Protection with LCZ696 (sacubitril/valsartan) against diastolic dysfunction and cardiac fibrosis in high-fat diet/streptozotocin mouse model

Introduction: Diabetic cardiomyopathy (DCM) involves complex pathophysiology with substantial changes at cellular and molecular level within the heart. Treatment options for DCM are limited; however, LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor (ARNI), may have therapeutic potential to improve diabetes-induced heart failure.

Objectives: We aimed to elucidate the cardio-protective effect of LCZ696 on diabetes induced heart failure in a well-established mouse model of DCM.

Methods: DCM was induced in male C57BL/6J mice following a high-fat diet (HFD) and a single dose of 100 mg/kg streptozotocin (STZ). LCZ696 (100 mg/kg/day) or valsartan(50 mg/kg/day) was added to drinking water. Echocardiography was performed to evaluate left ventricle (LV) function and cardiac structure. Collagen I and III gene expression were measured by RT-qPCR.

Results: The DCM phenotype in the HFD/STZ mouse model was characterised by diastolic dysfunction and LV hypertrophy, along with preserved ejection fraction. Mice treated with LCZ696 for 12 weeks showed improvement in diastolic function and cardiac fibrosis, compared with the valsartan treatment (p < 0.05). The MV E/A ratio is the first diastolic parameter change after 4 weeks of LCZ696 treatment. Moreover, LCZ696 illustrated prevention of chronic progression of DCM by decreased left atrial volume and left atrial area. The cardiac fibrosis markers, collagen I and III, were suppressed by LCZ696but not valsartan treatment. Neprilysin activity in the heart and plasma was inhibited by LCZ696 and comparable to control.

Conclusions: LCZ696 treatment improved diastolic dysfunction and cardiac fibrosis in the context of DCM. These beneficial effects may result from inhibiting the neprilysin enzyme which degrades several substrates related to cardiovascular diseases.