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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 147-149

Treatment modalities and prognosis of two arrhythmogenic right ventricular cardiomyopathy patients with familial PKP2 mutations

Department of Heart Failure, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China

Date of Web Publication10-Sep-2018

Correspondence Address:
Dr. Josephine Joseph Mwakisambwe
Department of Heart Failure, First Affiliated Hospital of Dalian Medical University, 222, Zhongshan Road, Dalian, Liaoning Province, 116000
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcs.jpcs_22_18

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) poses a diagnostic challenge due to incomplete penetrance of culprit genes and variable clinical presentation. We describe the diagnostic and therapeutic challenges in two males, Han Chinese “definite ARVC” patients with a familial heterozygous PKP2 mutation. Patient A, 72-year-old, with a 20 years' history of ARVC and recurrent ventricular tachycardia requiring cardioversion, radiofrequency ablation, and implantable cardiac devices implantation, and patient B, a 64-year-old with a 4-year history of ARVC with PKP2, DES, and TTN mutations. Due to the variable presentation of ARVC, tailored follow-up, and management of patients is paramount and more research is necessary to unveil pathogenic mutations in undiscovered genes. Further studies showing the relationship of genetic phenotypes and the clinical presentation of ARVC are essential.

Keywords: Arrhythmogenic right ventricular cardiomyopathy, gene-phenotype, implantable cardiac devices implantation, PKP2 mutation, ventricular tachycardia

How to cite this article:
Mwakisambwe JJ, Li X, Gong F, Liu J. Treatment modalities and prognosis of two arrhythmogenic right ventricular cardiomyopathy patients with familial PKP2 mutations. J Pract Cardiovasc Sci 2018;4:147-9

How to cite this URL:
Mwakisambwe JJ, Li X, Gong F, Liu J. Treatment modalities and prognosis of two arrhythmogenic right ventricular cardiomyopathy patients with familial PKP2 mutations. J Pract Cardiovasc Sci [serial online] 2018 [cited 2021 Jan 16];4:147-9. Available from: https://www.j-pcs.org/text.asp?2018/4/2/147/240955

  Introduction Top

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant inherited cardiomyopathy with a prevalence of about 1:5000, posing a diagnostic challenge due to incomplete penetrance of culprit genes and variable clinical presentation even among family members.[1] Previous studies have indicated the involvement of desmosomal gene mutations in PKP2, DSG2, DSC2, DSP JUP, and TMEM43 and minor involvement of DES, TTN, and RYR2 genes in ARVC pathology.[2] As scientific methods progress and improve, frequencies of newer genes associated with ARVC need to be uncovered.

ARVC progression includes the early/concealed phase, overt/electrical phase, and a diffuse/progressive phase. The “2010 revised Task force criteria,” a modification of the 1994 proposed criteria uses a combination of invasive and noninvasive sources of clinical information to diagnose a patient as having “definite ARVC,” “borderline ARVC,” or “possible ARVC.”[3]

Patients may present with syncope, palpitations, heart failure symptoms, and right ventricular morphological anomalies. Ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation) are a cause of sudden cardiac death (SCD) and worse prognosis, with differences occurring due to environmental factors such as exercise and inflammation. Epsilon waves (low amplitude complexes between QRS and T waves in the right precordial leads) are a major radiological diagnostic criteria.[4],[5]

Cardiac diseases such as right ventricular outflow tract (RVOT) dilatation, Brugada, dilated cardiomyopathy, hypertrophic cardiomyopathy myocarditis, share mutual features with ARVC, and issue a diagnostic challenge.

ARVC treatment aims at eliminating syncope and palpitations, preventing SCD, and limiting VT recurrences and heart failure by use of implantable cardiac devices (ICDs). The therapeutic means employed include antiarrhythmias drugs such as sotalol, amiodarone and propafenone, beta blocker, and angiotensin-converting-enzyme-inhibitors for heart failure and biventricular dysfunction, radiofrequency catheter ablation (RFCA) (combined epicardial and endocardial approach), and lifestyle changes (sports and exercise restrictions). Upon their consent, we highlight two ARVC patients with familiar PKP2 mutation but different clinical presentation and prognosis showing the importance of early implantation of ICD to prevent complications.

  Case Report Top

Patient A is a 72-year-old Han Chinese male diagnosed “definite ARVC” at the age of 50 years in 1997 and has been attending our hospital since. He is a hypertensive patient for 30 years and diabetic for 6 years. He presented with palpitations, shortness of breath, and chest tightness. The electrocardiogram (ECG) showed VT which was sufficiently managed with propafenone, and on achieving sinus rhythm, an epsilon wave was evident in lead V1. Echocardiogram showed right ventricle diameter dilatation of 42 mm, RVOT diameter dilatation of 49 mm. Cardiac magnetic resonance [Figure 1] showed right ventricle enlargement with crescent hyperintensities (adipose tissue) in lateral and anterior walls, with a significant decrease in the systolic and diastolic function of the right ventricle. A Holter ECG showed premature ventricular contractions (PVC) of 2943 times/24 h. After diagnosis confirmation, RFCA was done and he was symptom free for 16 years.
Figure 1: Cardiac magnetic resonance imaging before implantable cardiac devices implantation with right heart enlargement, ventricular wall thinning, and loss of structure.

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In 2013, he presented to the emergency department with a 2-month history of palpitations and heart failure evidenced by peripheral cyanosis, jugular venous distention, hepatomegaly 5 cm below costal margin, positive hepatojugular reflux and rales. An emergency ECG revealed VT (169 beats/min), which was managed by amiodarone. Follow-up ECGs showed atrial fibrillation (AF). Echocardiogram showed a right ventricle diameter dilatation of 58 mm, RVOT diameter dilatation of 53 mm and ejection fraction 55%. Heart failure was managed and improved to Stage III, metoprolol and warfarin were used for rate control and to prevent thrombotic events. The patient consented to an ICD implantation, and 2 months later, ICD interrogation showed successful termination of VT attacks and the AF had now converted to sinus rhythm.

In 2012, he developed VT that was not identified by ICD and could not be controlled antiarrhythmic medication. Electrical defibrillation was performed, and sinus rhythm was temporarily achieved, but the VT recurred. We opted for an emergency RFCA. Voltage mapping of the right ventricle showed a large number of low-voltage areas at the infundibulum, the apex and the outflow tract of the ventricle (triangle of dysplasia). These areas were ablated extensively, VT was terminated and could not be induced [Figure 2]. The postoperative ECG and Holter showed a recovered pacing rhythm and the patient was continued on heart failure medication. He attends our outpatient department, and no VT episodes have been recorded by the ICD. Occasional palpitations are reported which are caused by AF on ECG study and are controlled by amiodarone. The patient is now staged heart failure NYHA II. We conducted a gene study on the patient and his family and found a heterozygous PKP2 C.2047A > T p. Lys683Ter mutation.
Figure 2: The ablation site: Right oblique anterior view of endocardial voltage mapping showing mild fibrofatty replacement of the right ventricle.

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Patient B is also a Han Chinese male, 64-year-old diagnosed to have definite ARVC 4 years ago. He is a known hypertensive for 4 years. In 2015, he presented with palpitations associated with chest discomfort and sweating. An emergent ECG revealed VT (rate 205 beats/min) [Figure 3] and he underwent electrical cardioversion. Sinus rhythm was achieved, and amiodarone was prescribed. Further investigations were done, and ECG showed no ST-T changes and no epsilon waves, echocardiography showed an ejection fraction of 59%, right ventricular diameter dilatation 26 mm and fatty tissue infiltration of the right ventricular wall and chordae tendineae, both of which were collaborated by the CT scan. A Holter examination showed PVC of 172beats/24 h.
Figure 3: Ventricular tachycardia before electrical cardioversion.

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In 2016, he presented with palpitations and sudden onset chest pain radiating to both shoulders, with sweating, nausea, and vomiting. Emergency ECG revealed VT of 200 beats/min, electrical cardioversion was once again performed, and diltiazem prescribed. Coronary angiography showed 30% stenosis of the left anterior descending artery, the patient was managed per coronary artery disease protocol and consented to ICD implantation [Figure 4]. The patient is symptom free for 2 years. Family screening for Gene mutations was done, and he was found to have 3 gene mutations; PKP2 c. 2062C > T, DES c. 683G > T, and TTN c. 86956A > G.
Figure 4: Control electrocardiogram after pacemaker implantation.

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  Discussion Top

While both of our patients were male, of the same ethnicity and harboring a PKP2 mutation, their presentations and complications varied. Patient A with a single gene mutation had a more complicated outcome of refractory VT, heart failure, permanent AF, and had to undergo multiple therapies to control VT. At the same time, Ventricular dilation was less in patient B who had DES and TTN mutations that have been linked to DCM.[6] Patient A had severe chamber dilatation which could be due to other environmental factors,[4] and not just the presence of the mutation or the number of mutations harbored.

With regard to patient A it is still important to note that despite arrhythmia, heart failure is still a burden in ARVC[7] accounting for increased hospital visits and admission and reduced QALYs. We hypothesize that heart failure was worse in patient A because of the 16 years delay since ARVC diagnosis to ICD implantation, and wish to emphasize the importance of an ICD in limiting VT recurrence and heart failure progression.

With multiple ARVC therapies, patient consent for ICD implantation requires continuous patient and family education on the importance of reducing complications and preventing SCD, as was observed with our patients who initially did not consent to the implantation. Ethical issues that arise on long-term care need to be addressed per patient basis. We achieved optimum therapy with the use of both the ICD and antiarrhythmic medication.

The family screening was done in families of both patients and identification of culprit genes identified the members at risk but is also valuable in predicting the clinical picture and anticipation of complications among patients.

  Conclusion Top

Due to the variable presentation of ARVC tailored follow-up and management of patients is paramount and more research is necessary to unveil pathogenic mutations in undiscovered genes. Further studies showing the relationship of genetic phenotypes and the clinical presentation of ARVC are essential.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Pinamonti B, Brun F, Mestroni L, Sinagra G. Arrhythmogenic right ventricular cardiomyopathy. From genetics to diagnostic and therapeutic challenges. World J Cardiol 2014;6:1234-44.  Back to cited text no. 1
Bhonsale A, Groeneweg JA, James CA, Dooijes D, Tichnell C, Jongbloed JD, et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J 2015;36:847-55.  Back to cited text no. 2
Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Proposed modification of the task force criteria. Circulation 2010;121:1533-41.  Back to cited text no. 3
Sen-Chowdhry S, Syrris P, Pantazis A, Quarta G, McKenna WJ, Chambers JC, et al. Mutational heterogeneity, modifier genes, and environmental influences contribute to phenotypic diversity of arrhythmogenic cardiomyopathy. Circ Cardiovasc Genet 2010;3:323-30.  Back to cited text no. 4
Ruwald AC, Marcus F, Estes NA 3rd, Link M, McNitt S, Polonsky B,et al. Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy. Results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2015;36:1735-43.  Back to cited text no. 5
Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S,et al. The human gene mutation database: Towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 2017;136:665-77.  Back to cited text no. 6
Gilotra NA, Bhonsale A, James CA, Te Riele ASJ, Murray B, Tichnell C,et al. Heart failure is common and under-recognized in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circ Heart Fail 2017;10. pii: e003819.  Back to cited text no. 7


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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