Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: Evidence supporting the concept of arrhythmogenic cardiomyopathy

Paul A. Van Der Zwaag, Ingrid A W Van Rijsingen, Angeliki Asimaki, Jan D H Jongbloed, Dirk J. Van Veldhuisen, Ans C P Wiesfeld, Moniek G P J Cox, Laura T. Van Lochem, Rudolf A. De Boer, Robert M W Hofstra, Imke Christiaans, Karin Y. Van Spaendonck-Zwarts, Ronald H Lekanne Dit Deprez, Daniel P. Judge, Hugh Calkins, Albert J H Suurmeijer, Richard N W Hauer, Jeffrey E. Saffitz, Arthur A M Wilde, Maarten P. Van Den BergJ. Peter Van Tintelen

Research output: Contribution to journalArticle

Abstract

Aims To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).Methods and resultsWe screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 ) ARVC patients and in 39 (15 ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 of R14del carriers. Compared with R14del-DCM patients, R14del DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 vs. 10 , P <0.001), cardiac transplantation (18 vs. 2 , P <0.001), and a family history for sudden cardiac death (SCD) at <50 years (36 vs. 16 , P 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 ) R14del ARVC samples, but in only one of nine (11 ) R14del DCM samples (P 0.03).ConclusionsThe PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.

Original languageEnglish (US)
Pages (from-to)1199-1207
Number of pages9
JournalEuropean Journal of Heart Failure
Volume14
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Arrhythmogenic Right Ventricular Dysplasia
Dilated Cardiomyopathy
Cardiomyopathies
Mutation
Sudden Cardiac Death
Genes
gamma Catenin
phospholamban
Implantable Defibrillators
Heart Transplantation
Haplotypes
Electrocardiography
Immunohistochemistry
Phenotype

Keywords

  • Arrhythmia
  • Arrhythmogenic cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy
  • Dilated cardiomyopathy
  • Genetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Van Der Zwaag, P. A., Van Rijsingen, I. A. W., Asimaki, A., Jongbloed, J. D. H., Van Veldhuisen, D. J., Wiesfeld, A. C. P., ... Van Tintelen, J. P. (2012). Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: Evidence supporting the concept of arrhythmogenic cardiomyopathy. European Journal of Heart Failure, 14(11), 1199-1207. https://doi.org/10.1093/eurjhf/hfs119

Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy : Evidence supporting the concept of arrhythmogenic cardiomyopathy. / Van Der Zwaag, Paul A.; Van Rijsingen, Ingrid A W; Asimaki, Angeliki; Jongbloed, Jan D H; Van Veldhuisen, Dirk J.; Wiesfeld, Ans C P; Cox, Moniek G P J; Van Lochem, Laura T.; De Boer, Rudolf A.; Hofstra, Robert M W; Christiaans, Imke; Van Spaendonck-Zwarts, Karin Y.; Deprez, Ronald H Lekanne Dit; Judge, Daniel P.; Calkins, Hugh; Suurmeijer, Albert J H; Hauer, Richard N W; Saffitz, Jeffrey E.; Wilde, Arthur A M; Van Den Berg, Maarten P.; Van Tintelen, J. Peter.

In: European Journal of Heart Failure, Vol. 14, No. 11, 11.2012, p. 1199-1207.

Research output: Contribution to journalArticle

Van Der Zwaag, PA, Van Rijsingen, IAW, Asimaki, A, Jongbloed, JDH, Van Veldhuisen, DJ, Wiesfeld, ACP, Cox, MGPJ, Van Lochem, LT, De Boer, RA, Hofstra, RMW, Christiaans, I, Van Spaendonck-Zwarts, KY, Deprez, RHLD, Judge, DP, Calkins, H, Suurmeijer, AJH, Hauer, RNW, Saffitz, JE, Wilde, AAM, Van Den Berg, MP & Van Tintelen, JP 2012, 'Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: Evidence supporting the concept of arrhythmogenic cardiomyopathy', European Journal of Heart Failure, vol. 14, no. 11, pp. 1199-1207. https://doi.org/10.1093/eurjhf/hfs119
Van Der Zwaag, Paul A. ; Van Rijsingen, Ingrid A W ; Asimaki, Angeliki ; Jongbloed, Jan D H ; Van Veldhuisen, Dirk J. ; Wiesfeld, Ans C P ; Cox, Moniek G P J ; Van Lochem, Laura T. ; De Boer, Rudolf A. ; Hofstra, Robert M W ; Christiaans, Imke ; Van Spaendonck-Zwarts, Karin Y. ; Deprez, Ronald H Lekanne Dit ; Judge, Daniel P. ; Calkins, Hugh ; Suurmeijer, Albert J H ; Hauer, Richard N W ; Saffitz, Jeffrey E. ; Wilde, Arthur A M ; Van Den Berg, Maarten P. ; Van Tintelen, J. Peter. / Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy : Evidence supporting the concept of arrhythmogenic cardiomyopathy. In: European Journal of Heart Failure. 2012 ; Vol. 14, No. 11. pp. 1199-1207.
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abstract = "Aims To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).Methods and resultsWe screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 ) ARVC patients and in 39 (15 ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 of R14del carriers. Compared with R14del-DCM patients, R14del DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 vs. 10 , P <0.001), cardiac transplantation (18 vs. 2 , P <0.001), and a family history for sudden cardiac death (SCD) at <50 years (36 vs. 16 , P 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 ) R14del ARVC samples, but in only one of nine (11 ) R14del DCM samples (P 0.03).ConclusionsThe PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.",
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T1 - Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy

T2 - Evidence supporting the concept of arrhythmogenic cardiomyopathy

AU - Van Der Zwaag, Paul A.

AU - Van Rijsingen, Ingrid A W

AU - Asimaki, Angeliki

AU - Jongbloed, Jan D H

AU - Van Veldhuisen, Dirk J.

AU - Wiesfeld, Ans C P

AU - Cox, Moniek G P J

AU - Van Lochem, Laura T.

AU - De Boer, Rudolf A.

AU - Hofstra, Robert M W

AU - Christiaans, Imke

AU - Van Spaendonck-Zwarts, Karin Y.

AU - Deprez, Ronald H Lekanne Dit

AU - Judge, Daniel P.

AU - Calkins, Hugh

AU - Suurmeijer, Albert J H

AU - Hauer, Richard N W

AU - Saffitz, Jeffrey E.

AU - Wilde, Arthur A M

AU - Van Den Berg, Maarten P.

AU - Van Tintelen, J. Peter

PY - 2012/11

Y1 - 2012/11

N2 - Aims To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).Methods and resultsWe screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 ) ARVC patients and in 39 (15 ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 of R14del carriers. Compared with R14del-DCM patients, R14del DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 vs. 10 , P <0.001), cardiac transplantation (18 vs. 2 , P <0.001), and a family history for sudden cardiac death (SCD) at <50 years (36 vs. 16 , P 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 ) R14del ARVC samples, but in only one of nine (11 ) R14del DCM samples (P 0.03).ConclusionsThe PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.

AB - Aims To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).Methods and resultsWe screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 ) ARVC patients and in 39 (15 ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 of R14del carriers. Compared with R14del-DCM patients, R14del DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 vs. 10 , P <0.001), cardiac transplantation (18 vs. 2 , P <0.001), and a family history for sudden cardiac death (SCD) at <50 years (36 vs. 16 , P 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 ) R14del ARVC samples, but in only one of nine (11 ) R14del DCM samples (P 0.03).ConclusionsThe PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.

KW - Arrhythmia

KW - Arrhythmogenic cardiomyopathy

KW - Arrhythmogenic right ventricular cardiomyopathy

KW - Dilated cardiomyopathy

KW - Genetics

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