Metformin Reduces Left Ventricular Eccentric Re-modeling In Experimental volume Overload in the Rat

Abstract

Aims: Left ventricular hypertrophy (LVH) is often associated with a change in myocardial energy substrate preference from fatty acids to glucose. A possible antihypertrophic treatment strategy could aim at stimulating or restoring normal myocardial energy metabolism. Metformin, an adenosine monophosphate-activated protein kinase (AMPK) activator used in the management of glucose metabolism in diabetes, is also a fatty acid oxidation stimulator. The effect of metformin on the development of eccentric LVH and ventricular function in chronic left ventricular (LV) volume overload (VO) is unknown. This study was designed to study this question in a VO rat model caused by severe aortic valve regurgitation (AR). Methods:Male Wistar rats were divided in four groups (13-15 animals / group): Shams (S) treated or not (C) with metformin (M; 100 mg/kg/d PO) and severe AR receiving or not metformin. Treatment was started one week before surgery and the animals were sacrificed 9 weeks later. Results:As expected AR rats developed severe eccentric LVH during the course of the protocol. Metformin treatment did not influence the total heart weight. However, LV remodeling associated with the severe VO was severe in ARM than in ARC. Fractional shortening, a marker of systolic function, was significantly higher in ARM compared to ARC group. Metformin also increased the activity of enzymes associated with fatty acid oxidation while inhibiting phosphofructokinase, a glycolytic enzyme. Conclusion:A 2 month treatment with metformin reduced LV eccentric remodeling associated with severe VO and helped maintain a better systolic function.

Angiotensin II–Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling, and Myocardial Energetics in Experimental Aortic Regurgitation

“…We have recently reported this shift in substrate uptake in 8-week AR animals. 25 We observed that myocardial glucose uptake was increased, whereas fatty acid was reduced in those animals. The overall myocardial oxidative capacity remained unchanged.…”

“…32 We have recently shown in the same animal model that LV remodeling can be influenced by diet manipulation and by drugs, such as metformin and fenofibrate, which have significant metabolic effects, whereas lacking any hemodynamic effects. 17,25 This suggests that manipulating myocardial metabolism without hemodynamic effects can impact LV remodeling in AR.…”

Chronic high-fat diet-induced obesity decreased survival and increased hypertrophy of rats with experimental eccentric hypertrophy from chronic aortic regurgitation

“…We have previously showed that eccentric LVH caused by severe AR was associated with a shift in energy substrates preference from fatty acids to glucose [ 14 , 15 , 21 ]. Hydroxyacyl-Coenzyme A dehydrogenase (HADH) was reduced in AR animals (Figure 6 A).…”

“…It is possible that a synergy between hemodynamic overload, diet and hypertrophy which are all pro-hypertrophic factors exist but the mechanisms for the increased hypertrophy in AR rats fed with the HF diet remain unclear. We observed in the past that the Erk 1/2 and Stat3 pathways are activated in AR [ 14 , 15 , 33 ]. We did not observe such an activation for the Akt/mTOR pathway in the short protocols (8 weeks) but we did in longer ones (current and [ 34 ]).…”

“…Small pieces of LV (20-30 mg) were homogenized in a glass-glass homogenizer with 9 or 39 volumes of ice-cold extracting medium pH7.4 (250 mM sucrose, 10 mM Tris–HCl, 1 mM EGTA) depending on the enzyme activity assayed. Enzymatic activities were determined as previously described [ 14 , 15 ].…”