TY - JOUR
T1 - Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences
AU - Verdonschot, J.A.J.
AU - Merlo, M.
AU - Dominguez, F.
AU - Wang, P.
AU - Henkens, M.T.H.M.
AU - Adriaens, M.E.
AU - Hazebroek, M.R.
AU - Mase, M.
AU - Escobar, L.E.
AU - Cobas-Paz, R.
AU - Derks, K.W.J.
AU - van den Wijngaard, A.
AU - Krapels, I.P.C.
AU - Brunner, H.G.
AU - Sinagra, G.
AU - Garcia-Pavia, P.
AU - Heymans, S.R.B.
PY - 2021/1/7
Y1 - 2021/1/7
N2 - 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 indepth 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.[GRAPHICS].
AB - 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 indepth 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.[GRAPHICS].
KW - clustering
KW - dilated cardiomyopathy
KW - machine learning
KW - pathophysiology
KW - Dilated cardiomyopathy
KW - Pathophysiology
KW - Machine learning
KW - Clustering
U2 - 10.1093/eurheartj/ehaa841
DO - 10.1093/eurheartj/ehaa841
M3 - Article
C2 - 33156912
SN - 0195-668X
VL - 42
SP - 162
EP - 174
JO - European Heart Journal
JF - European Heart Journal
IS - 2
ER -