Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator

Christine Rootwelt-Norberg; Alex Hørby Christensen; Eystein T Skjølsvik; Monica Chivulescu; Christoffer R Vissing; Henning Bundgaard; Eivind W Aabel; Martin P Bogsrud; Nina E Hasselberg; Øyvind H Lie; Kristina H Haugaa

doi:10.1016/j.hrthm.2022.11.024

Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator

Christine Rootwelt-Norberg, Alex Hørby Christensen, Eystein T Skjølsvik, Monica Chivulescu, Christoffer R Vissing, Henning Bundgaard, Eivind W Aabel, Martin P Bogsrud, Nina E Hasselberg, Øyvind H Lie, Kristina H Haugaa^*

^*Corresponding author for this work

5 Citations (Scopus)

Abstract

BACKGROUND: LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA-risk VTA calculator published in 2019 has not been externally validated.

OBJECTIVE: The purpose of this study was to validate the LMNA-risk VTA calculator.

METHODS: We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA-risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis.

RESULTS: We included 118 patients (age 37 years [IQR 27-49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0-9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%-4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA-risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men.

CONCLUSION: Validation of the LMNA-risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model.

Original language	English
Journal	Heart Rhythm
Volume	20
Issue number	3
Pages (from-to)	423-429
Number of pages	7
ISSN	1547-5271
DOIs	https://doi.org/10.1016/j.hrthm.2022.11.024
Publication status	Published - Mar 2023

Keywords

Defibrillators, Implantable/adverse effects
Electrocardiography
Female
Humans
Lamin Type A
Laminopathies/complications
Male
Stroke Volume
Tachycardia, Ventricular/etiology
Ventricular Function, Left

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Rootwelt-Norberg, C., Christensen, A. H., Skjølsvik, E. T., Chivulescu, M., Vissing, C. R., Bundgaard, H., Aabel, E. W., Bogsrud, M. P., Hasselberg, N. E., Lie, Ø. H., & Haugaa, K. H. (2023). Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator. Heart Rhythm, 20(3), 423-429. https://doi.org/10.1016/j.hrthm.2022.11.024

Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator. / Rootwelt-Norberg, Christine; Christensen, Alex Hørby; Skjølsvik, Eystein T et al.
In: Heart Rhythm, Vol. 20, No. 3, 03.2023, p. 423-429.

Research output: Contribution to journal › Journal article › Research › peer-review

Rootwelt-Norberg, C, Christensen, AH, Skjølsvik, ET, Chivulescu, M, Vissing, CR, Bundgaard, H, Aabel, EW, Bogsrud, MP, Hasselberg, NE, Lie, ØH & Haugaa, KH 2023, 'Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator', Heart Rhythm, vol. 20, no. 3, pp. 423-429. https://doi.org/10.1016/j.hrthm.2022.11.024

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title = "Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator",

abstract = "BACKGROUND: LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA-risk VTA calculator published in 2019 has not been externally validated.OBJECTIVE: The purpose of this study was to validate the LMNA-risk VTA calculator.METHODS: We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA-risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis.RESULTS: We included 118 patients (age 37 years [IQR 27-49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0-9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%-4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA-risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men.CONCLUSION: Validation of the LMNA-risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model.",

keywords = "Defibrillators, Implantable/adverse effects, Electrocardiography, Female, Humans, Lamin Type A, Laminopathies/complications, Male, Stroke Volume, Tachycardia, Ventricular/etiology, Ventricular Function, Left",

author = "Christine Rootwelt-Norberg and Christensen, {Alex H{\o}rby} and Skj{\o}lsvik, {Eystein T} and Monica Chivulescu and Vissing, {Christoffer R} and Henning Bundgaard and Aabel, {Eivind W} and Bogsrud, {Martin P} and Hasselberg, {Nina E} and Lie, {{\O}yvind H} and Haugaa, {Kristina H}",

note = "Copyright {\textcopyright} 2022. Published by Elsevier Inc.",

year = "2023",

month = mar,

doi = "10.1016/j.hrthm.2022.11.024",

language = "English",

volume = "20",

pages = "423--429",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier Inc",

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T1 - Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator

AU - Rootwelt-Norberg, Christine

AU - Christensen, Alex Hørby

AU - Skjølsvik, Eystein T

AU - Chivulescu, Monica

AU - Vissing, Christoffer R

AU - Bundgaard, Henning

AU - Aabel, Eivind W

AU - Bogsrud, Martin P

AU - Hasselberg, Nina E

AU - Lie, Øyvind H

AU - Haugaa, Kristina H

PY - 2023/3

Y1 - 2023/3

N2 - BACKGROUND: LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA-risk VTA calculator published in 2019 has not been externally validated.OBJECTIVE: The purpose of this study was to validate the LMNA-risk VTA calculator.METHODS: We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA-risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis.RESULTS: We included 118 patients (age 37 years [IQR 27-49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0-9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%-4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA-risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men.CONCLUSION: Validation of the LMNA-risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model.

AB - BACKGROUND: LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA-risk VTA calculator published in 2019 has not been externally validated.OBJECTIVE: The purpose of this study was to validate the LMNA-risk VTA calculator.METHODS: We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA-risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis.RESULTS: We included 118 patients (age 37 years [IQR 27-49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0-9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%-4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA-risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men.CONCLUSION: Validation of the LMNA-risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model.

KW - Defibrillators, Implantable/adverse effects

KW - Electrocardiography

KW - Female

KW - Humans

KW - Lamin Type A

KW - Laminopathies/complications

KW - Male

KW - Stroke Volume

KW - Tachycardia, Ventricular/etiology

KW - Ventricular Function, Left

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DO - 10.1016/j.hrthm.2022.11.024

M3 - Journal article

C2 - 36494026

SN - 1547-5271

VL - 20

SP - 423

EP - 429

JO - Heart Rhythm

JF - Heart Rhythm

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ER -

Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator

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