Abstract 11846: Cardiac Mitofusin1 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 described as non-responders. The prognosis of non-responders is poor and it is our urgent task to understand the underlying mechanism and find new therapeutic targets for this critical condition. In this context, it is essential to find biological markers of non-responding patients. Here we show that mitochondrial size and number in cardiomyocytes is significantly reduced, and this condition associates with a low mitochondrial fusion marker in the cardiac tissue of non-responders with idiopathic dilated cardiomyopathy (IDCM). We examined 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 by the follow-up echocardiogram performed in 7-15months after the biopsy. No differences in the medications and age were observed between the groups. Transmission electron microscopy showed a significant reduction in both the size and number of mitochondria in the cardiomyocytes of non-responders (n=5) compared to responders (n=6) (0.2077±0.025 vs 0.2785±0.022μm 2 ; p<0.05, 250±32 vs 344±48 mitochondria/field; p<0.01). Quantitative PCR and immunofluorescence studies showed a significant reduction in mitofusin1, a critical regulator of mitochondrial fusion, but molecules involved in mitofission ( DNM1L and FIS1 ) and mitophagy ( BNIP3 and MAP1LC3A ) did not show difference between the groups. Studies with neonatal rat ventricular myocytes suggested that beta-1 adrenergic receptor mediated signaling pathway is critically involved in the regulation of Mfn1 , and the suppression of Mfn1 led to the significant reduction in mitochondrial respiration. We also found that cardiac ADRB1 is markedly reduced in non-responders. These results indicate that cardiac mitofusin1 would become a biomarker for non-responders in IDCM patients. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for heart failure patients.