Abstract 10678: Butyrate Improves Energetics, Diastolic Function and Contractile Reserve in Hearts from Mice with Hypertrophic Cardiomyopathy Due to Myosin R403Q Mutation
| Autor: | Tomas Baka, Dominique Croteau, Jordan Chambers, Huamei He, James Balschi, Fuzhong Qin, Wilson S Colucci, David Pimentel, Ivan Luptak |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Circulation. 144 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background: It is well established that hearts with hypertrophic cardiomyopathy (HCM) are energy starved as reflected by a decreased phosphocreatine to ATP ratio that corresponds to increased ADP and decreased free energy of ATP hydrolysis (ΔG ~ATP ). Notably, worsened energetics precedes hypertrophy in development of HCM and mitochondrial mutations impeding ATP synthesis frequently lead to a hypertrophic phenotype similar to HCM. It remains unclear whether targeted strategies to boost mitochondrial ATP synthesis may improve chronically depressed diastolic function and contractile reserve. Here we hypothesize that saturating mitochondria with an accessible substrate, butyrate, acutely improves energetics and function in HCM. Methods and Results: Isolated hearts from 6 months old mice with HCM due to R403Q myosin mutation (R403Q) vs. the wild type littermates (WT) were studied using 31 P NMR spectroscopy to measure ATP synthesis, ADP and ΔG ~ATP at low (LW) and high workload (HW) and HW plus 4 mM butyrate (HWB). As expected, compared to WT, R403Q hearts showed: ↑ATP synthesis associated with a trend for ↑rate pressure product (RPP, p=0.08) at LW but were unable to increase these parameters further at HW. Energetics (↑ADP and ↓ΔG ~ATP ) were depressed at LW and worsened further at HW. Diastolic dysfunction (↑EDP) developed at HW. Butyrate perfusion (HWB) significantly improved all energetic and contractile parameters in R403Q hearts. Conclusion: Here we show that mouse hearts with HCM due to myosin R403Q mutation have worsened energetics despite a higher ATP synthesis rate at baseline. With higher work demand R403Q hearts are unable to dynamically increase ATP synthesis or work. Acute saturation with butyrate enables a further increase in ATP synthesis, normalizing energetics and improving diastolic function and contractile reserve. Thus, our results suggest that targeting mitochondrial function may be a promising strategy in management of HCM. |
| Databáze: | OpenAIRE |
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