TY - JOUR
T1 - The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy
AU - Raafs, Anne G.
AU - Verdonschot, Job A. J.
AU - Henkens, Michiel T. H. M.
AU - Adriaans, Bouke P.
AU - Wang, Ping
AU - Derks, Kasper
AU - Abdul Hamid, Myrurgia A.
AU - Knackstedt, Christian
AU - van Empel, Vanessa P. M.
AU - Diez, Javier
AU - Brunner-La Rocca, Hans-Peter
AU - Brunner, Han G.
AU - Gonzalez, Arantxa
AU - Bekkers, Sebastiaan C. A. M.
AU - Heymans, Stephane R. B.
AU - Hazebroek, Mark R.
N1 - Funding Information:
This work was supported by Instituto de Salud Carlos III (CIBERCV CB16/11/00483 and PI18/01469 co‐financed by FEDER funds); Kootstra Talented Post‐doc Fellowship; and the European Union Commission's Seventh Framework Program under grant agreement No. 305507 [HOMAGE (Heart OMics in AGEing consortium)].
Publisher Copyright:
© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
PY - 2021/6
Y1 - 2021/6
N2 - Aims To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients. Methods and results We quantified fibrosis in 209 DCM patients at three levels: (i) non-invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life-threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90-6.60; P < 0.001 and PICP 1.02, 95% CI 1.01-1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles. Conclusion The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.
AB - Aims To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients. Methods and results We quantified fibrosis in 209 DCM patients at three levels: (i) non-invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life-threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90-6.60; P < 0.001 and PICP 1.02, 95% CI 1.01-1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles. Conclusion The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.
KW - Idiopathic dilated cardiomyopathy
KW - Fibrosis
KW - Late gadolinium enhancement
KW - Endomyocardial biopsy
KW - PICP
KW - PIIINP
KW - COLLEGE-OF-CARDIOLOGY
KW - HEART-FAILURE
KW - CIRCULATING BIOMARKERS
KW - INTERSTITIAL FIBROSIS
KW - EUROPEAN-SOCIETY
KW - THERAPY
KW - ASSOCIATION
KW - MANAGEMENT
KW - MORTALITY
KW - SPIRONOLACTONE
U2 - 10.1002/ejhf.2201
DO - 10.1002/ejhf.2201
M3 - Article
C2 - 33928704
SN - 1388-9842
VL - 23
SP - 933
EP - 944
JO - European journal of heart failure
JF - European journal of heart failure
IS - 6
ER -