Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

Luis Escobar-Lopez; Juan Pablo Ochoa; Ana Royuela; Job A J Verdonschot; Matteo Dal Ferro; Maria Angeles Espinosa; Maria Sabater-Molina; Maria Gallego-Delgado; Jose M Larrañaga-Moreira; Jose M Garcia-Pinilla; Maria Teresa Basurte-Elorz; José F Rodríguez-Palomares; Vicente Climent; Francisco J Bermudez-Jimenez; María Victoria Mogollón-Jiménez; Javier Lopez; Maria Luisa Peña-Peña; Ana Garcia-Alvarez; Bernardo López-Abel; Tomas Ripoll-Vera; Julian Palomino-Doza; Antoni Bayes-Genis; Ramon Brugada; Uxua Idiazabal; Jesus G Mirelis; Fernando Dominguez; Michiel T H M Henkens; Ingrid P C Krapels; Han G Brunner; Alessia Paldino; Denise Zaffalon; Luisa Mestroni; Gianfranco Sinagra; Stephane R B Heymans; Marco Merlo; Pablo Garcia-Pavia

doi:10.1016/j.jacc.2022.06.040

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

Luis Escobar-Lopez, Juan Pablo Ochoa, Ana Royuela, Job A J Verdonschot, Matteo Dal Ferro, Maria Angeles Espinosa, Maria Sabater-Molina, Maria Gallego-Delgado, Jose M Larrañaga-Moreira, Jose M Garcia-Pinilla, Maria Teresa Basurte-Elorz, José F Rodríguez-Palomares, Vicente Climent, Francisco J Bermudez-Jimenez, María Victoria Mogollón-Jiménez, Javier Lopez, Maria Luisa Peña-Peña, Ana Garcia-Alvarez, Bernardo López-Abel, Tomas Ripoll-VeraJulian Palomino-Doza, Antoni Bayes-Genis, Ramon Brugada, Uxua Idiazabal, Jesus G Mirelis, Fernando Dominguez, Michiel T H M Henkens, Ingrid P C Krapels, Han G Brunner, Alessia Paldino, Denise Zaffalon, Luisa Mestroni, Gianfranco Sinagra, Stephane R B Heymans, Marco Merlo, Pablo Garcia-Pavia^*

^*Corresponding author for this work

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

Abstract

BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.

OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.

METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.

RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).

CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.

Original language	English
Pages (from-to)	1115-1126
Number of pages	12
Journal	Journal of the American College of Cardiology
Volume	80
Issue number	12
DOIs	https://doi.org/10.1016/j.jacc.2022.06.040
Publication status	Published - 20 Sept 2022

Keywords

Cardiomyopathy, Dilated/diagnosis
Cohort Studies
Genotype
Humans
Risk Factors
Ventricular Dysfunction, Left

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Escobar-Lopez, L., Ochoa, J. P., Royuela, A., Verdonschot, J. A. J., Dal Ferro, M., Espinosa, M. A., Sabater-Molina, M., Gallego-Delgado, M., Larrañaga-Moreira, J. M., Garcia-Pinilla, J. M., Basurte-Elorz, M. T., Rodríguez-Palomares, J. F., Climent, V., Bermudez-Jimenez, F. J., Mogollón-Jiménez, M. V., Lopez, J., Peña-Peña, M. L., Garcia-Alvarez, A., López-Abel, B., ... Garcia-Pavia, P. (2022). Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy. Journal of the American College of Cardiology, 80(12), 1115-1126. https://doi.org/10.1016/j.jacc.2022.06.040

@article{5e04047b50cb4e4d97a72d90d50c7327,

title = "Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy",

abstract = "BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.",

keywords = "Cardiomyopathy, Dilated/diagnosis, Cohort Studies, Genotype, Humans, Risk Factors, Ventricular Dysfunction, Left",

author = "Luis Escobar-Lopez and Ochoa, {Juan Pablo} and Ana Royuela and Verdonschot, {Job A J} and {Dal Ferro}, Matteo and Espinosa, {Maria Angeles} and Maria Sabater-Molina and Maria Gallego-Delgado and Larra{\~n}aga-Moreira, {Jose M} and Garcia-Pinilla, {Jose M} and Basurte-Elorz, {Maria Teresa} and Rodr{\'i}guez-Palomares, {Jos{\'e} F} and Vicente Climent and Bermudez-Jimenez, {Francisco J} and Mogoll{\'o}n-Jim{\'e}nez, {Mar{\'i}a Victoria} and Javier Lopez and Pe{\~n}a-Pe{\~n}a, {Maria Luisa} and Ana Garcia-Alvarez and Bernardo L{\'o}pez-Abel and Tomas Ripoll-Vera and Julian Palomino-Doza and Antoni Bayes-Genis and Ramon Brugada and Uxua Idiazabal and Mirelis, {Jesus G} and Fernando Dominguez and Henkens, {Michiel T H M} and Krapels, {Ingrid P C} and Brunner, {Han G} and Alessia Paldino and Denise Zaffalon and Luisa Mestroni and Gianfranco Sinagra and Heymans, {Stephane R B} and Marco Merlo and Pablo Garcia-Pavia",

year = "2022",

month = sep,

day = "20",

doi = "10.1016/j.jacc.2022.06.040",

language = "English",

volume = "80",

pages = "1115--1126",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Science",

number = "12",

}

Escobar-Lopez, L, Ochoa, JP, Royuela, A, Verdonschot, JAJ, Dal Ferro, M, Espinosa, MA, Sabater-Molina, M, Gallego-Delgado, M, Larrañaga-Moreira, JM, Garcia-Pinilla, JM, Basurte-Elorz, MT, Rodríguez-Palomares, JF, Climent, V, Bermudez-Jimenez, FJ, Mogollón-Jiménez, MV, Lopez, J, Peña-Peña, ML, Garcia-Alvarez, A, López-Abel, B, Ripoll-Vera, T, Palomino-Doza, J, Bayes-Genis, A, Brugada, R, Idiazabal, U, Mirelis, JG, Dominguez, F, Henkens, MTHM , Krapels, IPC , Brunner, HG, Paldino, A, Zaffalon, D, Mestroni, L, Sinagra, G, Heymans, SRB, Merlo, M & Garcia-Pavia, P 2022, 'Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy', Journal of the American College of Cardiology, vol. 80, no. 12, pp. 1115-1126. https://doi.org/10.1016/j.jacc.2022.06.040

TY - JOUR

T1 - Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

AU - Escobar-Lopez, Luis

AU - Ochoa, Juan Pablo

AU - Royuela, Ana

AU - Verdonschot, Job A J

AU - Dal Ferro, Matteo

AU - Espinosa, Maria Angeles

AU - Sabater-Molina, Maria

AU - Gallego-Delgado, Maria

AU - Larrañaga-Moreira, Jose M

AU - Garcia-Pinilla, Jose M

AU - Basurte-Elorz, Maria Teresa

AU - Rodríguez-Palomares, José F

AU - Climent, Vicente

AU - Bermudez-Jimenez, Francisco J

AU - Mogollón-Jiménez, María Victoria

AU - Lopez, Javier

AU - Peña-Peña, Maria Luisa

AU - Garcia-Alvarez, Ana

AU - López-Abel, Bernardo

AU - Ripoll-Vera, Tomas

AU - Palomino-Doza, Julian

AU - Bayes-Genis, Antoni

AU - Brugada, Ramon

AU - Idiazabal, Uxua

AU - Mirelis, Jesus G

AU - Dominguez, Fernando

AU - Henkens, Michiel T H M

AU - Krapels, Ingrid P C

AU - Brunner, Han G

AU - Paldino, Alessia

AU - Zaffalon, Denise

AU - Mestroni, Luisa

AU - Sinagra, Gianfranco

AU - Heymans, Stephane R B

AU - Merlo, Marco

AU - Garcia-Pavia, Pablo

PY - 2022/9/20

Y1 - 2022/9/20

N2 - BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.

AB - BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.

KW - Cardiomyopathy, Dilated/diagnosis

KW - Cohort Studies

KW - Genotype

KW - Humans

KW - Risk Factors

KW - Ventricular Dysfunction, Left

U2 - 10.1016/j.jacc.2022.06.040

DO - 10.1016/j.jacc.2022.06.040

M3 - Article

C2 - 36109106

SN - 0735-1097

VL - 80

SP - 1115

EP - 1126

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 12

ER -

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

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Keywords

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