Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure-volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber. Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance. Using phospho-site-specific antibodies, we assay the phosphorylation of titin's PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin's stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness.
Highlights
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with preserved systolic function but diastolic stiffening that contributes to filling abnormalities
Effect of metformin on diastolic left ventricular (LV) function of mice with HFpEF-like symptoms To create an HFpEF-like state in the mouse, we induced a mineralocorticoid excess (DOCA pellet implantation) in the presence of chronic pressure overload (TAC surgery)
Mice treated with metformin for 5 wk after the transverse aortic constriction (TAC)/ deoxycorticosterone acetate (DOCA) procedure demonstrated that metformin did not affect the increased afterload experienced by TAC/DOCA hearts or the LV hypertrophy response, because end systolic LV pressures were comparable between TAC/DOCA groups (Table S1)
Summary
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with preserved systolic function but diastolic stiffening that contributes to filling abnormalities. The culmination of these changes is left ventricular (LV) hypertrophy, decreased cardiac reserve, and pulmonary edema (Norman et al, 2011; Borlaug, 2014). Studies on myocardial biopsies from HFpEF patients have revealed alterations in myocardial structure, function, and signaling These alterations include cardiomyocyte hypertrophy and interstitial fibrosis, increased cardiomyocyte stiffness, and down-regulation of cyclic guanosine monophosphate–protein kinase G (cGMP-PKG; Yusuf et al, 2003; Linke and Hamdani, 2014; van Heerebeek and Paulus, 2016).
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