Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction
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]
DOI:
10.1111/apha.14124
Publication Date:
2024-03-04T10:06:30Z
AUTHORS (15)
ABSTRACT
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.
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