Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure.

ABSTRACT

Background: A central issue hindering the development of effective anti-fibrosis drugs for heart failure is the unclear interrelationship between fibrosis and the immune cells. This study aims at providing precise subtyping of heart failure based on immune cell fractions, elaborating their differences in fibrotic mechanisms, and proposing a biomarker panel for evaluating intrinsic features of patients' physiological statuses through subtype classification, thereby promoting the precision medicine for cardiac fibrosis. Methods: We inferred immune cell type abundance of the ventricular samples by a computational method (CIBERSORTx) based on ventricular tissue samples from 103 patients with heart failure, and applied K-means clustering to divide patients into two subtypes based on their immune cell type abundance. We also designed a novel analytic strategy Large-Scale Functional Score and Association Analysis (LAFSAA), to study fibrotic mechanisms in the two subtypes. Results: Two subtypes of immune cell fractions pro-inflammatory and pro-remodeling subtypes, were identified. LAFSAA identified 11 subtype-specific pro-fibrotic functional gene sets as the basis for personalised targeted treatments. Based on feature selection, a 30-gene biomarker panel (ImmunCard30) established for diagnosing patient subtypes achieved high classification performance, with the area under the receiver operator characteristic curve corresponding to 0.954 and 0.803 for the discovery and validation sets, respectively. Conclusion: Patients with the two subtypes of cardiac immune cell fractions were likely having different fibrotic mechanisms. Patients' subtypes can be predicted based on the ImmunCard30 biomarker panel. We envision that our unique stratification strategy revealed in this study will unravel advance diagnostic techniques for personalised anti-fibrotic therapy.