Cardiac Mitochondrial Fusion Related Protein Level Predicts the Response to the Treatment of Heart Failure among Patients with Idiopathic Dilated Cardiomyopathy

Medications targeting cardiac remodeling have become first-line therapy for heart failure. Some patients do not respond to the established treatment and are described as non-responders. We examined idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum. Patients were classified as non-responders when their left-ventricular (LV) ejection fraction and LV end-diastolic dimension did not show more than 10% improvement after biopsy. Quantitative PCR and immunofluorescence studies revealed that expression of mitochondrial fusion related protein(MFRP), a critical regulator of mitochondrial fusion, was significantly down-regulated in non-responders, but expression of molecules involved in mitofission (DNM1L and FIS1) or mitophagy (BNIP3 and MAP1LC3A) did not differ between the groups. Studies with neonatal rat ventricular myocytes indicated that the beta-1 adrenergic receptor-mediated signaling pathway positively regulates MFRP expression, and suppression of MFRP caused a significant reduction in mitochondrial respiration of cardiomyocytes. We also found that expression of the beta-1 adrenergic receptor was markedly reduced in cardiac tissues of non-responders. These results indicate that cardiac MFRP would become a biomarker for non-responders with IDCM. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for severe heart failure patients.