Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction
Abstract
Aim Exercise intolerance is the central symptom in patients with heart failure with preserved ejection fraction. In the present study, we investigated the adrenergic reserve both in vivo and in cardiomyocytes of a murine cardiometabolic HFpEF model. Methods 12-week-old male C57BL/6J mice were fed regular chow (control) or a high-fat diet and L-NAME (HFpEF) for 15 weeks. At 27 weeks, we performed (stress) echocardiography and exercise testing and measured the adrenergic reserve and its modulation by nitric oxide and reactive oxygen species in left ventricular cardiomyocytes. Results HFpEF mice (preserved left ventricular ejection fraction, increased E/e', pulmonary congestion [wet lung weight/TL]) exhibited reduced exercise capacity and a reduction of stroke volume and cardiac output with adrenergic stress. In ventricular cardiomyocytes isolated from HFpEF mice, sarcomere shortening had a higher amplitude and faster relaxation compared to control animals. Increased shortening was caused by a shift of myofilament calcium sensitivity. With addition of isoproterenol, there were no differences in sarcomere function between HFpEF and control mice. This resulted in a reduced inotropic and lusitropic reserve in HFpEF cardiomyocytes. Preincubation with inhibitors of nitric oxide synthases or glutathione partially restored the adrenergic reserve in cardiomyocytes in HFpEF. Conclusion In this murine HFpEF model, the cardiac output reserve on adrenergic stimulation is impaired. In ventricular cardiomyocytes, we found a congruent loss of the adrenergic inotropic and lusitropic reserve. This was caused by increased contractility and faster relaxation at rest, partially mediated by nitro-oxidative signaling.
Citation
Semmler , L , Jeising , T , Huettemeister , J , Bathe-Peters , M , Georgoula , K , Roshanbin , R , Sander , P , Fu , S , Bode , D , Hohendanner , F , Pieske , B , Annibale , P , Schiattarella , G G , Oeing , C U & Heinzel , F R 2024 , ' Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction ' , Acta Physiologica , vol. Early View , e14124 . https://doi.org/10.1111/apha.14124
Publication
Acta Physiologica
Status
Peer reviewed
ISSN
1748-1708Type
Journal article
Description
This project is funded by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—SFB 1470—A01 to FRH and PA and A02 to GGS) and from the DZHK (German Centre for Cardiovascular Research to GGS). CUO is additionally funded by the DFG (OE 688/4-1).Collections
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