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Original Article

Outcome in Phospholamban R14del CarriersClinical Perspective

Results of a Large Multicentre Cohort Study

Ingrid A.W. van Rijsingen, Paul A. van der Zwaag, Judith A. Groeneweg, Eline A. Nannenberg, Jan D.H. Jongbloed, Aeilko H. Zwinderman, Yigal M. Pinto, Ronald H. Lekanne dit Deprez, Jan G. Post, Hanno L. Tan, Rudolf A. de Boer, Richard N.W. Hauer, Imke Christiaans, Maarten P. van den Berg, J. Peter van Tintelen, Arthur A.M. Wilde
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https://doi.org/10.1161/CIRCGENETICS.113.000374
Circulation: Genomic and Precision Medicine. 2014;7:455-465
Originally published June 8, 2014
Ingrid A.W. van Rijsingen
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Paul A. van der Zwaag
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Judith A. Groeneweg
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Eline A. Nannenberg
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Jan D.H. Jongbloed
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Aeilko H. Zwinderman
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Yigal M. Pinto
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Ronald H. Lekanne dit Deprez
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Jan G. Post
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Hanno L. Tan
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Rudolf A. de Boer
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Richard N.W. Hauer
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Imke Christiaans
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Maarten P. van den Berg
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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J. Peter van Tintelen
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Arthur A.M. Wilde
Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands.
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Abstract

Background—The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers.

Methods and Results—Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4–2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9–8.1) and 2.6 (95% confidence interval, 1.5–4.5), respectively.

Conclusions—Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards.

  • arrhythmias, cardiac
  • arrhythmogenic right ventricular dysplasia-cardiomyopathy
  • cardiomyopathy, dilated
  • genetics
  • mortality
  • phospholamban
  • risk factors
  • Received October 10, 2013.
  • Accepted May 8, 2014.
  • © 2014 American Heart Association, Inc.
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    Outcome in Phospholamban R14del CarriersClinical Perspective
    Ingrid A.W. van Rijsingen, Paul A. van der Zwaag, Judith A. Groeneweg, Eline A. Nannenberg, Jan D.H. Jongbloed, Aeilko H. Zwinderman, Yigal M. Pinto, Ronald H. Lekanne dit Deprez, Jan G. Post, Hanno L. Tan, Rudolf A. de Boer, Richard N.W. Hauer, Imke Christiaans, Maarten P. van den Berg, J. Peter van Tintelen and Arthur A.M. Wilde
    Circulation: Genomic and Precision Medicine. 2014;7:455-465, originally published June 8, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000374

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    Outcome in Phospholamban R14del CarriersClinical Perspective
    Ingrid A.W. van Rijsingen, Paul A. van der Zwaag, Judith A. Groeneweg, Eline A. Nannenberg, Jan D.H. Jongbloed, Aeilko H. Zwinderman, Yigal M. Pinto, Ronald H. Lekanne dit Deprez, Jan G. Post, Hanno L. Tan, Rudolf A. de Boer, Richard N.W. Hauer, Imke Christiaans, Maarten P. van den Berg, J. Peter van Tintelen and Arthur A.M. Wilde
    Circulation: Genomic and Precision Medicine. 2014;7:455-465, originally published June 8, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000374
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