HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy

Background Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro. Methods and Results We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (P<0.0001). Echocardiography showed that left ventricular end-diastolic diameter tends to decrease over time (58±7.3 to 51±6.6 mm; P<0.0001) in the low HE4 group (<59.65 pmol/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4-transfected human embryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis-related genes, and this was accompanied by the activation of extracellular signal-regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal-regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. Conclusions HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr; Unique identifier: UMIN000043062.