Background: Numerous studies have demonstrated that NLRP3 inflammasomes are key players in the progression of atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF). This study aimed to analyse the effect of pharmacological inhibition of NLRP3 inflammasomes using dapansutrile (DAPA), an oral NLRP3-specific inhibitor.
Methods: Dahl salt-sensitive rats were fed a high-salt diet (HSD, 8% NaCl) to induce HFpEF. Either DAPA (200 mg/kg/day) or saline was administered daily via gavage for 4 weeks. Electrophysiological studies were performed to assess the AF inducibility. Confocal fluorescence microscopy and western blot analysis were used to study calcium handling.
Results: The DAPA-treated HFpEF rats were less prone to AF induction by programmed electrical stimulation. Atrial fibrosis and inflammation were attenuated in DAPA-treated HFpEF hearts. Dapansutrile treatment showed an increase in the Ca transient sarcoplasmic reticulum-Ca load, and protein expression of SERCA2; NCX1 and phosphorylation of PLB at Thr17 were decreased following DAPA treatment. The increased frequency of spontaneous Ca spark in the HFpEF rats was related to the hyperphosphorylation of RyR2 at Ser2814, which was blunted in DAPA treatment. Dapansutrile treatment also decreased the phosphorylation of CaMKII expression in the HFpEF rats. Mechanistically, DAPA exerts an anti-arrhythmic effect, mainly by inhibiting activation of the NLRP3 inflammasome.
Conclusion: These data provide evidence that the beneficial cardiac effects of DAPA are associated with reduced atrial inflammation and improved CaMKII-dependent Ca-handling abnormalities via blunting activation of the NLRP3 inflammasome, and DAPA may be beneficial in a rat model of HFpEF-induced AF.
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http://dx.doi.org/10.1016/j.hlc.2023.09.017 | DOI Listing |
Endocr Metab Immune Disord Drug Targets
January 2025
Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China.
Background: Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF.
View Article and Find Full Text PDFDiscov Med (Cham)
January 2025
Institute of Biomedical Engineering, University of Toronto, Toronto, ON Canada.
Background: Microvascular dysfunction (MVD) is a recognized sign of disease in heart failure progression. Intact blood vessels exhibit abnormal vasoreactivity in early stage, subsequently deteriorating to rarefaction and reduced perfusion. In managing heart failure with preserved ejection fraction (HFpEF), earlier diagnosis is key to improving management.
View Article and Find Full Text PDFCardiovasc Res
December 2024
Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago 8331150, Chile.
Aims: Heart failure (HF) is an emerging epidemic worldwide. Despite advances in treatment, the morbidity and mortality rate of HF remain high, and the global prevalence continues to rise. Common clinical features of HF include cardiac sympathoexcitation, disordered breathing, and kidney dysfunction; kidney dysfunction strongly contributes to sodium retention and fluid overload, leading to poor outcomes of HF patients.
View Article and Find Full Text PDFBackground: Recent reports suggest increased myocardial iNOS expression leads to excessive protein -nitrosylation, contributing to the pathophysiology of HFpEF. However, the relationship between NO bioavailability, dynamic regulation of protein -nitrosylation by trans- and de-nitrosylases, and HFpEF pathophysiology has not been elucidated. Here, we provide novel insights into the delicate interplay between NO bioavailability and protein -nitrosylation in HFpEF.
View Article and Find Full Text PDFESC Heart Fail
December 2024
Heart Center Dresden, Laboratory of Molecular and Experimental Cardiology, TU Dresden, Dresden, Germany.
Aims: ZSF1 obese rats harbouring two mutant leptin receptor alleles (Lepr and Lepr) develop metabolic syndrome and heart failure with preserved ejection fraction (HFpEF), making them a widely used animal model in cardiometabolic research. Studies using ZSF1 rats have contributed significantly to the elucidation of pathophysiological mechanisms underlying HFpEF and therapeutic strategies against this multi-organ syndrome. In contrast, hybrid, lean ZSF1 rats (L-ZSF1) do not develop HFpEF and generally serve as controls, disregarding the possibility that the presence of one mutant Lepr allele might affect left ventricular ejection fraction (LVEF), diastolic dysfunction and other relevant HFpEF parameters, such as N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and cardiac inflammation, which could increase during disease manifestation.
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