; CD40L,clusterdifferentiation40ligand;CCR,chemokineCCmotifreceptor;CCL,chemokineCCmotifligand;VEGF,vascularendothelial growth factor; IL, interleukin; TIMP-2, tissue inhibitor of metalloproteinase-2; ACE, angiotensin converting enzyme; MCP-1, monocyte chemoattractantprotein-1;PON1,paraoxonase;TGF,transforminggrowthfactor;PBMCs,peripheralbloodmononuclearcells.
1996 sinoatrial conducting system may occur in rare cases. 3 IschemicMyocardialInjury Although ischemic heart disease is the major cause of death of patients with Kawasaki disease, many such deaths occur suddenly, and the number of patients exhibiting histopathological findings of AMI at autopsy is thus small.39 However, lesions of chronic myocardial infarction are often observed at autopsy in patients16 who did not experience cardiac episodes or exhibit findings of ischemia.39,40
JCS Joint Working Group suggested by the findings that (1) the incidence of Kawasaki disease in Japan is 10 to 20-fold that in Western countries,51 (2) the incidence of Kawasaki disease among siblings of patients is about 10-fold that in the general population,52 and (3) the incidence in offspring of parents with a history of Kawasaki disease is about twice that in the general population.53 There have been reports suggesting that genetic polymorphisms are associated with susceptibility to Kawasaki disease, risk for abnormal changes in the coronary arteries, and severity of disease and responses to immunoglobulin therapy. Table 6 lists case-control studies conducted after comprehensive analysis of genes associated with Kawasaki disease, and case-control studies on previously specified genes in at least 150 patients.
7. Genetic Background
Although Kawasaki disease is not a genetic disease, the possibility of a genetic predisposition toward it has been
III Examinations
1. Blood Tests
1 MyocardialInfarction Since no reference values for diagnosis have been established for blood biochemical markers of AMI in children, reference values in adult patients should be used instead. Blood biochemical markers of injury to cardiomyocytes include creatine kinase (CK) located in the cytoplasmic soluble fraction, CK-myocardial band (MB), myoglobin, heart-type fatty acid-binding protein (H-FABP), myosin light chain (MLC) in myofibril, and troponin T and troponin I (TnT, TnI). It is important to use appropriate markers based on the duration of time after onset of myocardial infarction. Myoglobin and H-FABP (with H-FABP 6.2 ng/mL classified as positive) are useful in the diagnosis of myocardial infarction immediately after onset,54,55 while CK-MB and TnT (with TnT 0.10 ng/mL classified as positive) are useful for the diagnosis of myocardial infarction 6 hours after onset. The principal biochemical markers of myocardial infarction are CK-MB and TnT54 (Table 7). 2 Arteriosclerosis The criteria for diagnosis of metabolic syndrome, which include hyperlipidemia and insulin resistance, are important in the diagnosis of arteriosclerosis. In the diagnosis of hyperlipidemia, levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglyceride (TG) are commonly used. Homocysteine level has attracted attention as an independent risk factor for arteriosclerosis. Since metabolic syndrome, for which visceral fat deposition is one of the principal criteria, may often lead to the development of type 2 diabetes and cardiovascular diseases in later life, it has been proposed that abdominal obesity and metabolic syndrome should be cared early in life. Table 8 lists the criteria for diagnosis of metabolic syndrome in children in Japan, Table 9 lists the reference values of serum lipid levels in children, and Table 10 lists the reference values of markers of hyperlipidemia in adults with a history of Kawasaki disease.
2. Physiological Examinations (ECG)

1 ECGatRest During the acute phase of Kawasaki disease, the ECG reveals findings suggestive of myocardial injury and abnormal repolarization such as prolonged PR interval, deep Q waves, prolonged QT interval, low voltage, ST-T changes, and arrhythmias.56,58 When myocardial infarction occurs in patients who still have coronary artery lesions, especially giant coronary aneurysms, during the remote phase, ST-T changes and abnormal Q waves that are consistent with the lesion of infarction are observed.59 2 HolterECG Holter ECG recording is worthwhile in patients complaining of frequent chest pain, chest discomfort, and/or palpitations. Patients with stenosis or giant aneurysms should undergo Holter ECG recording at least once to determine whether ischemic findings are present or development of high-risk arrhythmias is possible. 3 StressECG (1) Exercise ECG a) Double or Triple Masters Two-Step Test Although it has been reported that the Masters two-step test can be routinely performed from infancy, and may provide a load equivalent to that observed during treadmill testing in terms of oxygen consumption in preschool children 4 to 6 years of age,60 exercise ECG cannot detect abnormal findings in patients without severe ischemia. b) Treadmill Test and Ergometer Stress Test Treadmill tests and ergometer stress tests can be administered to school-age or older children, though their sensitivity in detecting ischemic findings is less than that of myocardial scintigraphy. It has therefore been recommended that pharmacological stress be added to increase the rate of detection, or that signal-averaged ECG be used. (2) Pharmacological Stress Tests and Body Surface Potential Mapping It has been reported that dipyridamole61 or dobutamine stress
1997
Table 7. Blood Biochemical Markers of Acute Myocardial Infarction (AMI) Marker CK-MB Strengths 1) Rapidandaccuratetest 2) Reinfarctioncanbedetectedpromptly Weaknesses 1) Lowmyocardialspecificity(specificityforAMIislowinpatientswith musculoskeletaldisorder) 2) Lowdetectionratewithin6hours afteronset 1) Poormyocardialspecificity 2) Sincethelevelreturnstonormal in1to2daysafteronset,itcannot bedetectedinpatientswho presentlateafterAMI Rapidtestkitsareavailable.Itis highlysensitiveduringtheearly diagnosis,butitsspecificityis relativelylow 1) Sensitivityislowwithin6hours afteronset(Retest8to12hours afteronset) 2) Sensitivitytolate-onsetsmallreinfarctionislow Clinical use CK-MBisoneoftheprinciple biochemicalmarkers,andcan beusedasastandardtestin almostallinstitutions Duetopoormyocardialspecificity, AMIcannotbediagnosedwith myoglobinalone
Myoglobin
1) Detectable1to2hoursimmediatery afteronset 2) Highlysensitive 3) Reperfusioncanbedetected 1) Detectable1to2hoursimmediatery afteronset 2) Infarctsizecanbeestimated 3) Reperfusioncanbedetected 1) Highlysensitiveandhighlyspecific 2) Diagnosisispossible8to12hoursafter onset 3) Diagnosisispossiblewhentestingis performedinthefirst2weeksafter onset 4) Promptdiagnosisispossiblewithrapid testkits 5) Reperfusioncanbedetected 1) Detectable4to6hoursafteronset 2) Diagnosisispossiblewhentestingin thefirst2weeksafteronset
H-FABP
Rapidtestkitsareavailable throughoutJapanandusefulin earlydiagnosis Rapidtestkitsareavailable throughoutJapan,andTnTis aprinciplebiochemicalmarker
TnT
MLC
1) Sensitivityisrelativelylow 2) MLCisexcretedrenallyandmay beabnormalinpatientswithrenal failure
Rapiddiagnostictestsarenot available
CK-MB,creatinekinase-myocardialband;H-FABP,heart-typefattyacid-bindingprotein;TnT,troponinT,MLC;myosinlightchain.
Table 8. Criteria for Diagnosis of Metabolic Syndrome in Japanese Children 6 to 15 Years of Age (Final Draft In 2006) Childrenmeeting(1)andatleast2ofitems(2)to(4)shouldbe diagnosedwithmetabolicsyndrome. >80cm(note) (1) Abdominalgirth (2) Serumlipid Triglyceride and/or HDLcholesterol (3) Bloodpressure Systolicpressure and/or Diastolicpressure (4) Fastingbloodglucose >70mmHg >100mg/dL >125mmHg <40mg/dL >120mg/dL
Table 9. Criteria for Diagnosis of Pediatric Hyperlipidemia (Serum Lipid levels in Fasting Blood)56 Total cholesterol (mg/dL) Normal Borderline Abnormal LDL cholesterol (mg/dL) Normal Borderline Abnormal HDL cholesterol (mg/dL) Cut-offvalue Triglyceride (mg/dL) Cut-offvalue 140 LDL,low-densitylipoprotein;HDL,high-densitylipoprotein. 40 <110 110to139 >140 <190 190to219 >220
Note:Childrenwithanwaist-to-heightratioof>0.5fulfillitem(1). Inelementaryschoolchildren(6to12yearsofage),thosewithan abdominalgirthof>75cmshouldbeconsideredtofulfillitem(1). HDL,high-densitylipoprotein.
tests62,63 using body surface potential mapping are useful in patients with myocardial ischemia due to Kawasaki disease with or without significant stenosis, including infants in whom exercise stress testing is not feasible. (3) Electrophysiological Tests Studies of patients with a history of Kawasaki disease who underwent electrophysiological evaluation with intracardiac catheters have revealed that the prevalence of abnormal sinus or atrioventricular nodal function is significantly higher in patients with than in those without cardiac sequelae,64 although the findings of abnormal nodal function were not consistent with the presence of coronary stenosis/occlusion, and are believed to result from myocarditis or abnormal microcircu-
Table 10. Criteria for Management of Hyperlipidemia in Adult Japanese for the Prevention and Treatment of Coronary Artery Disease57 Hypercholesterolemia Totalcholesterol HyperLDLcholesterolemia LDLcholesterol HypoHDLcholesterolemia HDLcholesterol Hypertriglyceridemia Triglyceride >150mg/dL LDL,low-densitylipoprotein;HDL,high-densitylipoprotein. <40mg/dL >140mg/dL >220mg/dL
1998
Table 11. Detection of Cardiac Complications by Common Physiological Examinations Investigators OsadaM,etal80 NakanishiT,etal59 OgawaS,etal81 GenmaY,etal82 TakechiN,etal83 Examination QTdispersion 12-leadECG Signal-averagedECG Dobutaminestress signal-averagedECG Dobutaminestress bodysurfacepotential mapping Target disease Coronaryarterylesions Inferiorwallinfarction Anteriorwallinfarction Lateralwallinfarction Myocardialischemia Myocardialischemia Myocardialischemia Criteria QT>60ms deepQinII,III,aVF deepwideQinV1-6 deepQinI,aVL LPpositive LPpositive nST>1 Imap<4 N 56 7 8 7 198 85 115 115 Sensitivity 100%(6/6) 86% 75% 57% 69.2% 87.5% 94.1% 41.7% Specificity 92% 97% 99% 100% 93.5% 94.2% 98.9% 96.9%
LP,latepotential;nST,non-stresstest;Imap,isopotentialmap.
lation in the conducting system. (4) Signal-Averaged ECG Signal-averaged ECG is believed to feature a better rate of detection of myocarditis associated with Kawasaki disease than standard 12-lead ECG, Holter ECG, echocardiography, and blood tests for cardiac enzymes.65 Positive ventricular late potential adjusted for body surface area is highly specific for the detection of ischemia and chronic myocardial infarction,66 and dobutamine stress tests may improve specificity further in children who cannot tolerate exercise testing. 4 SummaryofPhysiologicalExaminations Table 11 summarizes the physiological examinations commonly used for patients with Kawasaki disease and their rates of detection of cardiac complications.
reported that 3-dimensional (3D) echocardiography is useful in visualizing the right coronary artery and the circumflex artery, and in visualizing mural thrombi in coronary aneurysms. This technique is expected to become useful for the diagnosis of coronary artery lesions due to Kawasaki disease. Echocardiography is the most useful method for evaluation of deterioration of cardiac function due to myocardial injury and the severity of valvular disease.75 Detailed reports have been published on evaluation of myocardial injury during the acute phase using tissue Doppler imaging.76 (2) Stress Echocardiography Stress echocardiography is a method enabling real-time evaluation of left ventricular wall motion in patients during exercise (treadmill or ergometer)77 or with administration of dobutamine78 or dipyridamole.79 Dobutamine stress echocardiography is particularly useful for detecting coronary stenotic lesions and evaluating the viability of myocardium. In dobutamine stress echocardiography, dobutamine is administered in incremental doses, which are increased by 5 to 10 g/kg/ min every 5 minutes to a highest dose of 30 to 40 g/kg/min to check visually for abnormal wall motion in each slice. (3) Others Transesophageal echocardiography (TEE) may be useful in visualizing coronary arteries in adults suspected to have coronary aneurysms which are difficult to evaluate using transthoracic echocardiography.84 It also may be used to evaluate coronary blood flow. Myocardial contrast echocardiography, the use of which has advanced through the widespread use of intravenous myocardial contrast echocardiography and the improvement of ultrasonic device, is now able to provide evaluation equivalent to that by myocardial scintigraphy and is expected to prove useful in the future because of its convenience.85 3 RadionuclideImaging Myocardial perfusion imaging techniques available for patients with Kawasaki disease include Planar and single photon emission computed tomography (SPECT), the latter of which is more commonly used. Thallium (201Tl) is often used, and technetium (Tc)-labeled myocardial perfusion agents (Tc-99m sestamibi, Tc-99m tetrofosmin) which are low in radioactive exposure and suitable for scintigraphy are also commonly used.86,87 Stress myocardial SPECT is an important method of diagnosis of coronary stenotic lesions after Kawasaki disease, and both exercise stress SPECT and pharmacological stress SPECT are commonly performed.8893 In addition to myocardial perfusion imaging techniques,
3. Diagnostic Imaging
1 ChestXRay (1) X-Ray Finding of Calcified Coronary Aneurysms Since the presence of calcification of coronary aneurysms on chest X-ray suggests the presence or progression of giant aneurysms or stenotic lesions, CAG using MDCT or selective CAG is required.67,68 (2) Enlarged Heart Shadow due to Myocardial Ischemia or Valvular Diseases An enlarged heart shadow is observed in patients with poor cardiac function due to chronic myocardial infarction, and in patients with volume overload caused by mitral or aortic insufficiency. 2 Echocardiography (1) Echocardiography at Rest Echocardiography at rest is the most commonly performed test, because it is non-invasive and convenient, and can be used to evaluate coronary morphology over time to detect coronary dilatations specific to the coronary artery lesions associated with Kawasaki disease.69,70 Adults may be diagnosed with Kawasaki disease based on the visualizing of coronary aneurysms.71 The presence/absence of thrombi within aneurysms can also be determined with echocardiography.72 Although it is sometimes difficult to evaluate stenotic lesions with echocardiography,73,74 it has been reported that following the improvement of ultrasonic device, measurement of coronary blood flow with Doppler echocardiography enables accurate diagnosis of stenotic lesions. It has also been
JCS Guidelines for Kawasaki Disease evaluation of myocardial fatty acid metabolism with 123I methyl-p-iodophenyl-pentadecanoic acid (123I BMIPP) 94 and evaluation of cardiac sympathetic nerve activity with 123I metaiodobenzylguanidine (123I MIBG)95 are also used in the clinical setting. Ga-67 myocardial scintigraphy is useful in the diagnosis of myocarditis due to Kawasaki disease.20 (1) 201Tl Myocardial Perfusion Scintigraphy Lesions of myocardial ischemia may be located by obtaining stress images under administration of 201Tl and then obtaining delayed images to investigate redistribution in areas with poor perfusion. Redistribution images are considered especially useful in predicting cardiac events due to coronary artery lesions associated with Kawasaki disease.89 Specifically, 201Tl is administered during stress at 37 MBq (1 mCi) in infants under one year of age, 37 to 56 MBq (1 to 1.5 mCi) in children 1 to 10 years of age, and 56 to 74 MBq (1.5 to 2 mCi) in children 10 years of age, and delayed images (redistribution images) are obtained 3 to 4 hours after administration of 201Tl.96 To obtain clear images, physicians should (1) exercise special caution in avoiding body movement by children during imaging, (2) obtain stress images promptly after administration of 201Tl, since redistribution of 201Tl occurs within a short period of time, and (3) ensure that patients do not eat from administration of 201Tl until the time of delayed imaging. (2) Tc-Labeled Myocardial Perfusion Scintigraphy Tc-labeled myocardial perfusion agents such as Tc-99m sestamibi and Tc-99m tetrofosmin have been developed as alternatives to 201Tl for use in myocardial perfusion imaging. These agents allow high-resolution, low-exposure imaging because of their short half-life. Once absorbed into the myocardium, Tc-labeled myocardial perfusion agents remain in the myocardium for a long period of time and are not redistributed, as occurs with 201Tl. Images can thus be obtained regardless of time after administration, though images at rest should be obtained separately. Tc-labeled myocardial perfusion scintigraphy is performed under stress at a dose of 10 MBq/kg (maximum 370 MBq, 10 mCi), and the second dose is administered 2 to 3 hours after the first administration at 2 to 3 times the first dose (maximum 740 MBq, 20 mCi).97 To obtain clear images, physicians should (1) exercise special caution in avoiding body movement by children during imaging, (2) continue stress for at least one minute after administration of perfusion agents under stress, (3) promote elimination of perfusion agents from the liver and gallbladder by ingestion of egg products, milk or cocoa, and (4) obtain images at least 30 minutes after administration of perfusion agents to ensure elimination of perfusion agents accumulated in the liver. (3) ECG-Gated Myocardial Perfusion SPECT The availability of 3D automatic quantitative analysis of ECG-gated myocardial perfusion SPECT (quantitative gated SPECT, QGS) has allowed physicians to calculate left ventricular volume and ejection fraction (EF) by evaluating wall motion and to visualize the endocardium based on multidimensional 3D images.98 In patients with severe coronary artery lesions due to Kawasaki disease, detailed evaluation of postischemic myocardial stunning99 and viability of infarcted myocardium may be performed with QGS,100,101 though this method cannot be used effectively in patients with a small heart (diastolic volume of about 50 mL) under 6 years of age.
1999
Isotope IV
Ergometer
Isotope IV
Dobutamine
Isotope IV
Dipyridamole
Isotope IV
ATP
Isotope IV
Adenosine
Figure 3. Administrationofdrugsduringmyocardialperfusionscintigraphy.IV,intravascular;ATP,adenosinetriphosphate.
(4) Imaging of Myocardial Fatty Acid Metabolism Imaging of myocardial fatty acid metabolism using 123I BMIPP is a better technique for specification of segments with abnormal wall motion than myocardial perfusion imaging because it can specify abnormal energy production in the myocardium. Since areas with low myocardial uptake of 123 I BMIPP are strongly consistent with segments perfused by the culprit coronary vessel in patients with myocardial infarction or angina, this technique can be used in the evaluation of myocardial injury in patients with severe coronary artery lesions due to Kawasaki disease.94 (5) Imaging of Cardiac Sympathetic Nerve Activity Imaging of cardiac sympathetic nerve activity can be obtained with 123I MIBG imaging. Since abnormal cardiac sympathetic nerve activity follows the development of severe myocardial ischemia or myocardial infarction, 123I MIBG imaging in patients suspected of having cardiac events including infarction may allow physicians to specify culprit vessel(s) promptly, and is thus quite useful in patients with coronary artery lesions due to Kawasaki disease who often experience asymptomatic myocardial ischemia.95,102 (6) Positron Emission Tomography (PET) Quantitative evaluation of myocardial flow reserve can be performed in the evaluation of blood flow by PET using [O15]-water or [N-13]-ammonia. Low myocardial flow reserve and poor vascular endothelial function have been observed in patients with regression of coronary aneurysms. Evaluation of glucose metabolism in PET using [F-18]-fluorodeoxyglucose (FDG) permits precise evaluation of the viability of infarcted myocardium.103,104
2000
JCS Joint Working Group observe for thrombi and intimal hyperplasia.106,107 Although the rate of visualization of stenotic lesions is lower with MRCA than MDCT,108,109 MRCA is more useful in visualization of localized stenosis with calcification because it does not hinder visualization of vascular lumens.36,110 (3) Magnetic Resonance (MR) Myocardial Imaging MR myocardial imaging, which may be performed in a short time following MRCA, is a less expensive imaging technique without the need for radioisotopes, and may provide clearer 3D images than MRCA. Cine MRI is performed using SSFP without contrast media to acquire images from the left ventricular short axis view, long axis view, and four-chamber view to observe ventricular wall motion, and perfusion MRI is performed after infusion of gadolinium-based contrast media to evaluate the severity of myocardial ischemia by observing the first pass of contrast media in the myocardium during adenosine triphosphate (ATP) stress and at rest from the left ventricular short axis view.111 Delayed-contrast enhanced MRI can visualize the extent and depth of subendocardial infarct lesions by obtaining images 15 minutes after the administration of contrast media with a sequence using T1-weighted gradient echo with myocardial T1 signal suppression. This technique can visualize subendocardial infarct lesions and small infarct lesions in the right ventricle, which cannot be visualized with radioisotope myocardial imaging. Since the prevalences of occlusions and recanalization of the right coronary artery are especially high in patients with Kawasaki disease, precise evaluation of the right ventricular myocardium is important.112 5 CardiacCatheterizationandCAG (1) CAG a) Indications (1) Evaluation of Severity of Coronary Artery Lesions and Patient Follow-up Although in the case of adults CAG is indicated for those who exhibit findings of myocardial ischemia, it is recommended for patients with Kawasaki disease that CAG should be performed in those with medium or giant aneurysms during the convalescence phase or later to monitor for the development or progression of localized stenosis, since myocardial ischemia due to Kawasaki disease cannot be fully detected with other types of examinations and myocardial ischemia may manifest as sudden death.16 (2) Percutaneous Coronary Intervention (PCI) Before and After Coronary Artery Bypass Grafting (CABG) CAG is required before PCI to determine whether PCI is indicated, during angioplasty to ensure safe and effective intervention, and after angioplasty to evaluate the results of PCI and follow up patients.90,113 (3) Intracoronary Thrombolysis (ICT) Thrombi in coronary aneurysms may sometimes be observed during follow-up of medium to giant aneurysms with echocardiography. In such cases, cardiac catheterization and CAG are performed for ICT.
Figure 4. 64-rowMDCTandMRCAininfants.MDCT,multirowdetectorcomputedtomography;MRCA,magneticresonancecoronaryangiography.
(7) Administration of Drugs During Myocardial Perfusion Scintigraphy Figure 3 illustrates how drugs are administered during pharmacological myocardial perfusion scintigraphy. 4 MagneticResonanceCoronaryAngiography(MRCA) andMDCT Selective CAG has been considered a gold standard for the diagnosis of coronary artery lesions due to Kawasaki disease, and IVUS has been used concomitantly to observe for thrombi in aneurysms and intimal hyperplasia. Recently, MDCT and coronary artery imaging using MRI (MRCA) have been developed, and are increasingly used to obtain additional findings supportive of those of CAG. (1) MDCT Although it has been believed that MDCT is not feasible in children because of the extensive X-ray exposure associated with it, use of contrast media, administration of -blockers to slow heart rate, and the need for breath-holding, recent reports have indicated that 64-row MDCT provides clear images in young children who do not hold their breath during imaging38 and do not undergo induction of slow heart rate, and may overcome the problems regarding breath and heart rate control when used more widely in the future (Figure 4). (2) MRCA MRCA is a completely non-invasive imaging technique which requires neither X-ray exposure nor contrast media. Since MRCA can be performed during spontaneous breathing without slowing of the heart rate, infants and young children may undergo it during sleep.105 There are two imaging techniques of MRCA, the bright blood technique [steady-state free precession (SSFP)] which indicates blood flow as white, and the black blood technique, which indicates blood flow as black and occlusions and intimal hyperplasia as gray (Figure 4). The black blood technique includes M2D black blood turbo spin echo imaging and 2D Black blood Spiral k-space order TFE technique (indicates coronary transection) which allows physicians to
JCS Guidelines for Kawasaki Disease b) CoronaryArteryLesionsIndicatedforCAG (1) Dilatation Lesions In patients with aneurysms classified as medium or giant according to the severity classification of cardiovascular lesions in the present guidelines, it is desirable to perform CAG during the early part of the convalescence phase for detailed evaluation of the morphology and extent of coronary artery lesions and to specify the methods and duration of follow-up and treatment strategies. Since precise evaluation of coronary stenotic lesions is feasible with MRCA and MDCT, it is expected that in the future it will be possible to omit catheterization for the diagnosis of coronary stenotic lesions in some patients.105 Since the development of stenosis after regression of not only large aneurysms but also smaller ones12 and the development of arteriosclerotic degeneration14 have been observed in patients over 10 years after the onset of Kawasaki disease, patients should be followed for a long period of time using coronary imaging techniques such as MRCA and MDCT if follow-up CAG is not feasible. (2) Localized Stenosis During the remote phase, progressive localized stenosis develop mainly in the inlet and outlet of aneurysms. Multidirectional imaging is required to evaluate stenotic lesions. A significant stenosis is defined as a 75% stenosis in lumen diameter in the major coronary arteries and a 50% stenosis in lumen diameter in the left main coronary trunk. Patients with significant stenosis should be followed with angiography16 or other imaging techniques such as MRCA105 and MDCT114 at appropriate intervals based on the speed of progression of the stenosis (from 6 months to several years), even when no signs/symptoms of myocardial ischemia are present, and should be considered for aggressive treatment such as CABG113 and PCI 90 based on the results of the abovedescribed follow-up imaging as well as the results of other studies such as myocardial scintigraphy, exercise ECG, and evaluation of coronary flow reserve (CFR). (3) Occlusion Complete occlusion of a coronary artery is observed in about 16% of patients with coronary artery lesion due to Kawasaki disease, and 78% of occlusions are visualized with imaging within 2 years after the onset of Kawasaki disease.16 The finding of occlusion of the coronary arteries in asymptomatic patients on routine follow-up imaging is not uncommon. Collateral flows are visualized during angiography in all patients with coronary occlusion. Since the extent of collateral flow and growth/development of recanalized vessels differ among individuals and depend on the time after occlusion and cause of occlusion (thrombi vs intimal hyperplasia), follow-up angiography is required.17 (2) Cardiac Function Test Cardiac function is evaluated by determining ventricular pressure, cardiac output, ventricular volume, EF, and/or other parameters. (3) IVUS a) MorphologicalEvaluationofCoronaryArteryLesions IVUS is used to evaluate the severity of intimal hyperplasia, presence/absence of thrombi or calcification, and the severity of luminal narrowing. Severe intimal hyperplasia is observed not only in lesions of localized stenosis but also in
2001
Table 12. Indications of Imaging Techniques by Classification of Severity of Coronary lesions Due to Kawasaki Disease Chest X ray
ClassI ClassII ClassIII ClassI ClassII ClassIII
Severityclassification Severityclassification None Severityclassification None None Severityclassification Severityclassification None Severityclassification Severityclassification None
III,IV,V I,II
Echocardiography/12-lead ECG at rest I,II,III,IV,V
Exercise ECG
III,IV,V I,II
Holter ECG, signal-averaged ECG IV,V I,II,III
Body surface mapping, drug stress ECG, magnetocardiography

ClassI ClassII ClassIII
Severityclassification Severityclassification None
IV,V I,II,III
Stress echocardiography, myocardial contrast echocardiography

Severityclassification Severityclassification None Severityclassification Severityclassification None
IV,V I,II,III
Myocardial perfusion scintigraphy IV,V I,II,III
Evaluation of myocardial fatty acid metabolism, evaluation of cardiac sympathetic nerve activity
Severityclassification Severityclassification None Severityclassification Severityclassification None Severityclassification Severityclassification None Severityclassification Severityclassification Severityclassification
V I,II,III,IV
MRI, MDCT
IV,V I,II,III
PET
V(b) I,II,III,IV,V(a)
Cardiac catheterization IV,V III I,II
MRI, magnetic resonance imaging; MDCT, multi-row detector computedtomography;PET,positronemissiontomography.
Class I Class II
Conditionsforwhichthereisgeneralagreementthatthe procedureisusefulandeffective. Conditionsforwhichthereisadivergenceofopinion regardingtheusefulness/efficacyofaprocedure.
Conditionsforwhichthereisgeneralagreementthatthe Class III procedureisnotuseful/effectiveandmayinsomecases beharmful.
2002
Table 13. Performance of Common Imaging Techniques (Not Including Cardiac Catheterization) Investigator HiraishiS,etal73 NotoN,etal78 KondoC,etal88 KarasawaK,etal124 KarasawaK,etal124 KarasawaK,etal124 FukudaT,etal125 HoshinaM,etal94 KanamaruH,etal114 MiyagawaM,etal89 SuzukiA,etal36 Technique Transthoracicechocardiography Diagnosisofstenoticlesions Stressechocardiography Diagnosisofstenoticlesions
201Tl 201Tl 201Tl
Stress Atrest Dobutamine Dipyridamole Dobutamine ATP Exercise, ATP,Dobutamine Dipyridamole Atrest Atrest Dipyridamole Atrest
N 18 26 34 24 24 20 86 10 16 15 70
Sensitivity RCA:85%,LAD:80% 90% 88% 71% 83% 90% 90% 90% 87.5%(25vessels) 93% occlusion94.2%, stenosis94.4%
Specificity RCA:98%,LAD:97% 100% 93% 95% 92% 85% 100% 73.9% 92.5%(52vessels) 83% occlusion99.5%, stenosis97.2%
Diagnosisofstenoticlesions Diagnosisofstenoticlesions Diagnosisofstenoticlesions
Tc-99mtetrofosmin Diagnosisofstenoticlesions Tc-99mtetrofosmin Diagnosisofstenoticlesions

123IBMIPP
Diagnosisofstenoticlesions
MDCT Diagnosisofstenoticlesions*
201Tl
Predictionofcardiacevents
MRCA Diagnosisofstenoticlesions**
*Of80vesselsin16patientswithcoronarylesions,77vesselscouldbeevaluatedwithMDCT. **Among70patientswithcoronarylesions,evaluationwasperformedin210vesselsofpatientswithocclusionand54vesselsof18patients withregionalstenosis. Tl,thallium;Tc,technetium;BMIPP, -methyl-p-iodophenyl-pentadecanoicacid;MDCT,multi-rowdetectorcomputedtomography;MRCA,mag neticresonancecoronaryangiography;ATP,adenosinetriphosphate;RCA,rightcoronaryartery;LAD,leftanteriordescendingcoronaryartery.
aneurysms that have regressed. Intimal narrowing and calcification, not detected with angiography may be visualized with IVUS. It has been found that obvious intimal hyperplasia may develop during the remote phase in aneurysms with an internal diameter during the acute phase of >4 mm.19 Evaluation of lesions, and especially quantitative evaluation of calcified lesions with IVUS, is required when the means to be used for PCI are selected.28 b) CoronaryArterialVasodilatorFunction It has been reported that the absence of coronary vasodilatation in coronary artery wall following administration of isosorbide dinitrate (ISDN) or acetylcholine suggests the presence of chronic intimal dysfunction in patients with Kawasaki disease.27,115 However, since evaluation of coronary arterial vasodilator function may induce coronary spasm or other adverse reactions, its potential benefits and risks should be carefully weighed before it is performed. c) PCI Preoperative examination should be performed to determine the severity of stenosis and its calcification and the condition of the intima in detail in order to select appropriate means for the performance of PCI. IVUS should be performed in every step of PCI to ensure the safety and efficacy of treatment. IVUS is also useful in the evaluation of postoperative restenosis.28,116 (4) Functional Severity Evaluation Using Flow Wires or Pressure Wires Determination of average peak flow velocity (APV), CFR, and myocardial fractional flow reserve (FFRmyo) using a 0.014-inch guidewire equipped with an ultrasonic probe and a high-sensitivity pressure sensor (Doppler wires or pressure wires) is useful in evaluation of the functional severity of
coronary artery lesion in patients with coronary artery lesions due to Kawasaki disease. CFR (CFR = [stress APV] / [APV at rest], where APV is the value at peak dilatation after infusion of papaverine hydrochloride injection) and FFRmyo (FFRmyo = [Mean pressure at a site distal to the coronary lesion of interest] {[mean right atrial pressure] / [mean pressure at the coronary ostium]} [mean right atrial pressure]), where these pressures are obtained simultaneously at peak dilatation after infusion of papaverine hydrochloride) are particularly suitable for the evaluation of the presence/absence and severity of myocardial ischemia and presence/absence of peripheral coronary circulatory disorder. These values are also useful in selecting appropriate treatment strategies (catheter intervention vs CABG) and postoperative evaluation. Measurements obtained with pressure wires are useful in the evaluation of stenotic lesions, and those with Doppler wires in the evaluation of dilatation lesions.117 The reference values in children are 2.0 for CFR and 0.75117 for FFRmyo, and identical to those in adults.118121
4. Summary of Examinations
As Table 12 shows, appropriate imaging techniques should be selected based on the severity of coronary artery lesions. Table 13 lists the diagnostic performance of the imaging techniques mainly used in the evaluation of cardiovascular sequelae in Kawasaki disease. Selection of treatment strategies for cardiovascular sequelae in Kawasaki disease must be made on the basis of careful consideration of the pathological condition of each patient and the results of comprehensive multimodal analysis of findings obtained with different imaging techniques.
2003
Table 14. Guidelines for Treatment of Patients With Persistent Coronary Aneurysms/Dilatation During the Chronic Phase I Patients without angina or detectable ischemia Combinationtherapyusingantiplateletdrugs Examinationrevealedobviousischemia II Patients with angina Inadditiontocombinationtherapyusingantiplateletdrugs Anginaonexertion Anginaatrestorduringsleep Anginaatnight Nitrates,monotherapyorcombinationtherapyofCa-blockers,plus-blockersifineffective Ca-blockers Ca-blockers+nitratesorK-channelopeners(nicorandil) Antiplateletdrugs+Ca-blockers
III Patients complicated by cardiac dysfunction or valvular disease Severityofcardiacdysfunctionshouldbeevaluatedappropriately.Monotherapyorcombinationtherapyusing-blockers, ACEinhibitors,angiotensinIIreceptorblockers,orstatinsshouldbeaddedtoantianginaldrugs. ACE,angiotensinconvertingenzyme.
Table 15. Antiplatelet Drugs and Anticoagulant Drugs Drug Acetylsalicylicacid (BufferinorBayaspirin) Dose 30to50mg/kgdividedinto3dosesduringthe acutephase,3to5mg/kgoncedailyafterdefervescence 3to5mg/kg,dividedinto3doses Adverse drug reactions (ADRs) and precautions Hepaticfunctiondisorder,gastrointestinalulcer,Reye syndrome(higherincidenceat>40mg/kg),bronchial asthma Useotherdrugsduringvaricellainfectionandinfluenza. Hepaticfunctiondisorder,gastrointestinalulcer Usewhenseverehepaticdisorderduetoaspirin develops. Mayinduceanginainpatientswithseverecoronary stenosis. Coronarystealphenomenon,headache,dizziness, thrombocytopenia,hypersensitivity,dyspepsia Thromboticthrombocytopenicpurpura(TTP),leukopenia (granulocytopenia),serioushepaticfunctiondisorder Bloodtestsmustbeperformedeveryotherweekduring thefirst2monthsoftreatment. TTP,gastrointestinalsymptoms,malaise,myalgia,headache,rash,purpura,pruritus Bleedingtendencymaydevelopwhenusedwithaspirin. MajorADRs:Shock/anaphylactoidreaction,bleeding, thrombocytopenia,thrombocytopenia/thrombosisassociatedwithheparin-inducedthrombocytopenia(HIT)
Flurbiprofen (Froben) Dipyridamole (Persantin,Anginal)
2to5mg/kg,dividedinto3doses
Ticlopidine (Panaldine)
5to7mg/kg,dividedinto2doses
Clopidogrel (Plavix) Unfractionatedheparin (IV) Low-molecular-weight heparin (SC)
1mg/kg,oncedaily
Loadingdose50units/kg,maintenancedose 20units/kgtomaintainanAPTTof60to85sec (1.5to2.5timesbaseline) Infants<12monthsofage Treatment:3mg/kg/day,dividedinto2doses (every12hours) Prevention:1.5mg/kg/day,asabove Children/adolescents Treatment:2mg/kg/day,dividedinto2doses (every12hours) Prevention:1mg/kg/day,asabove 0.05to0.12mg/kg,oncedaily (0.05to0.34mg/kg/dayintheAHAguidelines) 3to7daysrequiredtoobtainefficacy
Warfarin (Warfarin)
DoseshouldbeadjustedtoanINRof1.6to2.5(2.0to 2.5intheAHAguidelines)andathrombotest(TT)value of10to25%. Sensitivitytothisdrug,hepaticfunctiondisorder,and bleedingADRsarepossible. Theeffectofwarfarinmaybereducedbybarbiturates, steroids,rifampicin,bosentanhydrate,andvitaminKrichfoodssuchasnatto,spinach,greenvegetables, chlorella,andgreenjuices.Theeffectofwarfarinmaybe increasedbychloralhydrate,NSAIDs,amiodarone, statins,clopidogrel,ticlopidine,antitumordrugs,antibiotics,andantifungaldrugs.
Thesafetyandefficacyoftheabovedrugshavenotbeenestablishedinchildren. IV,intravenous;SC,subcutaneous;APTT,activatedpartialthromboplastintime;AHA,AmericanHeartAssociation;INR,internationalnormalized ratio;NSAIDs,nonsteroidalantiinflammatorydrugs.
2004
IV Treatment Methods
1. Pharmacotherapy
1 TreatmentPolicy In assessment of cases of death during the remote phase in patients complicated by coronary artery lesion, the major cause of death has been found to be ischemic heart disease due to stenotic lesions resulting from coronary intimal hyperplasia or thrombotic occlusion.122,123 In general, treatment of myocardial ischemia is performed to: Increase coronary blood flow Prevent or relieve coronary spasm Inhibit the formation of thrombi Decrease cardiac work Accordingly, vessel wall remodeling and myocardial protection are the principal purposes of treatment.126 2 TreatmentofIschemicAttacks (1) Treatment During Attacks Sublingual administration of tablets of nitroglycerin, a fastacting nitrate, is commonly performed to treat attacks of stable angina. Attacks will subside in 1 to 2 minutes in patients responding to sublingual nitroglycerin, while patients not responding to it should take additional sublingual tablets 5 to 10 minutes later. Since the standard dose for children has not been established, nitroglycerin should be administered at a dose calculated from the standard dose in adults. (2) Prevention of Development of Angina Pectoris Table 14 summarizes treatment policies for patients who still have coronary aneurysm or dilatation during the chronic phase. (3) Prevention of Development (and Recurrence) of AMI Among those with AMI complicated by coronary artery lesions due to Kawasaki disease, AMI occurred during sleep or at rest in 63% of patients and was not closely associated with physical activity and exertion.127 In addition, asymptomatic AMI occurred in 37% of the patients. Pharmacotherapy for AMI should be designed to prevent the progression of intimal hypertrophy to stenotic lesions and inhibit the formation of thrombi, considering the poor myocardial oxygen consumption that may be present and possible involvement of coronary spasm in the development of myocardial infarction. 3 Pharmacotherapy (1) Antiplatelet drugs (Table 15) Platelet count decreases slightly immediately after the onset of Kawasaki disease (acute phase), and increases during the convalescence phase. Since platelet aggregation activity remains high during the first 3 months after onset and in some cases the first several months to 1 year after onset, it is preferable that patients with Kawasaki disease, including those without coronary sequelae, should be treated with antiplatelet drugs at low doses for about 3 months.128130 On the other hand, patients with coronary aneurysm due to Kawasaki disease should receive antiplatelet drugs continuously to prevent ischemic heart disease and prevent the formation or growth of thrombi by platelet activation. (2) Anticoagulant Drugs (Table 15) Treatment with anticoagulant drugs is indicated for patients with medium or giant coronary aneurysms, patients with a history of AMI, and patients with abrupt dilatation of a coronary artery associated with a thrombus-like echo, among others. Patients with thrombi in coronary aneurysms should be treated with warfarin or heparin. Combined use of aspirin and warfarin is needed to prevent thromboembolism in patients with giant coronary aneurysms.131,132 Patients should be carefully monitored for bleeding tendency due to excessive anticoagulant therapy. Children exhibit considerable individual differences in responses to anticoagulant therapy. (3) Coronary Vasodilators and Antianginal Drugs (Table 16) a) Ca-Blockers In patients with Kawasaki disease, myocardial infarction may occur at rest or during sleep. Addition of Ca-blockers to the existing regimen should be considered for patients complicated by coronary spasm133,134 and patients with post-infarct angina or myocardial ischemia. b) -Blockers Among patients with Kawasaki disease, -blockers may be administered to prevent reinfarction or sudden death in those with a history of myocardial infarction and to decrease longterm mortality. However, treatment with -blockers may exacerbate already-existing coronary spasm. -blockers exerts antianginal effects by decreasing myocardial oxygen consumption. c) Nitrates Although the coronary vasodilatative effects of nitrates are not expected to be beneficial in the treatment of acute ischemia due to lesions with poor endothelial sell function, nitrates in sublingual or oral spray form should be attempted in treating AMI.135,136 (4) Drugs for Heart Failure (Table 16) Angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) ACE inhibitors and ARBs may be administered to patients with left ventricular dysfunction (EF 40%) following myocardial infarction due to ischemic heart disease in order to decrease morbility, mortality, and the incidence of cardiac events. No study results have been published regarding the effects of ACE inhibitors and ARBs on the long-term prognosis of Kawasaki disease.
2. Non-Pharmacological Treatment
1 PCI Unlike coronary lesions in adults, which are typically atherosclerotic lesions, the coronary lesions in patients with Kawasaki disease are often characterized by severe calcification and fibrous thickening. It is thus inappropriate and in some cases even dangerous to apply the indications for and procedures of PCI for adult patients to the treatment of patients
2005
Table 16. Drugs for the Treatment of Angina, Heart Failure, and Ischemic Attacks Drug Drugs for angina Nifedipine (Adalat) Slow-releasenifedipine (Adalat-CR,Adalat-L) 0.2to0.5mg/kg/dose,TID (availableas5and10mgcapsules) Adultdose:30mg/day,dividedinto3doses 0.25to0.5mg/kg/day,dividedinto1to2doses, maximumdose3mg/kg/day (TabletsofAdalat-CR20mg,L10mg,andL20mgare available) Adultdose:40mg/kg,OD (Adalat-Lshouldbedividedinto2doses) 0.1to0.3mg/kg/dose,ODorBID (maximumdose0.6mg/kg/day) (Tabletsof2.5mgand5mgareavailable) Adultdose:5mg/day,OD 1.5to2mg/kg/day,TID (maximumdose6mg/day)(30mgtablets) Adultdose:90mg/daydividedinto3doses Startat0.1to0.2mg/kg/day,dividedinto3to4doses totitrateto1.0mg/kg/day(40mgtablets) Adultdose:60to120mg/day,dividedinto2to3doses Startat0.08mg/kg/day,maintainat0.46mg/kg/day (average) Adultdose:10to20mg/day,OD 0.08mg/kg/dose,OD(Tabletsof2.5mgand5mgare available) Adultdose:5to10mg/day,OD 0.02to0.06mg/kg/day,dividedinto1to2doses(1mg tablets) Adultdose:Startat0.5mg/day,ODandtitrate Sublingual:one-thirdtoone-halftablet/dose(5mg tablets) Oral:0.5mg/kg/day,dividedinto3to4doses Adultdose:1to2tablets/dose(sublingual) FrandoltapeSone-eighthto1sheet Adultdose:1sheet(40mg)/dose Slow-releasetablets(Nitrol-R,Frandoltablets) 0.5to1mg/kg/dose Adultdose:2tablets/day(20mgtablets) One-thirdtoone-halftablet/dosesublingual (0.3mgtablet) Adultdose:1to2tablets/dose Hypotension,dizziness,headache Careisneededinpatientswithpoor cardiacfunction. Sameasabove Dose Adverse drug reactions and precautions
Amlodipine (Norvasc)
Sameasabove
Diltiazem (Herbesser) Drugs for heart failure Metoprolol (Seloken) Carvedilol (Artist) Enalapril (Renivace) Cilazapril (Inhibace) Drugs for ischemic attacks Isosorbidedinitrate (Nitorol)
Sameasabove
Hypotension,poorcardiacfunction,bradycardia,hypoglycemia,bronchialasthma Sameasabove
Hypotension,erythema,proteinuria,cough, hyperkalemia,hypersensitivity,edema Sameasabove
Hypotension,headache,palpitations,dizziness,flushing
Nitroglycerin(NTG) Nitroglycerin (Nitropen)
Sameasabove Sameasabove
Thesafetyandefficacyoftheabovedrugshavenotbeenestablishedinchildren.Dosesshouldbedeterminedaccordingtotheadultdoses. NTG,nitroglycerin;TID,threetimesaday;OD,oncedaily;BID,twotimesaday.
with Kawasaki disease. The guidelines for catheterization in patients with Kawasaki disease published by the Taskforce on Long-term Management of Kawasaki Disease of the Ministry of Health and Welfare should be followed as basic guidelines.137 Many aspects of the long-term prognosis following PCI in patients with Kawasaki disease have yet to be clarified; these aspects require further study. When patients with Kawasaki disease undergo PCI, pediatricians and cardiologists must be fully aware of the pathophysiology and natural history of Kawasaki disease as well as the risks and benefits of PCI in this patient population. (1) Indications for PCI a) IndicationsforPCIinTermsofClinicalFindings Patients with signs/symptoms of ischemia Asymptomatic patients who exhibit ischemic findings on stress tests, stress myocardial scintigraphy, dobutamine stress echocardiography, or other suitable tests
PCI may be considered for patients in whom testing did not reveal significant findings of ischemia but who have severe stenotic lesions which may progress to serious coronary artery ischemia in the future. Selection of an appropriate treatment from among three options, ie, surgical treatment, PCI, or follow-up, should be made according to the circumstances of individual patients. PCI is not indicated for patients with left heart dysfunction. b) IndicationsforPCIinTermsofPathologicalFindings ofLesions Patients with severe stenosis (75%) Patients with localized lesions: PCI is contraindicated for patients with multivessel disease and those with significant stenosis or occlusion of the contralateral coronary arteries. Patients without coronary ostial lesions
2006 Patients without long segmental lesions (2) Types of PCI Techniques, Indications, and Precautions a) ICT ICT should be performed using urokinase (UK) at 1.0 10 4 units/kg (maximum daily dose for adults 9610 4 units), or during the acute phase of myocardial infarction (within 6 hours after onset), tisokinase, a tissue plasminogen activator (t-PA) with high affinity for fibrin, at 2.510 4 units/kg (maximum daily dose for adults 64010 4 units).138,139 Since these agents may in rare cases induce cerebral hemorrhage or gastrointestinal hemorrhage, care is needed in their administration. Following ICT, heparin should be infused continuously for at least 12 to 24 hours to prevent reformation of thrombi. Following heparin therapy, oral antithrombotic therapy should be continued. However, in adults thrombolysis is frequently associated with bleeding complications. Since intravenous t-PA provides efficacy nearly equivalent to intracoronary t-PA, t-PA is administered intravenously rather than in intracoronary fashion. The recanalization rate is low in patients in which thrombotic occlusion developed long before medical attention, such as patients with asymptomatic myocardial infarction. b) PlainOldBalloonAngioplasty(POBA) Since catheters for POBA are smaller in diameter than those for other techniques and thus more accessible and flexible, this technique is feasible in young children in whom stenting and rotational ablation (Rotablator) are difficult because of small body size. In addition, calcification is often mild in severity in coronary stenotic lesions that developed 6 years previously, and the efficacy of POBA is excellent in such lesions. However, it has been reported that the incidence of new aneurysms after POBA is higher in children with Kawasaki disease than in adult patients.140 The recommended balloon pressure is 8 to 10 atm.28,140,141 Children believed to require higher balloon pressures should be considered for other techniques such as rotablator treatment and CABG. Heparin should be infused continuously for 24 hours after POBA to avoid the development of thrombotic occlusion. c) Stenting Stenting is effective in older children in whom calcification of coronary lesions is relatively mild, when it is feasible. Stenting can achieve a larger lumen than POBA can. Stenting is also effective in the treatment of coronary arteries in which aneurysms and stenosis are present in succession. Since highly calcified lesions cannot be dilated sufficiently with balloon technique, stenting is not suitable for them. Heparin should be administered continuously immediately after stenting to avoid the development of thrombotic occlusion. It is very important to continue antithrombotic therapy and antiplatelet therapy after stenting. Only limited data are available on whether drug-eluting stents are more efficacious than conventional bare metal stents in the treatment of coronary artery lesions due to Kawasaki disease. d) CoronaryAngioplastyWithRotationalAblation Rotational ablation is a technique that involves shaving off lesions with a high-speed conical burr covered with diamond microcrystals to obtain a larger lumen at the site of stenosis. Rotational ablation is considered the most optimal PCI technique for coronary stenotic lesions during the remote phase of Kawasaki disease, since it can obtain a larger lumen at
JCS Joint Working Group locations with highly calcified lesions. Since this technique uses guiding catheters, and is thus difficult to perform in small children. e) ApplicationsofIVUS It is quite important to accurately evaluate the severity and extent of calcification of coronary artery lesions due to Kawasaki disease before treatment and select an appropriate treatment strategy, in order to ensure the efficacy of PCI and decrease the incidence and severity of complications of PCI. f) TherapeuticAngiogenesisUsingHeparinExerciseTherapy It has been reported that 10-day cycle ergometer exercise under intravenous heparin therapy may facilitate the development of collateral flow in patients with total occlusion of coronary artery lesion(s) due to Kawasaki disease.142 (3) Institutions and Backup System Requirements PCI for patients with coronary artery lesions due to Kawasaki disease should be performed in institutions with PCI specialists, pediatric cardiologists, and CABG specialists. (4) Postoperative Management, Evaluation, and Follow-up During the 3 to 6 months after PCI, selective CAG should be performed to evaluate the outcome of treatment. Sufficient data do not yet exist regarding the incidence of restenosis and the long-term outcome of patients undergoing PCI for the treatment of coronary artery lesions due to Kawasaki disease. Even when progress after PCI is favorable, patients should continue antithrombotic and antiplatelet therapy and should be educated on their condition and treatment. (5) Future Prospects: Especially Concerning the Use of CABG The incidence of ischemic heart disease associated with Kawasaki disease is expected to decrease further with the use of advanced catheter techniques available for the treatment of coronary artery lesion in this patient population. However, patients undergoing new techniques of this type should be followed for a long period of time to clarify the long-term outcomes of such procedures in patients with Kawasaki disease.143 PCI is not indicated for infants and young children, patients with multivessel disease, and patients with poor cardiac function. Appropriate combinations of less invasive bypass grafting and PCI are expected to enable less invasive, highly effective treatment. 2 CABG Although the incidence of coronary artery lesion in patients with Kawasaki disease has tended to decrease as use of gamma globulin therapy during the acute phase has become more common, coronary artery lesion persists or progresses during the remote phase, and eventually leads to pediatric ischemic heart disease in a small number of patients. For patients with ischemia not responding to medical treatment, CABG using pedicle internal mammary artery grafts is a reliable technique.144146 Since death after the acute phase of Kawasaki disease is mainly due to sudden death or myocardial infarction, it is essential to specify those children indicated for CABG in a timely fashion. Following CABG, no further cardiac events occurred in 70 to 80% of children, who also exhibited significant improvement of quality of life and exercise capacity as well as quality of school life.147,148
2007
Table 17. Indications for Surgical Treatment of Kawasaki Disease Coronaryarterybypassgrafting(CABG)maybeeffectiveinpatientswhohavesevereocclusivelesionsinmaincoronaryarteries(especially inthecentralportionsofthesearteries)orrapidlyprogressivelesionswithevidenceofmyocardialischemia.ItispreferabletoperformCABG usingautologouspedicleinternalmammaryarterygraftsregardlessofage.Treatmentsuchasmitralvalvesurgeryshouldbeconsidered whenmitralinsufficiencynotrespondingtomedicaltherapyispresent,althoughsuchcasesarerare. 1. CABG CABGisindicatedforpatientswithangiographicallyevidentsevereocclusivelesionsofthecoronaryarteriesandviabilityofmyocardium intheaffectedarea.Viabilityshouldbeevaluatedcomprehensively,basedonthepresence/absenceofanginaandfindingsofECG,thalliummyocardialscintigraphy,two-dimensionalechocardiography,leftventriculography(regionalwallmovement),andothertechniques. Findingsofcoronaryangiography Thefollowingfindingsaremostimportant.Whenoneofthefollowingfindingsispresent,considersurgicaltreatment. Severeocclusivelesionsinthemaintrunkoftheleftcoronaryartery Severeocclusivelesionsinmultiplevessels(2or3vessels) Severeocclusivelesionsinthedistalportionoftheleftanteriordescendingartery Jeopardizedcollaterals Inaddition,thefollowingconditionsshouldalsobeconsideredindeterminingtreatmentstrategy. (1) Whentheeventisconsideredasecondorthirdinfarctionduetothepresenceofchronicinfarctlesions,surgerymaybeindi cated.Forexample,surgerymaybeconsideredtotreatlesionslimitedtotherightcoronaryartery. (2) esionsassociatedwithrecanalizationoftheoccludedcoronaryarteryorformationofcollateralvesselsshouldbeevaluated L especiallycarefully.Surgerymaybeconsideredforpatientswithfindingsofseveremyocardialischemia. (3) hetherCABGisindicatedshouldbeconsideredcarefullyinyoungerchildrenbasedonlong-termpatencyofgrafts.In W general,youngchildrencontrollablewithmedicaltherapyarefollowedcarefullywithperiodiccoronaryangiographytoallow themtogrow,whilepatientswithseverefindingshaveundergonesurgeryat1to2yearsofage.Itisrecommendedthatpedicle internalmammaryarterygraftsbeusedinsuchcasesaswell. Findingsofleftventricularfunctiontesting Itisdesirablethatpatientswithfavorableleftventricularfunctionbetreatedwithsurgery,thoughpatientswithregionalhypokinesismay alsobeindicatedforsurgery.Patientswithseriousdiffusehypokinesismustbeevaluatedwithparticularcareandcomprehensivelybased onfindingsforthecoronaryarteriesandotheravailabledata.Hearttransplantationmaybeindicatedinrarecases. 2. Mitral valve surgery Valvuloplastyandvalvereplacementmaybeindicatedforpatientswithseveremitralinsufficiencyoflongdurationnotrespondingto medicaltreatment. 3. Other surgery Inrarecases,Kawasakidiseasehasbeencomplicatedbycardiactamponade,leftarteryaneurysm,aneurysmsoftheperipheralarteries, orocclusivelesion,patientswiththeseconditionsmaybeindicatedforsurgery. Source:StudyonKawasakiDisease,apsychosomaticdisorderstudysupportedbytheMinistryofHealthandWelfarein1985,withmodification.
(1) Indications for CABG Table 17 lists the criteria for indications for surgical treatment of cardiovascular sequelae in Kawasaki disease. Candidates for CABG should be comprehensively evaluated on the basis of clinical signs and symptoms as well as findings of CAG, exercise ECG, echocardiography, stress myocardial scintigraphy, left ventriculography, and other techniques to determine whether CABG is appropriate for them. (2) Age at Surgical Treatment Patients undergoing CABG for the treatment of coronary artery lesion due to Kawasaki disease are 11 years of age on average and range between 1 month and 44 years of age at the time of surgery, with children aged 5 to 12 years predominant.149 It has been reported that, with recent advances in technology, CABG can be performed safely even in children younger than those for whom it was previously considered indicated.150,151 (3) Surgical Techniques The most common surgical technique is CABG using pedicle internal mammary artery grafts or pedicle right gastroepiploic artery grafts. It has been reported that the diameter and length of such grafts increase with the somatic growth of children.147,152 CABG without cardiopulmonary bypass (offpump CABG, OPCABG) is also performed in this patient population. The surgical techniques used for CABG in this population are becoming less invasive.153
(4) Outcome of Surgery a) GraftPatency The patency of internal mammary artery grafts and right gastroepiploic artery grafts is quite favorable, as high as 91 to 98%,147,154,155 at 1 to 3 years after CABG. The patency of internal mammary artery grafts 20 years after CABG was 87.1%. When the patency of grafts is calculated for patients, not including those 12 years of age at the time of CABG, who were considered at risk of graft stenosis due to the previous technical difficulty of treatment in younger children, the patency of internal mammary artery grafts 20 years after CABG was 92.8%.147 Recent findings (1994 to 2006) indicated that the patency of internal mammary artery grafts 10 years after CABG was 94.4% in patients who were 12 years of age at the time of CABG.147 Lesions exhibiting anastomotic stenosis can be sufficiently treated with dilatation with POBA without stenting, and restenosis is rare.148 b) OutcomeofSurgery Following CABG, patients exhibit improvement in left ventricular function during exercise.156,157 Favorable outcomes have been reported in patients 20 years after CABG, with a survival rate and cardiac event-free survival of 98.4% and 78.1%,148 respectively. According to national survey data in patients evaluated 15 years after CABG, the rate of avoidance of sudden death was 94.3% in patients receiving internal mammary artery grafts.149
2008 (5) Other Surgery a) DownsizingOperationofGiantCoronaryAneurysms Attempts have been made to use the combination of CABG and downsizing operation to treat giant coronary aneurysms to improve flow rate and flow pattern in lesions by decreasing the diameter of the aneurysms, and to prevent the formation of thrombi by increasing shear stress on vessel walls. It has been reported that warfarin therapy could be terminated in some patients treated in this fashion.150,158 b) SurgicalTreatmentofMitralValveInsufficiency Unlike valvular disease due to rheumatic fever, mitral valve insufficiency due to Kawasaki disease is characterized by 1) the frequent development of complex coronary artery lesions requiring concurrent surgery and 2) the presence of severe myocardial injury and poor left ventricular function in many patients. Since valvar calcification may develop early after surgery in children undergoing valve replacement, mechanical valves are commonly used.159 c) SurgicalTreatmentofAorticAneurysmsandPeripheral Aneurysms In addition to coronary aneurysms, patients with Kawasaki disease may develop aneurysms in the ascending aorta, abdominal aorta, iliac artery, or axillary artery.160 Surgical treatment of aneurysms is indicated only for large or progressive lesions. d) HeartTransplantation More than ten cases of heart transplantation for the treatment of Kawasaki disease have been reported in the world. In 1996, Checchia et al161 reported 13 patients with Kawasaki disease who underwent heart transplantation. Heart transplantation is beneficial in (1) patients with significant left ventricular dysfunction, and (2) patients who have life-threatening arrhythmia and significant lesions in peripheral segments of the coronary arteries.
JCS Joint Working Group (3) Nitrates Nitroglycerin should be administered intravenously or sublingually. (4) Pain control Continuous chest pain increases myocardial oxygen consumption. Morphine hydrochloride (0.1 to 0.2 mg/kg) is the most effective agent for this, and should be slowly administered intravenously. Treatment with morphine may be avoided when symptoms are tolerable and blood pressure and pulse are stable. (5) Intravenous heparin therapy Use of heparin therapy prior to reperfusion therapy may increase the rate of recanalization rate. Heparin should be infused continuously at 10 to 20 units/kg/hr. (6) Treatment of complications Complications of AMI such as heart failure, cardiogenic shock, and arrhythmia should be treated accordingly. 2 ReperfusionTherapy (1) Thrombolytic Therapy Since AMI associated with Kawasaki disease is mainly caused by thrombotic occlusion of coronary aneurysms, thrombolytic therapy is of great importance. The sooner initiate thrombolytic therapy, the better effect of therapy will be expected. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for diagnosis, treatment, and long-term management of Kawasaki disease recommend that thrombolytic therapy be performed within 12 hours after the onset of AMI. There are no standard pediatric doses of the drugs used for thrombolytic therapy listed below. Thrombolytic agents should thus be administered carefully on the basis of the condition of individual patients. It has been reported that the rate of recanalization is 70 to 80% after intravenous thrombolytic therapy, and may be increased by about 10% when intracoronary administration of thrombolytic agents is added to intravenous therapy. Since thrombolytic therapy may be complicated by subcutaneous hemorrhage at the site of catheter insertion, cerebral hemorrhage, and reperfusion arrhythmia, patients should be carefully observed during and following thrombolytic therapy. t-PAs and pro-urokinase (pro-UK) are proteins and may induce anaphylactic shock. Intravenous thrombolysis a) UK: 1.0 to 1.610 4 units/kg (maximum dose 9610 4 units). Infuse over 30 to 60 minutes. b) t-PAs Alteplase (Activacin, Grtpa ): 29 to 43.5 10 4 units/kg. Administer 10% of the total dose over 1 to 2 minutes intravenously and infuse the remainder over 60 minutes. Monteplase (Cleactor): 2.7510 4 units/kg. Administer intravenously over 2 to 3 minutes. Pamiteplase (Solinase): 6.510 4 units/kg. Administer intravenously over 1 minute. ICT a) UK: Administer at a dose of 0.4104 units/kg over 10 minutes. Administration may be repeated at most four times. (2) PCI In general, PCI is indicated for patients within 12 hours after onset. Stenting is the most prevalent PCI technique, and the combination of thrombolysis and stenting is also common. Early treatment with oral antitplatelet drugs (aspirin, Plavix,
3. Initial (Medical) Treatment for AMI

GeneralGuidelinesforTreatment The main purpose of treatment of AMI in children is, as in adult patients, to decrease mortality during the acute phase and improve long-term prognosis.138,139,162165 Since AMI in children with a history of Kawasaki disease is caused by thrombotic occlusion of the coronary arteries, it is essential to initiate thrombolytic therapy or PCI as soon as possible to achieve reperfusion,166,167 as in the case of AMI in adult patients. During the initial treatment immediately after arrival at the emergency department or admission to hospital, prompt diagnosis and initial treatment should be performed to determine the treatment strategy for AMI and prepare for emergency CAG and reperfusion therapy. InitialTreatment 1 GeneralTreatment (1) Oxygen therapy Oxygen is administered to control myocardial injury. (2) Establishment of vascular access More than one means of vascular access should be established to ensure prompt treatment of complications possibly associated with AMI.
JCS Guidelines for Kawasaki Disease and Pletaal) or intravenous heparin is promptly begun after PCI to prevent the development of in-stent thrombosis. 3 AnticoagulantTherapyandAntiplateletTherapy toPreventRecurrenceofAMI (1) Heparin Heparin should be infused intravenously at a dose of 200 to 400 units/kg/day, and the dose should be adjusted to maintain an activated partial thromboplastin time (APTT) 1.5 to 2.5 times the baseline value. (2) Warfarin Warfarin should be administered at a dose of 0.1 mg/kg/day once daily, and the dose should be adjusted to maintain an international normalized ratio (INR) of about 1.6 to 2.5. (3) Aspirin168 3 to 5 mg/kg/day (maximum dose of 100 mg) Table 18 lists the indications of treatment by classification of severity of coronary artery lesions.
2009
Table 18. Indications of Treatment by Classification of Severity of Coronary Artery Lesions Antithrombotic drugs (aspirin, dipyridamole, ticlopidine)
Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification
IV,V III I,II IV,V III I,II
Anticoagulant drugs (warfarin)
Coronary vasodilators (Ca-blockers, -blockers, nitrates, etc.)

Severityclassification Severityclassification Severityclassification
V IV I,II,III
Drug for heart failure (ACE inhibitors, angiotensin II receptor blockers, -blockers)
Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification Severityclassification
V IV I,II,III V(b) V(a) I,II,III,IV V(b) V(a) I,II,III,IV
4. Guidance on Activities of Daily Life and Exercise (Including the School Activity Management Table)
As in the previous guidelines, the guidance on activities of daily life and exercise mainly includes management of daily activities in school.168 Since no definitive evidence have been obtained on the effects of daily activities on long-term prognosis and lifestyle-related risk factors for the development of arteriosclerotic lesions or cardiomyopathy during the remote phase, the present guidelines indicate preferable management of school activities in students with a history of Kawasaki disease. The 2002 edition of the School Activity Management Table is available for elementary school students and junior and senior high school students. Table 19 shows the table for junior and senior high school students. 1 ChildrenWithoutEvidenceofCoronaryArteryLesions DuringtheAcutePhase No restriction of activities of daily life or exercise is needed. In the School Activity Management Table, physicians may indicate no management needed for children 5 years after onset. During the 5-year period after onset, E-Allowed (ie, Category E [intense exercise is allowed] in terms of management, with school sport club activities allowed) should be selected in the Table. Follow-up evaluation should be performed at 1 month, 2 months, 6 months, 1 year, and 5 years after the onset of Kawasaki disease. School activity management after this follow-up period should be performed based on discussion with parents (or patients). It is preferable that physicians provide patients with the Acute phase Kawasaki disease in summary (Figure 6) when they are assigned the no management needed rating. 2 PatientsNotEvaluatedforCoronaryArteryLesionsDuring theAcutePhase (1) Patients in whom examination after the acute phase revealed no coronary lesions No restriction of activities of daily life or exercise is needed. Follow the instructions in Section 1 (1 Children (2) Patients in whom examination after the acute phase
WithoutEvidenceofCoronaryArteryLesionsDuringtheAcute Phase) above.
PCI
CABG
ACE, angiotensin converting enzyme; PCI, percutaneous coronaryintervention;CABG,coronaryarterybypassgrafting. Class I Class II Conditionsforwhichthereisgeneralagreementthat thetreatmentisusefulandeffective. Conditionsforwhichthereisadivergenceofopinion regardingtheusefulness/efficacyofatreatment.
Class III Conditionsforwhichthereisgeneralagreementthat thetreatmentisnotuseful/effectiveandmayinsome casesbeharmful.
revealed persistent coronary artery lesions according to the criteria for severity of coronary artery lesions in this guideline a) Patients in whom CAG revealed the absence (or regression) of coronary artery lesions No restriction of activities of daily life or exercise is needed. Follow the instructions in Section 1 (1 b) Patients who did not undergo CAG Follow the instructions on activities of daily life and exercise in Section 3 (3 Patients Who Have Been Patients should be categorized into the following groups, and provided with instructions accordingly. It is desirable that patients in groups (2) and (3) undergo CAG. (1) Patients in whom echocardiography detected small coronary aneurysms or dilatation (2) Patients in whom echocardiography detected medium aneurysms (3) Patients in whom echocardiography detected
Children Without Evidence of Coronary Artery Lesions DuringtheAcutePhase) above.
Evaluated for Coronary Artery Lesions During and After theAcutePhase) below.
2010
Table 19
[Edited in 2002]
School Activity Management Table ( for junior and senior high school students)
Date ( Class Name of institution Next visit School sport club activity Level of management ___ years ____ months later Management required: A, B, C, D, E Name of club No management required Allowed Note: Prohibited or when symptoms develop Name of physician:
Intense exercise (E - allowed) Exercise with maximum endurance, speed, and muscle strength
Name years) School Grade
M/F
Birth date
Diagnosis (findings)
(seal)
Level of management: A - Requires treatment at home or in hospital, B - Goes to school but must avoid exercise, C - Can do mild exercise, D - Can do moderate exercise, E - Can do intense exercise Mild exercise (C, D, E - allowed)
Light exercises, rhythmic movement, basic movement (exercise-play) (throwing, hitting, catching, kicking, jumping)
Sport activity Exercise to improve flexibility, techniques, high-force movement, and endurance Practice of low-grade technique, running to perform actions such as holding, jumping, and rotation
Intensity of exercise Moderate exercise (D, E - allowed)
Warming-up exercise Strength-training exercise Calisthenics, light mat exercise, balance exercise, light jumping, rotation Standing broad jump, light throwing, basic motion, light jumping Jogging, short run and jump
Basic exercise Apparatus gymnastics
(mat, horizontal bar, balance beam, and vaulting box)
Performance, competition, combination of actions Long-distance running, sprint race, competition, time race Competition, performance, time race, diving Goalkeeping Goalkeeping, tackling
Athletics
(racing, jumping, throwing)
breaststroke, Swimming (freestyle,sidestroke) backstroke, butterfly, Basketball Handball Volleyball
Soccer Smash, strong serve, receive, rally
Slow swimming Dribble shoot, combination play (offense, defense) Dribble shoot, combination play (offense, defense) Spiking, blocking, combination play (offense, defense) Dribbling and head shooting, volley shot, combination play (offense, defense)
Ball sports
Tennis
Type of sport
Slow exercise without running
Training with footwork (with no close body contact)

Easy movement in water, float, prone float, kick and float, etc. Passing, shooting, dribbling, feinting Passing, shooting, dribbling Passing, servicing, receiving, feinting Dribbling, shooting, lifting, passing, feinting, trapping, throwing Ground stroking, servicing, lobbing, volleys, serve and receive Passing, kicking, handling Forehand, backhand, servcing, receiving Servcing, receiving, flight Throwing, catching, batting Pitching, catching, batting Grip, swing, stance Etiquette, basic movement, ukemi, swinging Passing, kicking, handling Forehand, backhand, serve, receive High clear, drop, drive, smash Base-running, combination play, running-catch Base-running, combination play, running-catch Short course golf (e.g. ground golf) Practicing simple techniques and forms Dance with rhythmical movement (excluding rock and samba), Japanese folk dance Walking on ice/snow or slow skiing/skating Hiking on flatlands, playing while floating in the water, surfing, wind surfing Most cultural activities not described in the right column Improvised performance, hand gesture, steps Playing on water, snow, or ice Cultural activities not requiring long-term physical activity
Applied practice, competition Rhythmical dance, original dance, dance recital Common outdoor activities Climbing, swimming marathon, dive, canoe, boat, scuba diving Playing instruments requiring physical exertion (such as trumpet, trombone, oboe, bassoon, horn), playing or conducting quick rhythmical music, playing in a marching band
Rugby Table tennis Badminton Softball Baseball Golf Martial art Judo, kendo, (sumo, kyudo, naginata, wrestling) Original dance, folk dance, Dance modern dance Play in the snow or on the ice, skiing, skating, camping, Outdoor activity climbing, swimming marathon, water-front activities
Cultural activities
School events, other activities
Follow the above intensity of exercise during athletic festival, during athletic meetings, ball sports competitions, and exercise tests. Students other than those in Category E should consult with their school physician or their attending physicians in determining whether they will participate in other special school activities such as class trips, camp schools, seaside schools, and training camp.
Time race, applied practice, simplified game, game, competition
Ruck, maul, scrum, line-out, tackle
JCS Guidelines for Kawasaki Disease giant aneurysms c) Patients in whom CAG revealed persistent coronary lesions Follow the instructions on activities of daily life and exercise in Section 3 (3 PatientsWhoHaveBeen Patients should be categorized into the following groups, and provided with instructions accordingly. (1) Patients in whom CAG revealed small aneurysms or dilatation remaining (2) Patients in whom CAG revealed medium aneurysms remaining (3) Patients in whom CAG revealed giant aneurysms remaining # Since the accuracies of MDCT and MRI in evaluating the coronary arteries have recently improved, physicians may consider classifying patients on the basis of findings of these techniques in order to instruct them on daily life and exercise, provided that the limitations of MDCT and MRI are fully understood.
2011 ment Table, D-prohibited (Category D [moderate exercise is allowed] in terms of management, with school sport club activities prohibited) should be selected. Patients with no change after the first year after onset may be instructed with E-prohibited. b) Patients with findings of stenosis or myocardial ischemia Severe exercise should be restricted. The level of allowable exercise should be rated at D or more severe category. School sport club activities should be prohibited. The level of management should be selected from A to D on the basis of the results of exercise testing and evaluation of myocardial ischemia. Patients should receive a full explanation of the importance of drug treatment. When patients undergo catheter-based therapy, the level of management may be changed. c) Patients with a history of myocardial infarction Activities of daily life and exercise should be restricted: Patients should be rated as Category A to E on the basis of their condition. School sport club activities should be prohibited in principle. Level of management (A to E) should be determined on the basis of results of cardiac function tests or other examinations. Patients should be educated regarding possible adverse drug reactions such as bleeding tendency. 4 LesionsOtherThanCoronaryLesions (1) Valvular Disease Cardiologists should evaluate patients with valvular disease due to Kawasaki disease to determine whether their activities of daily life and exercise should be restricted. Cardiac functions and indications for surgical treatment should be evaluated. Patients exhibiting improvement of echocardiographic findings may assigned the rating no management needed. (2) Arrhythmia Cardiologists should evaluate patients with arrhythmia due to Kawasaki disease to determine whether their activities of daily life and exercise should be restricted. The criteria for management of patients with arrhythmia should be followed when cardiac function is normal and myocardial ischemia can be ruled out. Arrhythmia patients with findings of abnormal cardiac function or myocardial ischemia should be collectively evaluated based on all available data. (3) Aneurysms Other Than Coronary Aneurysms Cardiologists should manage these lesions individually based on their location and severity. 5 ManagementAfterHeartSurgery Cardiologists should follow patients undergoing heart surgery such as CABG, valvular surgery, and heart transplantation to ensure appropriate follow-up evaluation and patient education. 6 Vaccinations Maternal antibodies play important roles in preventing measles, rubella, mumps and varicella infections.169 Vaccinations against these diseases should be performed in order at least 6 months after high-dose gamma globulin therapy. 7 LifestyleChangestoPreventArteriosclerosis Since there is concern that a history of Kawasaki disease may
Evaluated for Coronary Artery Lesions During and After theAcutePhase) below.
3 PatientsWhoHaveBeenEvaluatedforCoronaryArtery LesionsDuringandAftertheAcutePhase (1) Patients in whom transient coronary dilatation disappeared after the acute phase No restriction of activities of daily life or exercise is needed. Follow the instructions in Section 1 (1 Children (2) Patients with remaining small aneurysms or dilatation No restriction of activities of daily life or exercise is needed. E-allowed should be selected in the School Activity Management Table. a) Follow the instructions in Section 1 (1 Children b) Patients with remaining coronary artery lesions should be followed up at 2 months, 6 months, and 1 year after onset and annually or later. Since findings of echocardiography may be not consistent with those of CAG, it is desirable that patients be evaluated with CAG at least once. Cardiologists should determine the need and type of drug treatment. (3) Patients with remaining medium or giant coronary aneurysms It is desirable that patients of this type be followed by cardiologists. a) Patients with no findings of stenosis or myocardial ischemia No restriction of activities of daily life or exercise is needed. E-allowed should be selected in the School Activity Management Table not including giant aneurysms. Patients should receive a full explanation of the importance of drug treatment and instructed to take drugs as prescribed. Patients should also be educated regarding the signs and symptoms of myocardial ischemia and actions to take if they are observed. Patients with remaining coronary artery lesions should undergo follow-up evaluation at least annually until regression of them is confirmed. The severity of exercise allowed must be determined on the basis of examinations. Patients with giant aneurysms should not be allowed to participate in school sport club activities. In the School Activity ManageWithoutEvidenceofCoronaryArteryLesionsDuringthe AcutePhase) above when coronary lesions regress. Without Evidence of Coronary Artery Lesions During the AcutePhase) above.
2012 be a risk factor for the development of arteriosclerosis in later life, it is preferable that patients be educated on the prevention of lifestyle-related diseases when they receive their Acute phase Kawasaki disease in summary.
JCS Joint Working Group 8 CooperationWithCardiovascularInternists Patients with sequelae of Kawasaki disease should be followed by cardiovascular internists when they grow up. Attending physicians should discuss with patients (or family) the schedule of follow-up by different departments in order to ensure lack of interruption of follow-up evaluation.
V Follow-up Evaluation
There are no clearly defined policies on the timing and duration of non-invasive follow-up evaluation of patients with a history of Kawasaki disease in Japan. The following guidelines are designed for patients who underwent periodic echocardiography during the acute phase of Kawasaki disease. Patients are classified by severity of coronary artery lesions on the basis of echocardiographic findings for the coronary arteries during roughly the first 30 days after onset, and guidance on how to follow up coronary artery lesions by cardiologists is provided based on the severity of echocardiographic coronary findings. to the severity classification of cardiovascular lesions in Kawasaki disease (Table 2-b) changes over time depending on the duration after onset. Figure 5 shows typical relationships between the two classification systems.
3. Follow-up Evaluation According to the Echocardiography-Based Severity Classification

A-1: This category corresponds to Category I of the severity classification of cardiovascular lesions for Kawasaki disease. Since patients in this category have not been followed in detail for a long period of time, findings regarding them are quite limited and their long-term prognosis remains unclear. However, it is believed that these patients have no significant problems in terms of coronary artery lesions.13,19,27,115,135 Patients in this category should be followed for 5 years, ie, at 1, 2, and 6 months and 1 and 5 years after the onset of Kawasaki disease. Further follow-up should be scheduled individually through consultation between patients/family and attending physicians. Follow-up evaluation should include ECG, echocardiography, and, if required, chest X-ray. It is desirable that patients be evaluated with exercise ECG at the time of final evaluation. A-2: This category corresponds to Category II of the severity classification of cardiovascular lesions of Kawasaki disease. As in the case of Category A-1, findings regarding the patients in this category are limited. However, it is believed that these patients have no significant problems in terms of coronary artery lesions.13,19,27,115,135 Followup examination should be performed as specified in the section on Category A-1. A-3: This category corresponds to relatively mild cases among those classified in Category III of the severity classification of cardiovascular lesions in Kawasaki disease. In principle, patients should be followed every 3 months until findings of dilatation disappear and then annually until entry into elementary school (age of 6, 7), then in 4th grade (age 9, 10), at entry into junior high school (age of 12, 13), and at entry into senior high school (age of 15, 16). Follow-up examination should be performed as specified in the section on Category A-1, and exercise ECG should be added in children at ages when it is feasible. A-4: This category corresponds to some cases among those classified in Categories III, IV, and V. Since long-term prognosis in this category differs significantly among patients, the duration of follow-up should be determined individually according to patient
1. Classification of Severity of Coronary Artery Lesions Based on Echocardiographic Findings

A-1. Patients with no dilatation of coronary arteries: The coronary arteries tend to be larger in patients during the acute phase of Kawasaki disease than in control children.170,171 The absence of dilatation is defined for purposes of reporting as the absence of localized dilatation detectable with echocardiography. A-2. Patients with slight and transient dilatation of coronary arteries which subsides within 30 days after the onset of Kawasaki disease. A-3. Patients who have small coronary aneurysms at 30 days after the onset of Kawasaki disease. A-4. Patients who have medium coronary aneurysms at 30 days after the onset of Kawasaki disease. A-5. Patients who have giant coronary aneurysms at 30 days after the onset of Kawasaki disease.
2. Relationship Between EchocardiographyBased Severity Classification and the Severity Classification of Cardiovascular Lesions in Kawasaki Disease (Figure 5)
The severity of cardiovascular lesions evaluated according
A-1 A-2 A-3 A-4 A-5
Figure 5. Relationshipbetweentheechocardiography-based severity classification (Left) and the severity classification ofcardiovascularlesionsinKawasakidisease(Right).
JCS Guidelines for Kawasaki Disease condition. Patients should be evaluated once every 1 to 3 months with ECG, echocardiology, chest X-ray (when necessary), and exercise ECG (when feasible) until dilatation is no longer observed on echocardiology. Following the disappearance of dilatation, patients should be evaluated annually. Patients with aneurysms remaining 1 year after onset should be evaluated once every 3 to 6 months. Although selective CAG may be considered on an individual basis, patients who had aneurysms with a diameter of 6 mm during the acute phase must undergo follow-up with CAG at least once during the early convalescence phase and at the time of disappearance of echocardiographically evident coronary dilatations. Patients with persistent aneurysms should be followed appropriately or later. When signs/symptoms or laboratory findings suggestive of ischemia are obtained on clinical examination, echocardiography, ECG, or exercise ECG, patients should undergo stress myocardial scintigraphy and then CAG. Patients in this category, including those with regression of aneurysms, should be evaluated once every 2 to 5 years with stress myocardial scintigraphy, MRI, MRCA, MDCT or other appropriate techniques to identify the progression of the stenotic lesion. A-5: This category corresponds to Categories IV and V of the severity classification of cardiovascular lesions in Kawasaki disease. It is believed that aneurysms in patients in this category do not regress completely and may frequently progress to coronary occlusive lesions172174 Patients with persistent giant aneurysms must be followed for life and receive treatment continuously, and should be individually evaluated to design tailor-made treatment. All patients in this category should undergo initial selective CAG during the early convalescence phase of Kawasaki disease to specify the extent of lesions. Patients should be carefully observed for clinical signs/ symptoms and followed with appropriate combinations of ECG, exercise ECG, echocardiography, stress myocardial scintigraphy, selective CAG, MRI, MRCA, MDCT or other appropriate techniques. The duration of follow-up differs among individual patients. In general,
2013
Acute phase Kawasaki disease in summary Name: Sex: M/F Birth date: Onset of Kawasaki disease: Age at onset: Hospitalized on: Discharged on:
Clinical findings (1) Fever present ( days), absent (2) Bilateral conjunctival congestion present, absent (3) Redding of lips, strawberry tongue present, absent (4) Polymorphous exanthema present, absent (5) Indurative erythema, redding of present, absent palms/soles, membranous desquamation from fingertips present, absent (6) Cervical lymphadenopathy present, absent Other symptoms: Treatment (1) Aspirin present, absent (2) Immunoglobulin present, absent (3) Steroids present, absent (4) Other drugs:
echographic findings of coronary artery (1): dischraged right coronary artery: no abnormality, transient dilatation, dilatation, aneurysm, giant aneurysm left coronary artery: no abnormality, transient dilatation, dilatation, aneurysm, giant aneurysm echographic findings of coronary artery (2): one to two months after onset right coronary artery: no abnormality, transient dilatation, dilatation, aneurysm, giant aneurysm left coronary artery: no abnormality, transient dilatation, dilatation, aneurysm, giant aneurysm other cardiac complications: absent present ( ) special instructions
This summary contains important medical information such as symptoms, treatment, and presence/absence of cardiac complications when Kawasaki disease developed. Please keep this summary by clipping it into the mother-child notebook or otherappropriate methods, and refer to it whenever necessary. Name, address, phone number of hospital, and name of physician are as follows:
Described on:
Supervised by the Japan Kawasaki Disease Research Society
Figure 6. AcutephaseKawasakidiseaseinsummary.
patients should be evaluated once every 1 to 3 months during the first year, and once every 3 to 6 months or later.
4. Acute Phase Kawasaki Disease in Summary (Supervised by the Japan Kawasaki Disease Research Society) (Figure 6)
Although correct information on the clinical course of Kawasaki disease is required for the diagnosis and treatment of children with a history of Kawasaki disease, parents may be unable to recall the history or course of Kawasaki disease in their children in detail. It is therefore considered important that pediatricians describe medical information (eg, clinical symptoms, treatment, and cardiac complications) and provide it to parents so that patients may refer to it whenever necessary and thus ensure appropriate subsequent management of patients. In 2003, the Japan Kawasaki Disease Research Society developed Acute phase Kawasaki disease in summary.175 Pediatricians are encouraged to include findings during the acute phase on the summary and provide it to their parents.
VI Management of Adults With a History of Kawasaki Disease and Cooperation With Cardiovascular Internists
Currently, No data with a high level of evidence on the treatment or prognosis of adults with a history of Kawasaki disease have been obtained in scientifically sound studies, and no standards are available for the diagnosis and treatment of such patients. Exercise ECG Exercise or pharmacological stress myocardial scintigraphy Holter ECG TEE 176 MRCA177,178 Multislice 3D-computed tomography (CT) CAG179 Patients should be evaluated as follows, depending on the presence/absence of coronary aneurysm during childhood. 1 PatientsWithoutCoronaryAneurysmsDuringChildhood Although it is believed that patients with normal echocardiographic findings after the acute phase may not require treatment,180 the possibility that a history of Kawasaki disease
1. Diagnosis
In adult patients, correct evaluation of coronary artery lesions is often difficult with transthoracic echocardiography, the principal technique used in the diagnosis of Kawasaki disease when they were children. The following noninvasive techniques or catheter-based methods of CAG are required for the evaluation of coronary artery lesions.
2014 is associated with progression of arteriosclerosis in midlife or later cannot be ruled out.181 Family and patients should discuss with attending physicians the need for follow-up evaluation on an individual basis, and patients may undergo noninvasive evaluation once every several years during adulthood if they request it.182 2 AsymptomaticPatientsWithCoronaryAneurysms PersistingFromChildhood Patients should be stratified by cardiac risk factors and followed for a long period of time.183 It is desirable that patients with coronary aneurysms persisting into adulthood, including those who are asymptomatic, should be evaluated with noninvasive techniques 2 to 3 times each year and that CAG should be performed once every several years. 3 PatientsWithAnginaPectoris,MyocardialInfarction, HeartFailure,orSevereArrhythmiainAdulthood Patients with angina pectoris, myocardial infarction, heart failure, or severe arrhythmia in adulthood should be followed in a fashion similar to patients with such conditions associated with etiologies other than Kawasaki disease. It is desirable that patients should be evaluated with noninvasive techniques 3 to 4 times each year and CAG as appropriate. 4 AdultPatientsWithCoronaryAneurysmsWithUnknown HistoryofKawasakiDisease The presence/absence of history of Kawasaki disease is unknown in many young adults with coronary aneurysms.184,185 It is considered appropriate for such patients to be diagnosed as having sequelae in Kawasaki disease if other diseases causing secondary coronary aneurysms can be ruled out.186 Basically, young adults with coronary aneurysms should be followed similarly to patients who had coronary aneurysms in childhood as described in Section 2 (2 AsymptomaticPatients WithCoronaryAneurysmsPersistingFromChildhood) above.
JCS Joint Working Group 4 AdultPatientsWithCoronaryAneurysmsWithUnknown HistoryofKawasakiDisease Basically, young adults with coronary aneurysms should be treated as described in Sections 2 (2 Asymptomatic Patients With Coronary Aneurysms Persisting From Childhood) and 3 ( 3
PatientsWithAnginaPectoris,MyocardialInfarction,HeartFailure, orSevereArrhythmiainAdulthood) above.
3. Management of Daily Life and Exercise

History of Kawasaki disease may be an unavoidable risk factor for arteriosclerosis in adulthood. Coronary risk factors, at least those known to promote arteriosclerosis during adulthood, should be controlled through substantial improvement of daily life and exercise management. 1 ImprovementofLifestyleandTreatmentofCoronary RiskFactors Antihypertensive therapy according to the relevant guidelines Smoking cessation Diabetes management Antihyperlipidemic therapy Weight control in obese patients Reduction of psychological/social stress 2 ManagementofExercise Exercise training may decrease body weight, yield a sense of well-being, and decrease the need for pharmacological treatment of coronary artery lesions. Patients should be evaluated to determine the risks associated with exercise testing or other appropriate techniques, and prescribed exercise accordingly.
4. Understanding of Kawasaki Disease by Internists

General internists are not sufficiently aware of the pathophysiology of Kawasaki disease during the acute phase. It is important for internists, especially cardiovascular internists, to understand the pathophysiology of Kawasaki disease in adults.
2. Treatment
1 PatientsWithoutCoronaryAneurysmsDuringChildhood Patients without coronary aneurysms during childhood may discontinue antiplatelet treatments such as aspirin. 2 AsymptomaticPatientsWithCoronaryAneurysms PersistingFromChildhood Asymptomatic patients with coronary aneurysms persisting from childhood must in principle continue to take aspirin and other appropriate drugs. In addition to improvements of lifestyle such as weight control and smoking cessation, prevention and appropriate treatment of coronary risk factors such as diabetes mellitus, hyperlipidemia, and hyperuricemia are necessary. 3 PatientsWithAnginaPectoris,MyocardialInfarction, HeartFailure,orSevereArrhythmiainAdulthood These patients should be treated in a fashion similar to patients with such conditions associated with etiologies other than Kawasaki disease. In addition to aspirin, antitplatelet drugs, antianginal drugs, diuretics, and other drugs for the treatment of heart failure, or antiarrhythmic drugs may be required. When ischemia is demonstrated on exercise ECG or radionuclide imaging, PCI should be performed as appropriate.
5. Coronary Aneurysms and Myocardial Infarction in Young Patients and Kawasaki Disease
Young adults with myocardial infarction or cardiovascular findings should be investigated to determine the presence/ absence of Kawasaki disease during early childhood.187
6. Comparison With Adult-Type Myocardial Infarction

In the pathologic evaluation of patients with Kawasaki disease, no severe atherosclerotic lesions are observed although substantial arteriosclerosis is present.185 It is thus currently unclear whether sequelae of vasculitis due to Kawasaki disease promote atherosclerosis. Remodeling of coronary artery lesions in patients with sequelae in Kawasaki disease may persist for years after onset, and is associated with intimal hyperplasia and neovascularization. These findings differ from those in juvenile patients with arteriosclerosis not associated with Kawasaki disease.29
2015
VII Summarized Guidelines

Table 20
Severity I Nodilatation Pathophysiology Thereisnoevidencewhetheror notahistoryofKawasakidisease isafactorassociatedwitharterioscleroticiesion. Duringtheacutephase,histopathologicallyvasculitisdevelopsin theouterlayerofthetunicamedia andthenexpandstotheintimain coronaryarteries. Echocardiographyrevealsdiffuse dilatationofcoronaryarteries,but thesechangessubsidewithin30 daysafteronset. Inmanycasesregressionmay occur1to2yearsafteronset, particularlyinsmallormedium aneurysms.Inthesegmentwith regression,decreaseincoronary diastolicfunction,abnormalfunctionofvascularendothelium,and substantialintimalhyperplasia havebeenreported. Diagnosis / clinical course Followuppatientsfor5years. Evaluateat30days,60days,6 months,1year,and5yearafter onsetwithECG,echocardiography,and,ifnecessary,chestXray.Itisdesirablethatpatientsbe evaluatedwithexerciseECGat thefinalexamination. Treatment Basically,notreatmentisrequired duringtheremotephase.Patients withnocoronaryaneurysmsafter theacutephasemaydiscontinue antiplateletdrugssuchasaspirin. Daily life/exercise management* Norestrictionisplacedondailylife orexercise. ManagementTable:Nomanagementneededforchildren5 yearsafteronset.Consultwith parents(orpatients)todetermine furtherman-agement.Lifetime preventionoflifestyle-related diseasesisimportant.Juniorand seniorhighschoolstudentsshould beeducatedonlifestyle-related diseases(bloodlipidmeasurement,educationonsmoking cessation,andpreventionof obesity). Norestrictionisplacedondaily lifeorexercise.FollowtherecommendationsforCategoriesIand II.
II
Transientdilatationduring theacute phase
III
Regression
Basically,followpatientsannually withECG,echocardiography,and chestX-rayuptoentryinto elementaryschool(ageof6,7), andthenwiththesamemethods andexerciseECGin4thgrade (age9,10),atentryintojunior highschool(age12,13),and entryintoseniorhighschool(age 15,16).Followpatientswhohad coronaryaneurysmswithalarge internaldiameterduringtheacute phasewithanappropriatecombinationofimagingtechniques**. Patientsmustbefollowedwith exerciseECGandanappropriate combinationofimagingtechniques.**Itisdesirablethat patientswhohadcoronaryaneurysmswithalargeinternaldiameterduringtheacutephasebe evaluatedwithstressmyocardial scintigraphyevery2to5yearsto monitorforprogressiontostenotic lesions. Continuetreatmentwithantiplateletagentssuchasaspirin.Anticoagulanttherapymaybeneededin patientswithgiantcoronaryaneurysmsorthrombiincoronary aneurysms.CABGmaybeindicatedforpatientswithgiantcoronaryaneurysmsnotaccompanied bysignifcantstenoticlesionswhen myocardialischemiahas occurred.
IV
Remaining coronaryaneurysms
Aneurysmsremainingduringthe convalescencephaseorlaterare consideredsequelae.Histopathologically,progressionofinflammationleadstoruptureoftheinternal elasticband,causingpanangiitis. Theinternalandexternalelastic bandsarebrokenintofragments andrupturedbyarterialpressure toformaneurysms.Patientswith giantaneurysmsmustbe observedcarefullyformyocardial ischemia,sinceinsuchpatients myocardialischemiamaydevelop evenifnosignificantstenotic lesionsarepresent.
Norestrictionisplacedondaily lifeorexercise. ManagementTable:E-allowed. Patientswithgiantaneurysms: InstructasD-prohibitedinthe ManagementTable.Inthesecond yearafteronsetorlater,Eprohibitedispossiblewhenno changesarenoted.
Thromboticocclusionofmedium orgiantaneurysmsmaydevelop duringtherelativelyearlystage afteronset.Suddendeathmay occur,thoughtwo-thirdspatients withocclusionareasymptomatic. Patientsoftenshowimprovement ofmyocardialischemiaduetothe developmentofrecanalized vesselsandcollateralflowafter occlusion.Development/progressionofregionalstenosisduring theremotephaseismoreprevaV-b Coronary stenoticlesions lentintheleftcoronaryarterythan (withfindingsof intherightcoronaryartery.The segmentswithgreatestprevaischemia) lencearetheproximalsegmentor themaintrunkoftheleftanterior descendingartery.Theriskof progressiontostenosis/occlusion ishigherinlargeraneurysms. Stenosismaydevelopduring long-termfollowup. V-a Coronary stenoticlesions (nofindingsof ischemia)
Patientsmustbefollowedforlife, andphysiciansmustdesignthe tailor-mademanagementplanfor individualpatients. Follow-upexaminationmust includeexerciseECGandan appropriatecombinationof imagingtechniques**.Although schedulemaydifferamongindividuals,patientsaregenerally evaluatedevery3to6months.
Continuetreatmentwithantiplateletdrugssuchasaspirin.UseCablockers,nitrates,-blockers, ACEinhibitors,andangiotensin receptorIIblockerstoprevent ischemicattacksandheartfailure.
Norestrictionisplacedondailylife orexercise. ManagementTable:E-allowedfor patientsotherthanthosewithgiant aneurysms.Explaintheimportance ofdrugtreatmentandensure adherence,aswellassymptoms whichmayoccurandactionstobe takenwhenischemiadevelops. Patientsmustbefollowedatleast annuallyuntilregressionofaneurysmsisdocumented. Exerciseshuldberestricted. CategorizeinDorhighercategorybasedonpatientcondition. Schoolsportclubactivitiesshould beprohibited.Selectthemost appropriatecategoryfromAto Donthebasisoffindingsof exercisetestingandevaluationof severityofmyocardialischemia. Educatepatientswellaboutthe importanceofdrugtreatment.
Followtheinstructionsfordrug treatmentinCategoryV-a. ConsiderCABGorappropriate PCItechniquewhenexercise ECGorstressmyocardialscintigraphyrevealsischemia.
*SeeTable19. **Imagingtechniquesincludeechocardiography(includingstressechocardiography),stressmyocardialscintigraphy,selectiveCAG,IVUS,MRI,MRA,andMDCT. CABG,coronaryarterybypassgrafting;ACE,angiotensinconvertingenzyme;PCI,percutaneouscoronaryintervention;CAG,coronaryangiography;IVUS,intravascular ultrasound;MRI,magneticresonanceimaging;MRA,magneticresonanceangiography;MDCT,multi-rowdetectorcomputedtomography.

2016

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123. Takahashi K, Hirota A, Naoe S, Tsukada T, Masuda H, Tanaka N. A morphological study of intimal thickening in sequelae of coronary arterial lesions of Kawasaki disease (1). The Journal of Japanese College of Angiology 1991; 31: 17 25 (in Japanese). 124. Karasawa K, Ayusawa M, Ymasita T. Pharmacologic stress myocardial perfusion imaging for the detection of coronary stenotic lesions due to Kawasaki disease: Comparison of dobutamine and adenosine triphosphate disodium. KAWASAKI DISEASE 1995; 472 478. 125. Fukuda T, Ishibashi M, Yokoyama T, Otaki M, Shinohara T, Nakamura Y, et al. Myocardial ischemia in Kawasaki disease: Evaluation with dipyridamole stress technetium 99m tetrofosmin scintigraphy. J Nucl Cardiol 2002; 9: 632 637. 126. Guidelines for the Diagnosis and Treatment of Cardiovascular Diseases (19981999 JCS Joint Working Groups Report). The guidelines for secondary prevention of myocardial infarction. Jpn Circ J 2000; 64(Suppl IV): 1081 1127 (in Japanese). 127. Kato H, Ichinose E, Kawasaki T. Myocardial infarction in Kawasaki disease: Clinical analyses in 195 cases. J Pediatr 1986; 108: 923 927. 128. Shirahata A, Nakamura T, Ariyoshi N. Blood coagulation status in patients beyond 1 year after the onset of Kawasaki disease. J Jpn Pediatr Soc 1990; 94: 2608 2613 (in Japanese). 129. Shirahata A, Nakamura T, Asakura A. Optimal aspirin therapy for Kawasaki disease: Discussion of antithrombotic therapy. J Jpn Pediatr Soc 1985; 89: 2207 2214 (in Japanese). 130. Yamada K, Fukumoto T, Shinkai A, Shirahata A, Meguro T. The platelet functions in acute febrile mucocutaneous lymph node syndrome and a trial prevention for thrombosis by antiplatelet agent. Nippon Ketsueki Gakkai Zasshi 1978; 41: 791 802. 131. Onouchi Z, Hamaoka K, Sakata K, Ozawa S, Shiraishi I, Itoi T, et al. Long-term changes in coronary artery aneurysms in patients with Kawasaki disease: Comparison of therapeutic regimens. Circ J 2005; 69: 265 272. 132. Suzuki A, Kamiya T, Ono Y, Kinoshita Y. Thrombolysis in the treatment of patients with Kawasaki disease. Cardiol Young 1993; 3: 207 215. 133. Flynn J. Pediatric use of antihypertensive medications: Much more to learn. Curr Ther Res Clin Exp 2001; 62: 314 328. 134. Tsuda E, Yasuda T, Naito H. Vasospastic angina in Kawasaki disease. J Cardiol 2008; 51: 65 69. 135. Sugimura T, Kato H, Inoue O, Takagi J, Fukuda T, Sato N. Vasodilatory response of the coronary arteries after Kawasaki disease: Evaluation by intracoronary injection of isosorbide dinitrate. J Pediatr 1992; 121: 684 688. 136. Ishikita T, Umezawa T, Saji T, Matsuo N, Yabe Y. Functional abnormality of coronary arteries in children after Kawasaki disease: Distensibility of coronary arterial wall by isosorbide dinitrate. Pediatric Cardiology and Cardiac Surgery 1992; 8: 265 270 (in Japanese). 137. Ishii M, Ueno T, Akagi T, Baba K, Harada K, Hamaoka K, et al. Guidelines for catheter intervention in coronary artery lesion in Kawasaki disease. Pediatr Int 2001; 43: 558 562. 138. Kato H, Inoue O, Ichinose E, Akagi T, Sato N. Intracoronary urokinase in Kawasaki disease: Treatment and prevention of myocardial infarction. Acta Paediatr Jpn 1991; 33: 27 35. 139. Tsubata S, Ichida F, Hamamichi Y, Miyazaki A, Hashimoto I, Okada T. Successful thrombolytic therapy using tissue-type plasminogen activator in Kawasaki disease. Pediatr Cardiol 1995; 16: 186 189. 140. Akagi T, Ogawa S, Ino T, Iwasa M, Echigo S, Kishida K, et al. Catheter interventional treatment in Kawasaki disease: A report from the Japanese Pediatric Interventional Cardiology Investigation group. J Pediatr 2000; 137: 181 186. 141. Ino T, Nishimoto K, Akimoto K, Park I, Shimazaki S, Yabuta K, et al. Percutaneous transluminal coronary angioplasty for Kawasaki disease: A case report and literature review. Pediatr Cardiol 1991; 12: 33 35. 142. Tateno S, Terai M, Niwa K, Jibiki T, Hamada H, Yasukawa K, et al. Alleviation of myocardial ischemia after Kawasaki disease by heparin and exercise therapy. Circulation 2001; 103: 2591 2597. 143. Akagi T. Interventions in Kawasaki disease. Pediatr Cardiol 2005; 26: 206 212. 144. DAmico T, Sabiston DJ. Kawasakis disease. In: Sabiston DC, Spencer FC, editors. Surgery of the chest, 5th edn vol.2. Philadelphia: WB Saunders, 1990; 1759 1766. 145. Kitamura S, Kawachi K, Oyama C, Miyagi Y, Morita R, Koh Y, et al. Severe Kawasaki heart disease treated with an internal mammary artery graft in pediatric patients: A first successful report. J Thorac Cardiovasc Surg 1985; 89: 860 866.
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146. Mavroudis C, Backer CL, Muster AJ, Pahl E, Sanders JH, Zales VR, et al. Expanding indications for pediatric coronary artery bypass. J Thorac Cardiovasc Surg 1996; 111: 181 189. 147. Tsuda E, Kitamura S, Kimura K, Kobayashi J, Miyazaki S, Echigo S, et al. Long-term patency of internal thoracic artery grafts for coronary artery stenosis due to Kawasaki disease: Comparison of early with recent results in small children. Am Heart J 2007; 153: 995 1000. 148. Kitamura S, Tsuda E, Wakisaka Y. Pediatric coronary artery bypass grafting for Kawasaki disease: 20-years outcome. Nippon Rinsho 2008; 66: 380 386 (in Japanese). 149. Tsuda E, Kitamura S; Cooperative Study Group of Japan. National survey of coronary artery bypass grafting for coronary stenosis caused by Kawasaki disease in Japan. Circulation 2004; 110: II-61 II-66. 150. Yamauchi H, Ochi M, Akaishi J, Ohmori H, Hinokiyama K, Saji Y, et al. Surgical therapy in patients with giant coronary artery aneurysms due to Kawasaki disease. Pediatric Cardiology and Cardiac Surgery 2004; 20: 94 99 (in Japanese). 151. Ozkan S, Saritas B, Aslim E, Akay TH, Aslamaci S. Coronary bypass surgery in Kawasaki disease in a four-year-old patient: Case report. J Card Surg 2007; 22: 511 513. 152. Kitamura S, Seki T, Kawachi K, Morita R, Kawata T, Mizuguchi K, et al. Excellent patency and growth potential of internal mammary artery grafts in pediatric coronary artery bypass surgery: New evidence for a live conduit. Circulation 1988; 78: I-129 I-139. 153. Matsuura K, Kobayashi J, Bando K, Niwaya K, Tagusari O, Nakajima H, et al. Redo off-pump coronary bypass grafting with arterial grafts for Kawasaki disease. Heart Vessels 2006; 21: 361 364. 154. Torii S. Follow-up study of coronary artery bypass grafting in children with Kawasaki disease. Pediatric Cardiology and Cardiac Surgery 1997; 13: 62 70 (in Japanese). 155. Suda Y, Takeuchi Y. Thirty years experience of coronary artery bypass grafting in patients with Kawasaki disease. The Journal of Tokyo Womens Medical University 2007; 77: 167 170 (in Japanese). 156. Kawachi K, Kitamura S, Seki T, Morita R, Kawata T, Hasegawa J, et al. Hemodynamics and coronary blood flow during exercise after coronary artery bypass grafting with internal mammary arteries in children with Kawasaki disease. Circulation 1991; 84: 618 624. 157. Kitamura S, Kawashima Y, Kawachi K, Fujino M, Kozuka T. Left ventricular function in patients with coronary arteritis due to acute febrile mucocutaneous lymph node syndrome or related diseases. Am J Cardiol 1977; 40: 156 164. 158. Ogawa S. Issues in healthcare in adults: Current medical and surgical treatment of cardiovascular sequelae of Kawasaki disease. Yamabiko Tsushin 2006; 142: 2 7 (in Japanese). 159. Endo M. Surgical treatment of Kawasaki disease in the future. Prog Med 1991; 11: 97 99 (in Japanese). 160. Kitamura S. Surgical management for cardiovascular lesions in Kawasaki disease. Cardiol Young 1991; 1: 240 253. 161. Checchia PA, Pahl E, Shaddy RE, Shulman ST. Cardiac transplantation for Kawasaki disease. Pediatrics 1997; 100: 695 699. 162. Sato Y, Nishi T. A case of acute myocardial infarction developing following Kawasaki disease in whom PTCR PTCA proved effective. Pediatric Cardiology and Cardiac Surgery 1996; 12: 777 782 (in Japanese). 163. Ohkubo M, Ino T, Shimazaki S, Akimoto K, Nishimoto K, Matsubara K, et al. Successful percutaneous transluminal coronary recanalization with tissue plasminogen activator in Kawasaki disease. J Jpn Pediatr Soc 1994; 98: 1758 1765 (in Japanese). 164. Nakagawa M, Watanabe N, Okuno M, Okamoto N, Fujino H. Effects of intracoronary tissue-type plasminogen activator treatment in kawasaki disease and acute myocardial infarction. Cardiology 2000; 94: 52 57. 165. Shiraishi J, Sawada T, Tatsumi T, Azuma A, Nakagawa M. Acute myocardial infarction due to a regressed giant coronary aneurysm as possible sequela of Kawasaki disease. J Invasive Cardiol 2001; 13: 569 572. 166. Gruppo Italiano per lo Studio della Streptochinasi nellInfarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397 402. 167. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349 360. 168. Guidelines for the Diagnosis and Treatment of Cardiovascular
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Appendix
Chair: Shunichi Ogawa, Department of Pediatrics, Nippon Medical School Members: Teiji Akagi, Cardiac Intensive Care Unit, Okayama University Hospital Kiyoshi Baba, Department of Pediatrics, Osaka Developmental Rehabilitation Center Hisayoshi Fujiwara, Hyogo Prefectural Amagasaki Hospital Kenji Hamaoka, Department of Pediatric Cardiology and Nephrology, Kyoto Prefectural University of Medicine Graduate School of Medical Science Masahiro Ishii, Department of Pediatrics, Kitasato University Kensuke Karasawa, Department of Pediatrics, Nihon University School of Medicine Tsutomu Saji, First Department of Pediatrics, Toho University Tomoyoshi Sonobe, Department of Pediatrics, Japanese Red Cross Medical Center Atsuko Suzuki, Department of Pediatrics, Tokyo Teishin Hospital Collaborators: Mamoru Ayusawa, Department of Pediatrics, Nihon University School of Medicine Ryuji Fukazawa, Department of Pediatrics, Nippon Medical School Kazuhiko Nishigaki, Second Department of Internal Medicine, Gifu University Hirotaro Ogino, Department of Pediatrics, Kansai Medical University Tomoo Okada, Department of Pediatrics, Nihon University School of Medicine Independent Assessment Committee: Shigeyuki Echigo, Echigo Clinic Makoto Nakazawa, Pediatric and Lifelong Congenital Cardiology Institute, Southern Tohoku General Hospital Masami Ochi, Division of Cardiovascular Surgery, Nippon Medical School Tetsu Yamaguchi, Toranomon Hospital (The affiliations of the members are as of March 2010)
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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.

JCS Joint Working Group

Introduction of the Revised Guidelines

JCS Guidelines for Kawasaki Disease

(b) Severity classification

Otherclinicalsymptomsoffindings: henpatientshavemoderateorseverevalvulardisease,heartfailure,severearrhythmia,orother W cardiacdisease,suchconditionsshouldbedescribedinadditiontotheseverityofKawasakidisease.

Class III Conditionsforwhichthereisevidenceand/orgeneral agreementthattheprocedureortreatmentisnot useful/effectiveandmayinsomecasesbeharmful.

2. Mortality and Prognosis of Patients With Kawasaki Disease

Circulation Journal Vol.74, September 2010

3. Advancement in Intravenous Immunoglobulin (IVIG) Therapy

5. Advancement in Treatment for Patients Not Responding to IVIG Therapy

4. Changes Over Time in the Incidence of Coronary Artery Lesion

6. Problems With Incomplete (Atypical) Kawasaki Disease

II Pathology, Pathophysiology, and Natural History of Cardiac Sequelae in Kawasaki Disease

Circulation Journal Vol.74, September 2010

JCS Guidelines for Kawasaki Disease

Circulation Journal Vol.74, September 2010

JCS Joint Working Group

5. Non-Coronary Vessel Disorders

4. Arteriosclerosis (Especially Progression to Atherosclerosis)

6. Summary of Pathology, Pathophysiology, and Natural History of Cardiac Sequelae

Ring dilatation Papillary muscle dysfunction

Valvulitis Atrioventricular valve Aortic valve

Transient atrioventricular valvular regurgitation

Remote phase Heart failure Figure 2. Mechanismofdevelopmentofvalvulardiseases.

Circulation Journal Vol.74, September 2010

*Susceptibility toKD RiskforCAL

78KDsibling pairs Casecontrol studyin 276KDpatients and282controls

Susceptibility toKD Susceptibility toKD

427KDpatients 476controls 170KDpatients 300controls

CCR3CCR2CCR5 cluster CCR5 CCL3L1

Susceptibility toKD Susceptibility toKD

170KDpatients 300controls 220KD families(trio)

German Caucasians Americans Canadians

246KDpatients 147controls 184KDpatients

2. Physiological Examinations (ECG)

JCS Guidelines for Kawasaki Disease

Rapidtestkitsareavailable throughoutJapanandusefulin earlydiagnosis Rapidtestkitsareavailable throughoutJapan,andTnTis aprinciplebiochemicalmarker

1) Sensitivityisrelativelylow 2) MLCisexcretedrenallyandmay beabnormalinpatientswithrenal failure

Note:Childrenwithanwaist-to-heightratioof>0.5fulfillitem(1). Inelementaryschoolchildren(6to12yearsofage),thosewithan abdominalgirthof>75cmshouldbeconsideredtofulfillitem(1). HDL,high-densitylipoprotein.

Circulation Journal Vol.74, September 2010

JCS Joint Working Group

Circulation Journal Vol.74, September 2010

Circulation Journal Vol.74, September 2010

Circulation Journal Vol.74, September 2010

Echocardiography/12-lead ECG at rest I,II,III,IV,V

Holter ECG, signal-averaged ECG IV,V I,II,III

Body surface mapping, drug stress ECG, magnetocardiography

Severityclassification Severityclassification None

Stress echocardiography, myocardial contrast echocardiography

Severityclassification Severityclassification None Severityclassification Severityclassification None

Myocardial perfusion scintigraphy IV,V I,II,III

Cardiac catheterization IV,V III I,II

MRI, magnetic resonance imaging; MDCT, multi-row detector computedtomography;PET,positronemissiontomography.

Conditionsforwhichthereisgeneralagreementthatthe procedureisusefulandeffective. Conditionsforwhichthereisadivergenceofopinion regardingtheusefulness/efficacyofaprocedure.

Conditionsforwhichthereisgeneralagreementthatthe Class III procedureisnotuseful/effectiveandmayinsomecases beharmful.

Circulation Journal Vol.74, September 2010

JCS Joint Working Group

Diagnosisofstenoticlesions Diagnosisofstenoticlesions Diagnosisofstenoticlesions

Tc-99mtetrofosmin Diagnosisofstenoticlesions Tc-99mtetrofosmin Diagnosisofstenoticlesions

Circulation Journal Vol.74, September 2010

JCS Guidelines for Kawasaki Disease

Flurbiprofen (Froben) Dipyridamole (Persantin,Anginal)

Clopidogrel (Plavix) Unfractionatedheparin (IV) Low-molecular-weight heparin (SC)