Background: We have introduced skeletal myoblast cell sheet (SMBs) transplantation for treating severe heart failure (HF) to maximize the paracrine effects, which enhance the native regenerative process of failing heart. However, because this treatment may target to such orphan diseases like non-ischemic dilated cardiomyopathy (NIDCM), how to select NIDCM patients responding to this treatment is essential to achieve satisfactory outcomes. We hypothesized that preoperative factors including epigenetic modification in the ventricular tissue may be associated with clinical outcome of SMBs transplantation for NIDCM.
Methods: Twenty-four NIDCM patients with low ejection fraction less than 35% underwent SMBs transplantation (average: 3.8±2.2х108 cells) via the left thoracotomy without concomitant procedures. Preoperatively biopsied cardiac tissue was immunohistologically labeled by histone3 lysine 4 tri-methylation (H3K4me3) indicating cardiomyocyte viability and the percentage of positive staining cardiac cell nuclei was evaluated.
Results: Postoperatively, 5 patients necessitated LVAD implantation and 2 patients died of HF and 3 patients showed increasing of incidence of HF (Group N), whereas 14 patients had no cardiac event and decreasing of incidence of HF compared with pre value (Group R). Preoperative NYHA classification, BNP level and pulmonary capillary wedge pressure were significantly lower in the patients in Group R (2.5±0.5 vs. 3.0±0.5 p=0.03, 257±181 vs. 560±348 pg/dl, p =0.03 and 8.9±4.3 vs. 15.6±7.3 p=0.02, respectively). Furthermore, the positive rate of H3K4me3 was significantly higher in Group R (84.0±8.0 vs. 69.4±10.9 p=0.01). Multivariate analysis demonstrated the positive rate of H3K4me3 was independent predictor of responder of SMBc implantation (hazard ratio=0.82, p=0.04). In the Group R, their NYHA classification, BNP level and 6 minutes’ walk distance were significantly improved at 1year after SMBs transplantation.
Conclusion: Maintained histone methylation in cardiomyocytes strongly correlated with good clinical outcome and functional recovery after SMBs transplantation in NIDCM, suggesting that epigenetic parameters may indicate good responder to paracrine effect of SMBs transplantation.