Background: Risk stratification in patients with non-ischemic cardiomyopathy (NICM) comprising inflammatory (ICM) and dilative cardiomyopathy (DCM) is pivotal for optimal pharmacological and necessary device therapy at early stages of the disease. Several pro-inflammatory and pro-fibrotic markers comprising macrophage migration inhibitory factor (MIF), its endogenous antagonist Gremlin-1, CyclophylinA (CYPA), Emmprin, CXCL16, and CXCL12 are highly expressed in the inflamed and failing myocardium. Myocardial protein expression of these markers helps to identify high-risk patients with NICM for an unfavorable outcome. However, the impact of their myocardial protein and gene expression on local inflammation, fibrosis, apoptosis, and necrosis remains unclear.

Methods: We retrospectively analyzed 433 consecutive patients with new onset ICM (n=294) or DCM (n=139), who underwent endomyocardial biopsy for diagnostic and prognostic evaluation. Biopsy specimens were analyzed by established histopathological and immunohistochemical criteria along with gene expression using NanoString technology. Median follow up (FU) was 9.6 years. The primary endpoint was defined as all-cause mortality. The secondary EP was a combination of all-cause mortality, HF-related re-hospitalization, heart transplantation, sustained ventricular tachycardia and aborted sudden cardiac death.

Results: Baseline characteristics showed that patients with ICM were younger (p=0.010), presented more often with acute clinical symptoms indicated by NYHA class ≥ 2 (p=0.016), were characterized by less impaired LVEF (p<0.0001) and LVEDD (p<0.0001) and higher levels of troponin I (TNI) (p=0.036). Immunohistochemical analysis revealed increased numbers of CD68+ and CD3+ infiltrating inflammatory cells in ICM (p<0.0001). MIF, CYPA, CXCL16, and CXCL12 protein expression was significantly enhanced in patients with ICM (p < 0.05). Gene expression analysis detected differences in signaling pathways mediating inflammation, fibrosis, apoptosis, and necrosis. Proinflammatory as well as pro-fibrotic signaling was enhanced in patients with ICM. In particular, ICM was characterized by an upregulation of genes associated with inflammation and apoptosis (p<0.05). In DCM patients, signaling pathways associated with irreversible fibrosis were enhanced in gene expression analysis. During a mean follow-up of 9.6 years, 39 patients (9%) reached the primary EP. 109 patients reached the combined secondary EP. Overall prognosis was worse in DCM patients compared to ICM. However, subgroup analysis revealed that patients with ICM and significant upregulation of inflammatory pathways showed an even worse clinical outcome compared to DCM (p<0.05).

Conclusions: Endomyocardial protein and gene expression of markers of inflammation, fibrosis, and apoptosis show different expression patterns in ICM compared to DCM patients. Enhanced inflammatory gene expression in ICM identifies high-risk patients for adverse outcome within the group of ICM.