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Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences

European heart journal, 2021-01, Vol.42 (2), p.162-174 [Peer Reviewed Journal]

The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. 2020 ;The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. ;ISSN: 0195-668X ;EISSN: 1522-9645 ;DOI: 10.1093/eurheartj/ehaa841 ;PMID: 33156912

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  • Title:
    Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences
  • Author: Verdonschot, Job A J ; Merlo, Marco ; Dominguez, Fernando ; Wang, Ping ; Henkens, Michiel T H M ; Adriaens, Michiel E ; Hazebroek, Mark R ; Masè, Marco ; Escobar, Luis E ; Cobas-Paz, Rafael ; Derks, Kasper W J ; van den Wijngaard, Arthur ; Krapels, Ingrid P C ; Brunner, Han G ; Sinagra, Gianfranco ; Garcia-Pavia, Pablo ; Heymans, Stephane R B
  • Subjects: Cardiomyopathy, Dilated - genetics ; Clinical Research ; Cluster Analysis ; Humans ; Italy ; Phenotype ; Spain
  • Is Part Of: European heart journal, 2021-01, Vol.42 (2), p.162-174
  • Description: Abstract Aims The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups. Methods and results We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping. Conclusion The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach. Graphical Abstract
  • Publisher: England: Oxford University Press
  • Language: English
  • Identifier: ISSN: 0195-668X
    EISSN: 1522-9645
    DOI: 10.1093/eurheartj/ehaa841
    PMID: 33156912
  • Source: Oxford Journals Open Access Collection
    GFMER Free Medical Journals
    MEDLINE
    Alma/SFX Local Collection
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