Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms

Karim Taha; Wouter P. te Rijdt; Tom E. Verstraelen; Maarten J. Cramer; Rudolf A. de Boer; Rianne H.A.C.M. de Bruin-Bon; Berto J. Bouma; Folkert W. Asselbergs; Arthur A.M. Wilde; Maarten P. van den Berg; Arco J. Teske

doi:10.1016/j.jcmg.2020.09.030

Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms

Karim Taha^*, Wouter P. te Rijdt, Tom E. Verstraelen, Maarten J. Cramer, Rudolf A. de Boer, Rianne H.A.C.M. de Bruin-Bon, Berto J. Bouma, Folkert W. Asselbergs, Arthur A.M. Wilde, Maarten P. van den Berg, Arco J. Teske

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.

BACKGROUND: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.

METHODS: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.

RESULTS: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).

CONCLUSIONS: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

Original language	English
Pages (from-to)	885-896
Number of pages	12
Journal	JACC: Cardiovascular Imaging
Volume	14
Issue number	5
Early online date	13 Nov 2020
DOIs	https://doi.org/10.1016/j.jcmg.2020.09.030
Publication status	Published - May 2021

Keywords

deformation imaging
early detection
echocardiography
family screening
phospholamban
risk stratification

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10.1016/j.jcmg.2020.09.030

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Taha, K., te Rijdt, W. P., Verstraelen, T. E., Cramer, M. J., de Boer, R. A., de Bruin-Bon, R. H. A. C. M., Bouma, B. J., Asselbergs, F. W., Wilde, A. A. M., van den Berg, M. P., & Teske, A. J. (2021). Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms. JACC: Cardiovascular Imaging, 14(5), 885-896. https://doi.org/10.1016/j.jcmg.2020.09.030

@article{44fd65efb4ce43a58b5916f2472553c3,

title = "Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms",

abstract = "OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.BACKGROUND: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.METHODS: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.RESULTS: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).CONCLUSIONS: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.",

keywords = "deformation imaging, early detection, echocardiography, family screening, phospholamban, risk stratification",

author = "Karim Taha and {te Rijdt}, {Wouter P.} and Verstraelen, {Tom E.} and Cramer, {Maarten J.} and {de Boer}, {Rudolf A.} and {de Bruin-Bon}, {Rianne H.A.C.M.} and Bouma, {Berto J.} and Asselbergs, {Folkert W.} and Wilde, {Arthur A.M.} and {van den Berg}, {Maarten P.} and Teske, {Arco J.}",

note = "Funding Information: This work was supported by the PLN Genetic Heart Disease Foundation, Netherlands Heart Institute, and the Dutch Heart Foundation (CVON2015-12 eDETECT and CVON2018-30 PREDICT2). Dr. te Rijdt is supported by the Dutch Heart Foundation (CVON PREDICT Young Talent Program) and the Leducq Foundation (CURE-PLaN Postdoctoral Fellowship). Prof. Dr. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Prof. Dr. de Boer has received speaker fees from Abbott, AstraZeneca, Novartis, and Roche. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: {\textcopyright} 2021 American College of Cardiology Foundation Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

doi = "10.1016/j.jcmg.2020.09.030",

language = "English",

volume = "14",

pages = "885--896",

journal = "JACC: Cardiovascular Imaging",

issn = "1936-878X",

publisher = "Elsevier",

number = "5",

}

Taha, K, te Rijdt, WP, Verstraelen, TE, Cramer, MJ, de Boer, RA, de Bruin-Bon, RHACM, Bouma, BJ, Asselbergs, FW, Wilde, AAM, van den Berg, MP & Teske, AJ 2021, 'Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms', JACC: Cardiovascular Imaging, vol. 14, no. 5, pp. 885-896. https://doi.org/10.1016/j.jcmg.2020.09.030

TY - JOUR

T1 - Early Mechanical Alterations in Phospholamban Mutation Carriers

T2 - Identifying Subclinical Disease Before Onset of Symptoms

AU - Taha, Karim

AU - te Rijdt, Wouter P.

AU - Verstraelen, Tom E.

AU - Cramer, Maarten J.

AU - de Boer, Rudolf A.

AU - de Bruin-Bon, Rianne H.A.C.M.

AU - Bouma, Berto J.

AU - Asselbergs, Folkert W.

AU - Wilde, Arthur A.M.

AU - van den Berg, Maarten P.

AU - Teske, Arco J.

N1 - Funding Information: This work was supported by the PLN Genetic Heart Disease Foundation, Netherlands Heart Institute, and the Dutch Heart Foundation (CVON2015-12 eDETECT and CVON2018-30 PREDICT2). Dr. te Rijdt is supported by the Dutch Heart Foundation (CVON PREDICT Young Talent Program) and the Leducq Foundation (CURE-PLaN Postdoctoral Fellowship). Prof. Dr. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Prof. Dr. de Boer has received speaker fees from Abbott, AstraZeneca, Novartis, and Roche. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: © 2021 American College of Cardiology Foundation Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5

Y1 - 2021/5

N2 - OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.BACKGROUND: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.METHODS: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.RESULTS: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).CONCLUSIONS: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

AB - OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.BACKGROUND: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.METHODS: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.RESULTS: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).CONCLUSIONS: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

KW - deformation imaging

KW - early detection

KW - echocardiography

KW - family screening

KW - phospholamban

KW - risk stratification

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U2 - 10.1016/j.jcmg.2020.09.030

DO - 10.1016/j.jcmg.2020.09.030

M3 - Article

C2 - 33221241

AN - SCOPUS:85097245917

SN - 1936-878X

VL - 14

SP - 885

EP - 896

JO - JACC: Cardiovascular Imaging

JF - JACC: Cardiovascular Imaging

IS - 5

ER -

Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms

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