Abstract
BACKGROUND: Fibrocytes are bone marrow-derived mesenchymal progenitors that have been linked to various fibrotic disorders. This study was undertaken to investigate whether fibrocytes are increased in diffuse myocardial fibrosis in humans. METHODS AND RESULTS: Thirty-seven patients with hypertrophic cardiomyopathy (HCM) and 20 healthy controls were recruited. Cardiac magnetic resonance imaging with postcontrast T1 mapping was performed to non-invasively quantify diffuse myocardial fibrosis and these patients were classified into 2 groups (T1 < 470 ms or T1 ≥ 470 ms, as likely or unlikely to have diffuse fibrosis, respectively). Circulating fibrocytes (CD45+/CD34+/collagen I+) were measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were cultured for 13 days and fibrocytes were quantitated by flow cytometry (CD45+/collagen I+) and real-time PCR (gene expression of matrix proteins). Plasma cytokines/chemokines mediating fibrocyte trafficking and differentiation were measured by multiplex assays. Circulating fibrocytes were decreased in HCM patients compared to controls. The proportion of fibrocytes derived from PBMCs was increased in patients with diffuse fibrosis compared with those without or controls (31.1 ± 4.1% versus 18.9 ± 3.9% and 10.9 ± 2.0%, P < 0.05 and P < 0.001, respectively), and the proportion of fibrocytes was inversely correlated with T1 time (r = -0.37, P = 0.03). Plasma levels of stromal cell-derived factor-1 were elevated in patients with diffuse fibrosis compared with those without or controls (5131 ± 271 pg/mL versus 3893 ± 356 pg/mL and 4172 ± 185 pg/mL, respectively, both P < 0.05). CONCLUSIONS: HCM patients with diffuse fibrosis as assessed by postcontrast T1 mapping have elevated plasma SDF and an enhanced ability of PBMCs to differentiate into fibrocytes, suggesting that fibrocytes may contribute to the pathogenesis of myocardial fibrosis.