Abstract
Prognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.
Highlights
Prognosis of severe heart failure remains poor
Patients were classified as non-responders when the left ventricular ejection fraction (LVEF) did not show > 10% improvement on follow-up Ultrasonic echocardiography (UCG) performed at 7 and 15 months after biopsy (Fig. 1A)
Examination of the biopsy specimens by transmission Electron microscopy (EM) revealed that both the size and area of the mitochondria were significantly lower in the cardiomyocytes of non-responders than in those of responders, but the number of mitochondria was similar in the groups (Fig. 1B,C)
Summary
Prognosis of severe heart failure remains poor. Urgent new therapies are required. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn[1], was observed in non-responders. In vitro studies in NRVMs indicated negative regulation of Mfn[1] by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Therapies targeting mitochondrial dynamics and homeostasis are generation therapy for non-responding heart failure patients. Cardiac Mfn[1] expression is suppressed in non-responders together with reduction in the size and number of mitochondria in cardiomyocytes. Some progress has been made in this field, the prognosis of severe heart failure remains unacceptably poor and there is an urgent need to understand the pathology of this critical condition and discover new therapeutic targets. The clinical outcome is poor for non-responders and the mechanisms underlying such refractory heart failure are largely unknown
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