Clinical features of arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in plakophilin-2

Darshan Dalal, Lorraine H. Molin, Jonathan Piccini, Crystal Tichnell, Cynthia James, Chandra Bomma, Kalpana Prakasa, Jeffrey Towbin, Frank I. Marcus, Philip J. Spevak, David A. Bluemke, Theodore Abraham, Stuart D. Russell, Hugh Calkins, Daniel P. Judge

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Abstract

Background - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results - DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28 ± 11 years) than in those without (36 ± 16 years) (P < 0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P < 0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P < 0.05). Conclusions - Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.

Original languageEnglish (US)
Pages (from-to)1641-1649
Number of pages9
JournalCirculation
Volume113
Issue number13
DOIs
StatePublished - Apr 1 2006

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Plakophilins
Arrhythmogenic Right Ventricular Dysplasia
Mutation
Defibrillators
Cardiac Arrhythmias
Right Ventricular Dysfunction
Survival

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Dalal, D., Molin, L. H., Piccini, J., Tichnell, C., James, C., Bomma, C., ... Judge, D. P. (2006). Clinical features of arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in plakophilin-2. Circulation, 113(13), 1641-1649. https://doi.org/10.1161/CIRCULATIONAHA.105.568642

Clinical features of arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in plakophilin-2. / Dalal, Darshan; Molin, Lorraine H.; Piccini, Jonathan; Tichnell, Crystal; James, Cynthia; Bomma, Chandra; Prakasa, Kalpana; Towbin, Jeffrey; Marcus, Frank I.; Spevak, Philip J.; Bluemke, David A.; Abraham, Theodore; Russell, Stuart D.; Calkins, Hugh; Judge, Daniel P.

In: Circulation, Vol. 113, No. 13, 01.04.2006, p. 1641-1649.

Research output: Contribution to journalArticle

Dalal, D, Molin, LH, Piccini, J, Tichnell, C, James, C, Bomma, C, Prakasa, K, Towbin, J, Marcus, FI, Spevak, PJ, Bluemke, DA, Abraham, T, Russell, SD, Calkins, H & Judge, DP 2006, 'Clinical features of arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in plakophilin-2', Circulation, vol. 113, no. 13, pp. 1641-1649. https://doi.org/10.1161/CIRCULATIONAHA.105.568642
Dalal, Darshan ; Molin, Lorraine H. ; Piccini, Jonathan ; Tichnell, Crystal ; James, Cynthia ; Bomma, Chandra ; Prakasa, Kalpana ; Towbin, Jeffrey ; Marcus, Frank I. ; Spevak, Philip J. ; Bluemke, David A. ; Abraham, Theodore ; Russell, Stuart D. ; Calkins, Hugh ; Judge, Daniel P. / Clinical features of arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in plakophilin-2. In: Circulation. 2006 ; Vol. 113, No. 13. pp. 1641-1649.
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abstract = "Background - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results - DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43{\%}) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28 ± 11 years) than in those without (36 ± 16 years) (P < 0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P < 0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P < 0.05). Conclusions - Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.",
author = "Darshan Dalal and Molin, {Lorraine H.} and Jonathan Piccini and Crystal Tichnell and Cynthia James and Chandra Bomma and Kalpana Prakasa and Jeffrey Towbin and Marcus, {Frank I.} and Spevak, {Philip J.} and Bluemke, {David A.} and Theodore Abraham and Russell, {Stuart D.} and Hugh Calkins and Judge, {Daniel P.}",
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T1 - Clinical features of arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in plakophilin-2

AU - Dalal, Darshan

AU - Molin, Lorraine H.

AU - Piccini, Jonathan

AU - Tichnell, Crystal

AU - James, Cynthia

AU - Bomma, Chandra

AU - Prakasa, Kalpana

AU - Towbin, Jeffrey

AU - Marcus, Frank I.

AU - Spevak, Philip J.

AU - Bluemke, David A.

AU - Abraham, Theodore

AU - Russell, Stuart D.

AU - Calkins, Hugh

AU - Judge, Daniel P.

PY - 2006/4/1

Y1 - 2006/4/1

N2 - Background - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results - DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28 ± 11 years) than in those without (36 ± 16 years) (P < 0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P < 0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P < 0.05). Conclusions - Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.

AB - Background - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations. Methods and Results - DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28 ± 11 years) than in those without (36 ± 16 years) (P < 0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P < 0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P < 0.05). Conclusions - Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.

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