Background:
Risk stratification in patients with non-ischemic cardiomyopathy comprising inflammatory (ICM) and dilative cardiomyopathy (DCM) is pivotal for optimal pharmacological and necessary device therapy at early stages of the disease. CXCL12 is an inflammatory chemokine expressed in the inflamed and failing myocardium. Myocardial CXCL12 protein expression identifies high-risk patients with suspected myocarditis. However, the impact of myocardial 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 analysis of 607 pre-specified genes 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). CXCL12 protein expression was significantly enhanced in patients with ICM (p < 0.001). Gene expression analysis detected differences in signaling pathways mediating inflammation, fibrosis, apoptosis, and necrosis. In detail, proinflammatory interleukin-6 (IL6)- and macrophage migration inhibitory factor (MIF)-related signaling as well as pro-fibrotic transforming growth factor beta 1(TGF-ß1)-related signaling was enhanced in patients with ICM.  Gene expression of inflammatory (CXCL12, MIF, C3, CD14), hypoxic (ETs1), and apoptotic (RAF1, STAT1, MAPK1) markers were significantly upregulated in ICM, while caspase 2 and 3, NFkB, IL1, IL13, IL17B, IL19, IL22, IL23R, TLR1, CXCL1, CXCL9, CXCR1, CXCR2 and CXCR4 were downregulated in ICM compared to DCM. During a mean follow-up of 9.6 years, 39 patients (9%) died and reached the primary EP. 109 patients reached the combined secondary EP. On cox regression analysis LVEF<35%, TNI levels >0,1ng/mL, increased CXCL12 and STAT1 genes expression remained independent predictors of all-cause mortality in the patient cohort. Overall prognosis is worse in DCM patients compared to ICM. However, subgroup analysis revealed that patients with ICM and significant CXCL12 upregulation show even worse clinical outcome compared to DCM (p=0.005).

Conclusions:
Endomyocardial gene expression of markers of inflammation, fibrosis, apoptosis, and necrosis show different expression patterns in ICM compared to DCM patients. CXCL12 gene expression is enhanced in ICM and identifies high-risk patients for adverse outcome within the group of ICM. CXCL12 serves as a predictor of mortality in both, patients with ICM and DCM.