Rationale: Over 50% of heart failure patients have preserved, rather than reduced ejection fraction (HFpEF vs. HFrEF). Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. Objective: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model.Methods and Results: By combining the age, long-term high-fat diet and desoxycorticosterone pivalate challenge in a mouse model we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of interleukin (IL)-1β/IL-18, and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate (β-OHB) level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokines-triggered mitochondrial dysfunction and fibrosis. Moreover, β-OHB downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of citrate synthase and inhibition of fatty acid uptake. Conclusions: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis which can be ameliorated by promoting β-OHB abundance.

Introduction Abnormal coagulation function has been demonstrated to be involved in the disease progression of COVID-19. However, the association between D-dimer levels and the severity of COVID-19 is not clear. The study was aimed to investigate the association between D-dimer levels and the severity of COVID-19 based on a cohort study and meta-analysis. Materials and methods Demographic and clinical data of all confirmed cases with COVID-19 on admission to Tongji Hospital from January 27 to March 5, 2020, were collected and analyzed, and coagulation function parameters were described and compared between patients with severe infection and those with non-severe infection. Cohort studies reporting risk estimates for the D-dimer and severity of COVID-19 association were searched and included to perform a meta-analysis. Results In our cohort study, patients with severe disease were more likely to exhibit dysregulated coagulation function, and a significantly higher D-dimer level (median 1.8 μg/ml [interquartile range 0.9–4.6] vs 0.5 [0.3–1.1], p < 0.001) was found in severe cases than the mild ones, on admission. In the meta-analysis of 13 cohort studies (including the current study), patients with severe disease had an increase in mean D-dimer value by 0.91 (95% confidence interval, 0.51–1.31, p < 0.001) μg/ml compared to those with non-severe disease, and odds of severe infection was associated with D-dimer greater than 0.5 μg/ml (odds ratio = 5.78, 95% confidence interval, 2.16–15.44, p < 0.001) on admission. Conclusions Patients with severe COVID-19 have a higher level of D-dimer than those with non-severe disease, and D-dimer greater than 0.5 μg/ml is associated with severe infection in patients with COVID-19.

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