The burden of early phenotypes and the influence of wall thickness in hypertrophic cardiomyopathy mutation carriers: Findings from the HCMNet study

HCMNet Investigators

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

IMPORTANCE: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. OBJECTIVES: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH−), and healthy related control individuals (G−/LVH−) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016. EXPOSURES :The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT. MAIN OUTCOMES AND MEASURES: Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts. RESULTS: Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH− (20 [10] years), and 42 G−/LVH− (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E′ velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH−, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than −1.85 or the combination of an LV end-diastolic dimension z score of −1.85 or higher and a septal E′ velocity z score less than −0.52 as having 74% accuracy in discriminating G+/LVH− participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition. CONCLUSIONS AND RELEVANCE: G+/LVH− individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G− controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree–based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.

Original languageEnglish (US)
Pages (from-to)419-428
Number of pages10
JournalJAMA Cardiology
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2017

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Hypertrophic Cardiomyopathy
Hypertrophy
Phenotype
Mutation
Sarcomeres
Electrocardiography
Natriuretic Peptides
Troponin
Left Ventricular Hypertrophy
Serum
Stroke Volume
Multicenter Studies
Observational Studies
Echocardiography
Cohort Studies
Biomarkers
Genotype
Regression Analysis

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

The burden of early phenotypes and the influence of wall thickness in hypertrophic cardiomyopathy mutation carriers : Findings from the HCMNet study. / HCMNet Investigators.

In: JAMA Cardiology, Vol. 2, No. 4, 01.04.2017, p. 419-428.

Research output: Contribution to journalArticle

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abstract = "IMPORTANCE: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. OBJECTIVES: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH−), and healthy related control individuals (G−/LVH−) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016. EXPOSURES :The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT. MAIN OUTCOMES AND MEASURES: Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts. RESULTS: Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH− (20 [10] years), and 42 G−/LVH− (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E′ velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH−, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than −1.85 or the combination of an LV end-diastolic dimension z score of −1.85 or higher and a septal E′ velocity z score less than −0.52 as having 74{\%} accuracy in discriminating G+/LVH− participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition. CONCLUSIONS AND RELEVANCE: G+/LVH− individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G− controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree–based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.",
author = "{HCMNet Investigators} and Ho, {Carolyn Y.} and Day, {Sharlene M.} and Colan, {Steven D.} and Russell, {Mark W.} and Towbin, {Jeffrey A.} and Jeffrey Towbin and Canter, {Charles E.} and Jefferies, {John L.} and John Jefferies and Cirino, {Allison L.} and Abraham, {Theodore P.} and Matthew Taylor and Luisa Mestroni and Bluemke, {David A.} and Petr Jarolim and Ling Shi and Sleeper, {Lynn A.} and Seidman, {Christine E.} and Orav, {E. John}",
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TY - JOUR

T1 - The burden of early phenotypes and the influence of wall thickness in hypertrophic cardiomyopathy mutation carriers

T2 - Findings from the HCMNet study

AU - HCMNet Investigators

AU - Ho, Carolyn Y.

AU - Day, Sharlene M.

AU - Colan, Steven D.

AU - Russell, Mark W.

AU - Towbin, Jeffrey A.

AU - Towbin, Jeffrey

AU - Canter, Charles E.

AU - Jefferies, John L.

AU - Jefferies, John

AU - Cirino, Allison L.

AU - Abraham, Theodore P.

AU - Taylor, Matthew

AU - Mestroni, Luisa

AU - Bluemke, David A.

AU - Jarolim, Petr

AU - Shi, Ling

AU - Sleeper, Lynn A.

AU - Seidman, Christine E.

AU - Orav, E. John

PY - 2017/4/1

Y1 - 2017/4/1

N2 - IMPORTANCE: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. OBJECTIVES: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH−), and healthy related control individuals (G−/LVH−) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016. EXPOSURES :The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT. MAIN OUTCOMES AND MEASURES: Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts. RESULTS: Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH− (20 [10] years), and 42 G−/LVH− (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E′ velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH−, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than −1.85 or the combination of an LV end-diastolic dimension z score of −1.85 or higher and a septal E′ velocity z score less than −0.52 as having 74% accuracy in discriminating G+/LVH− participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition. CONCLUSIONS AND RELEVANCE: G+/LVH− individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G− controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree–based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.

AB - IMPORTANCE: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. OBJECTIVES: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH−), and healthy related control individuals (G−/LVH−) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016. EXPOSURES :The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT. MAIN OUTCOMES AND MEASURES: Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts. RESULTS: Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH− (20 [10] years), and 42 G−/LVH− (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E′ velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH−, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than −1.85 or the combination of an LV end-diastolic dimension z score of −1.85 or higher and a septal E′ velocity z score less than −0.52 as having 74% accuracy in discriminating G+/LVH− participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition. CONCLUSIONS AND RELEVANCE: G+/LVH− individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G− controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree–based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.

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