Family Clinical Research With Gene Diagnosis And Stratified Therapy About Arrhythmogenic Right Ventricular Cardiomyopathy

Objective:We investigate the relation between genotype and phenotype by genetic screening of the family members of proband,and evaluate the risk stratification of relatives with gene mutation in order to identify high-risk members,it is conducive to prevent sudden cardiac death and guide follow-up treatment.Methods:A retrospective research on the proband,in order to analyse ECG,clinical and evolutionary process,therapy and prognosis of the disease.DNA had been detected in order to analyse the relation between genotype and phenotype.We collected clinical data of his family members,including symptoms,12 lead ECG recordings,ultrasonic echocardiography and also the blood samples for genetic testing.We divided them into 4groups:mutation carriers were Grovp ?,without mutation carriers were Group ?,and then we divided Group ? into Group ?(consanguinity)and Group ?(spouse).Cardiac magnetic resonance was taken by Group ?,for this part of families,we notified them to avoid competitive sports activities.2010 Task Force diagnostic criteria were suitable for all families.Definite diagnosis:2 major criteria,l major and 2 minor criteria,or 4 minor criteria from different categories;Critical diagnosis:1 major criteria and 1 minor criteria,or 3 minor criteria from different categories;Suspected diagnosis:1 major criteria,or 2 minor criteria from different categories.We adopted the risk stratification method which were proposed first by Bhonsale in 2013 to evaluate the arrhythmia risk in Group ?.If there were confirmed members,when we could take the implantable cardioverter defibrillator(ICD)to prevent the occurrence of sudden death,we take the ICD indication flow chart of 2015 international consensus to evaluate the risk stratification.Results:(1)The proband was a man with sudden heart palpitations and dizziness for the first time in his middle age,12 lead ECG recordings showed Epsilon wave and inverted T waves in right precordial,premature ventricular contractions and ventricle tachycardia with left bundle branch block type.There were two types of ventricle tachycardia,one from outflow tract of right ventricle(positive QRS in leads ?,? aVF,negative QRS in V1-V3),another from apex of right ventricle(negative QRS in leads II,III,aVF,negative QRS in Vland V3).Cardiac magnetic resonance showed decreased systolic and diastolic function of RV.The combination of clinical manifestations and physical examination findings confirmed 2010Task Force diagnose of ARVC.(2)The ventricle tachycardia hadn't been re-occurred for 15 years after we take RFCA therapy for the first time.While,when the arrhythmia re-occorred,we ablated the basal part,the apex,and the outflow tract of the right ventricle(triangle of dysplasia)extensively until all low voltage areas with scattered low amplitude and fragmented potentials couldn't be detected.Two years on,neither VT attacks nor the ICD had recorded any discharge events.(3)For the patient with heart failure and arrhythmia,we adopted compound treatment plan that included implantation of an ICD to prevent sudden cardiac death and malignant arrhythmia,and drug regime to control the symptoms of heart failure and reduce the risk of VT attack and ICD discharge.However,the management of slow VT with amiodarone has been reported as ineffective,so RFCA,which was certainly not expected to be a remedy,was the only option to increase the patient's chance of survival.(4)Gene test revealed a heterozygous PKP2(C.2047A>T)gene mutation in proband,this heterozygous nonsense mutation had been reported previously,but the function of the mutation is unknown.In this case,there was no significant change in the left ventricular diameter,which was not consistent with the previous research that the nonsense mutation of the desmosomes could increase the systolic and diastolic diameter of left ventricle.(5)The family has 4 generations and 28 members,including the proband's parents,12 cases of the same generation(brothers,sisters and their spouses),11 cases of children generation including spouses,and 5 cases of grandchildren.There is no family history of sudden death.The parents of proband were died few years ago,and there was no heart palpitations,chest tightness,syncope and other symptoms.The elder sister of proband was died by cervical cancer,and there was no history of heart disease.Due to the restriction,11 cases(including some spouses)are take gene detection.There are 6 cases with gene mutation,among which 2 cases are male,and 4 are female.(6)There were no symptom of heart palpitations,chest stuffiness,syncope and amaurosis in Group I.The ECG hadn't record Epsilon wave,inverted T waves in right precordial and low voltage in limb lead.Echocardiography and magnetic resonance imaging showed neither right ventricular enlargement,motion abnormalities and dysfunction of ventricular wall nor myocardial fatty infiltration.(7)There is a statistic difference of the QRSv1+v2+v3 and QRSvl+v2+v3/QRS v4+v5+v6 between Group ? and ?.There is a statistic difference between QRSv1+v2+v3 and QRS v4+v5+v6 in Group I but opposite in Group ?.(8)2 members were consanguinity in Group ?,another 3 were spouse.There is no statistic difference of QRSv1+v2+v3?QRSv4+v5+v6 and QRSv1+v2+v3/QRS v4+v5+v6 between Group ? and ?.Conclusions:1.Arrythymogenic right ventricular cardiomyopathy is an inherited autosomal dominant cardiomyopathy with a higher risk of sudden cardiac death.2.Radio frequency catheter ablation therapy may be the preferred treatment option for patients who do not require ICD implantation,and may become an indispensable remedial measure for those taking anti-arrhythmia drugs and ICD when slow VT is not recognized.3.PKP2 is the main pathogenic gene of ARVC,the gene mutation of desmosomes uauslly manifested as ventricular tachycardia with left bundle branch block type and inversion T wave in right precordial.Not all the nonsense mutation of PKP2 will increase the systolic and diastolic diameter of left ventricle.The relationship between the genotype and phenotype remains a problem.4.Although there were no family members with QRS duration ?120ms,but he duration of QRS in right precordial are longer in healthy mutation carriers,and QRSv1+v2v3/QRSv4+v5+v6>1.2?5.When a patient has been diagnosed,the whole family members should be screened for gene test,in order to detect the gene mutation carriers and high-risk groups timely and formulate the therapy strategies,to achieve accurate treatment.Affected patients should be performed on a regular basis(every 1-2 years)depending on the age,symptoms,and disease severity.Healthy gene carriers and family members should also be offered repeat clinical assessment(every 2-3 years),mostly during adolescence and young adulthood.