Effects of semaglutide and peptide YY in a rat model of heart failure with preserved ejection fraction: Focus on excitation-contraction coupling and mitochondrial function

Background Glucagon-like-peptide 1 receptor agonists are well-established in diabetes and obesity treatment, with semaglutide (SEMA) having the strongest body weight reducing effect. SEMA has proven beneficial effects on cardiovascular outcomes, especially on heart failure with preserved ejection fraction (HFpEF). Another incretin of increasing interest is peptide YY (PYY), especially PYY3-36, the most abundant circulating form mediating its anorexic effects via neuropeptide Y type 2 receptors. Due to its anorexic action, PYY alone and especially in combination with semaglutide might be useful in the treatment of HFpEF.

Methods and Results Male Wistar rats were fed standard chow (CO) for 16 weeks or high fat/fructose (HFD) diet combined with L-Name (0.25mg/ml) via drinking water for 8 weeks to induce obesity and HFpEF. HFD fed rats were then randomly assigned to receive SEMA (120μg/kg s.c.) plus PYY3-36 via osmotic minipump (0.1mg/kg/day) (HF+S&P) or PYY3-36 like before and saline s.c. (HF+PYY) or only saline s.c. (HF) for additional 8 weeks. Rats of the HF, HF+S&P and HF+PYY group could choose between HFD and low-fat diet ad libitum under treatment. Thereafter, cardiac ventricular myocytes (n=3 rats/group, min. 33 cells) and mitochondria (n=4-8 rats/group) were isolated. Sarcomere length (SL), cytosolic Ca²⁺ (Indo1, AM) and mitochondrial redox state (MRS: auto fluorescents NAD(P)H and FAD+), mitochondrial membrane potential (MMP: TMRM), and ROS (DCF) in myocytes was measured using Ionoptix fluorescence setups. Pacing at 0.3 Hz, followed by β-adrenergic stimulation and 3 Hz for 3 minutes, was used to subject cardiac myocytes to a physiological stress regimen. The HF group compared to CO showed a significantly shorter diastolic SL and increased diastolic and systolic [Ca²⁺]. Fractional shortening (FS) was comparable, while Ca-transient amplitude was increased in HF. MRS was more oxidized in the HF compared to the CO group, but MMP was more negative and more stable and ROS production was reduced. BNP blood levels were significantly increased in HF compared to CO. Both HF+S&P and HF+PYY, rescued diastolic SL. Additionally, HF+S&P rescued MRS, increased FS and reduced ROS production compared to CO. HF+PYY was not able to fully rescue the MRS, but increased ROS production compared to HF. The MMP was more stable and negative in the HF and HF+S&P group than in the CO group. In the HF+PYY group the MMP was more negative than in the HF group. In isolated mitochondria, mitochondrial respiration, Ca²⁺-retention capacity (Ca-Green), MMP (TMRM) and H₂O₂ production (AmplexRed) was examined. In HF+PYY mitochondrial respiration is rescued, independent of the substrate (pyruvate/malate, succinate, fatty acid-mix), while in HF+S&P not. MMP was more stable in the HF group compared HF+S&P and HF+PYY. The Ca²⁺-retention capacity was comparable in the HF+PYY and HF group, while it was lower in HF+S&P. H₂O₂ production was unchanged in HF+S&P as well as in HF+PYY, independent of the substrate.

Conclusions The treatment of rats with HFD and L-NAME is sufficient to generate Ca mishandling and mitochondrial dysfunction typical for HFpEF. A therapy with SEMA and PYY is able to rescue these typical HFpEF signs and reduce ROS burden. PYY alone only partially rescues typical HFpEF signs. While clinical data show beneficial effects of SEMA in HFpEF patients, effects of PYY are less clear. Additional studies are necessary to evaluate the effects of PYY in HFpEF.