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. 2021 Jun;23(6):933-944.
doi: 10.1002/ejhf.2201. Epub 2021 Jun 24.

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

Anne G Raafs  1 , Job A J Verdonschot  1   2 , Michiel T H M Henkens  1 , Bouke P Adriaans  1   3 , Ping Wang  2 , Kasper Derks  2 , Myrurgia A Abdul Hamid  4 , Christian Knackstedt  1 , Vanessa P M van Empel  1 , Javier Díez  5   6   7 , Hans-Peter Brunner-La Rocca  1 , Han G Brunner  2   8 , Arantxa González  5   6 , Sebastiaan C A M Bekkers  1 , Stephane R B Heymans  1   9   10 , Mark R Hazebroek  1
Affiliations

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

Anne G Raafs et al. Eur J Heart Fail. 2021 Jun.

Abstract

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.

Keywords: Endomyocardial biopsy; Fibrosis; Idiopathic dilated cardiomyopathy; Late gadolinium enhancement; PICP; PIIINP.

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Figures

Figure 1
Figure 1
Example of a patient with late gadolinium enhancement on cardiac magnetic resonance and corresponding histology. (A) Cardiac magnetic resonance image in short‐axis view with visible inferoseptal late gadolinium enhancement. (B) Sirius red staining corresponding to 17% of total endomyocardial biopsy.
Figure 2
Figure 2
Correlation between collagen volume fraction (CVF) in cardiac tissue and serum carboxy‐terminal propeptide of procollagen type I (PICP) in the total cohort and heart failure severity. PICP levels and histological CVF correlated in the total cohort (A) and even more so in patients with severe heart failure in terms of left ventricular ejection fraction (LVEF) <35% (B), New York Heart Association (NYHA) class ≥III (C), or both (D).
Figure 3
Figure 3
Long‐term outcomes in dilated cardiomyopathy patients classified according to different fibrosis assessments. (A) Late gadolinium enhancement (LGE), (B) carboxy‐terminal propeptide of procollagen type I (PICP), and (C) amino‐terminal propeptide of procollagen type III (PIIINP) are associated with worse prognosis. Histological fibrosis (D) is not. CVF, collagen volume fraction.
Figure 4
Figure 4
Evaluation of the predictive value of carboxy‐terminal propeptide of procollagen type I (PICP) and late gadolinium enhancement (LGE) after adjustment for clinical parameters using a series of nested models. PICP and LGE did not significantly improve discrimination based on Harrel's C‐index, neither did the combination of LGE and PICP (A). The combination of PICP and LGE improves the goodness‐of‐fit (B) and reclassification (C,D) compared to the individual markers. IDI, integrated discrimination improvement; NRI, net reclassification index.
Figure 5
Figure 5
Long‐term outcomes in dilated cardiomyopathy patients classified according to presence (+) or absence (−) of late gadolinium enhancement (LGE) and above (+) or below (−) median values of carboxy‐terminal propeptide of procollagen type I (PICP). Dilated cardiomyopathy patients with LGE+/PICP+ had a significantly worse outcome as compared to the other groups.
Figure 6
Figure 6
Principal component analysis based on cardiac RNA‐sequencing data of dilated cardiomyopathy patients classified according to presence (+) or absence (−) of late gadolinium enhancement (LGE) and above (+) or below (−) median values of carboxy‐terminal propeptide of procollagen type I (PICP). Principal component analysis revealed a distinct clustering of RNA transcript levels separating three groups of patients: low degree of fibrosis (LGE‐/PICP‐), intermediate degree of fibrosis (LGE‐/PICP+ and LGE+/PICP‐), and high degree of fibrosis (LGE+/PICP+).
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References

    1. Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, Morarji K, Brown TD, Ismail NA, Dweck MR, Di Pietro E, Roughton M, Wage R, Daryani Y, O'Hanlon R, Sheppard MN, Alpendurada F, Lyon AR, Cook SA, Cowie MR, Assomull RG, Pennell DJ, Prasad SK. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 2013;309:896–908. - PubMed
    1. Hazebroek MR, Moors S, Dennert R, van den Wijngaard A, Krapels I, Hoos M, Verdonschot J, Merken JJ, de Vries B, Wolffs PF, Crijns HJ, Brunner‐La Rocca HP, Heymans S. Prognostic relevance of gene‐environment interactions in patients with dilated cardiomyopathy: applying the MOGE(S) classification. J Am Coll Cardiol 2015;66:1313–1323. - PubMed
    1. Verdonschot JAJ, Hazebroek MR, Ware JS, Prasad SK, Heymans SRB. Role of targeted therapy in dilated cardiomyopathy: the challenging road toward a personalized approach. J Am Heart Assoc 2019;8:e012514. - PMC - PubMed
    1. de Boer RA, De Keulenaer G, Bauersachs J, Brutsaert D, Cleland JG, Diez J, Du XJ, Ford P, Heinzel FR, Lipson KE, McDonagh T, Lopez‐Andres N, Lunde IG, Lyon AR, Pollesello P, Prasad SK, Tocchetti CG, Mayr M, Sluijter JPG, Thum T, Tschope C, Zannad F, Zimmermann WH, Ruschitzka F, Filippatos G, Lindsey ML, Maack C, Heymans S. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology. Eur J Heart Fail 2019;21:272–285. - PMC - PubMed
    1. Shanbhag SM, Greve AM, Aspelund T, Schelbert EB, Cao JJ, Danielsen R, Þorgeirsson G, Sigurðsson S, Eiríksdóttir G, Harris TB, Launer LJ, Guðnason V, Arai AE. Prevalence and prognosis of ischaemic and non‐ischaemic myocardial fibrosis in older adults. Eur Heart J 2019;40:529–538. - PMC - PubMed

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