Large cardiovascular outcome trials have reported favorable effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on heart failure. To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin-induced cardiomyopathy model and identified the toll-like receptor 9 (TLR9), NAD-dependent deacetylase sirtuin-3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. The interactions and implications in mitochondrial function were evaluated with TLR9 deficient, SIRT3 deficient, Beclin 1 haplodeficient, and autophagy reporter mice and confirmed in a patient with SIRT3 point mutation and reduced enzymatic activity. The SGLT2 inhibitor, empagliflozin, protects the heart from doxorubicin cardiomyopathy in mice, by acting through a novel Beclin 1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. TLR9 and SIRT3 were both essential for the protective effects of empagliflozin. The dilated cardiomyopathy patient with SIRT3 point mutation and reduced enzymatic activity is associated with reduced TLR9 activation and the absence of mitochondrial responses in the heart after the SGLT2 inhibitor treatment. Our data indicate a dynamic communication between autophagy and Beclin 1-TLR9-SIRT3 complexes in the mitochondria in response to empagliflozin that may serve as a potential treatment strategy for heart failure.

Acute myocardial infarction (AMI) complicated by cardiogenic shock has high mortality and remains challenging even in the revascularization era. We conducted this study to understand patients’ outcomes. We retrospectively analyzed electronic medical records data from 1175 patients with AMI complicated by cardiogenic shock that developed within 3 days of admission to a multicenter medical care system between January 1, 2000, and July 31, 2018. Patients with AMI were classified into the ST-segment elevation MI (STEMI) group or the non-ST-segment elevation MI (NSTEMI) group. The short-term and 1-year mortality and adverse events after index admission were analyzed via logistic regression and a Cox proportional hazards model. When compared with NSTEMI, patients with STEMI tended to be younger (65.68 ± 14.05 years vs 70.70 ± 12.99 years, P < .001), men (73.29% vs 60.87%, P < .001), and have fewer underlying chronic diseases. Short-term mortality at index hospitalization was 14.83% in the STEMI group and 21.30% in the NSTEMI group; long-term mortality was 17.06% for the STEMI group and 24.13% for the NSTEMI group. No difference was observed between the 2 groups for patients who developed a cerebral vascular accident during the admission period. However, the major and gastrointestinal bleeding rates were higher in the STEMI group (2.66% vs 0.22%, P = .014; 3.36% vs 0.22%, P = .007, respectively). Age and respiratory failure were the most significant risk factors for short-term mortality. Revascularization may be beneficial for the short-term outcome but did not reach significance in multivariable analysis. In patients with AMI with cardiogenic shock, NSTEMI was associated with a significantly higher mortality rate in short-term results.

The comparison of clinical effectiveness and safety across different nonvitamin K antagonist direct oral anticoagulants (DOACs) in Asian patients with venous thromboembolism (VTE) remains unclear. Therefore, we assessed the real-world benefits of different DOACs in these patients. A cohort of 1480 patients with VTE were identified from the Chang Gung Research Database between 1 January 2012, and 31 December 2019. The composite outcomes of recurrent VTE and major bleeding were evaluated for four DOACs. The composite outcomes of recurrent VTE and major bleeding occurred in 9.06%, 9.80%, 8.61%, and 10.86% of the apixaban, dabigatran, edoxaban, and rivaroxaban groups, respectively, within 12 months of treatment initiation. The risk of the composite outcomes was similar in the rivaroxaban group and the apixaban, dabigatran, and edoxaban groups, with a subdistribution hazard ratio (SHR) of 0.80 (95% CI, 0.49–1.29), 0.81 (95% CI, 0.34–1.95), and 0.76 (95% CI, 0.42–1.39), respectively. No significant differences in the rates of recurrent VTE or major bleeding were observed between the rivaroxaban and other DOAC groups at the 12-month follow-up. According to real-world practice in Asian patients with VTE, the DOAC type was not associated with the differences in the risk of recurrent VTE or major bleeding within 12 months of treatment initiation.