Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction

• DOI: 10.1111/apha.14124
• Publication Date: 2024-03-04T10:06:30Z
• Authors: Lukas Semmler; Tobias Jeising; Judith Huettemeister; Marc Bathe‐Peters; Konstantina Georg...; Rashin Roshanbin; Paulina Sander; Shu Fu; David Bode; Felix Hohendanner; Burkert Pieske; Paolo Annibale; Gabriele G. Schia...; Christian U. Oeing; Frank R. Heinzel
• Keywords: Male; 0301 basic medicine; RM; Exercise intolerance; 610; Nitric Oxide; Ventricular Function, Left; Mice; Adrenergic Agents; 0302 clinical medicine; Humans; Animals; Heart Failure; Cardiac output reserve; 600; Stroke Volume; Nitro-oxidative signaling; Molecular Processes and Therapies [Topic 2]; RM Therapeutics. Pharmacology; Mice, Inbred C57BL; RR-NDAS; Disease Models, Animal; Heart failure with preserved ejection fraction; Adrenergic signaling; Cardiovascular and Metabolic Diseases; Integrative Biomedicine [Topic 3]

AbstractAimExercise 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.Methods12‐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.ResultsHFpEF 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.ConclusionIn 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.