Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox‐induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox‐induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol‐requiring enzyme 1α (IRE1α)/spliced X‐box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox‐treated hearts. CaMKII inhibition with KN‐93 ameliorated Dox‐induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox‐induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox‐treated hearts. The IRE1α inhibitor 4μ8C blocked the protective effect of CaMKII inhibition against Dox‐induced cardiotoxicity. Mechanistically, 4μ8C prevented the effects of CaMKII inhibition on Dox‐induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox‐treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13‐TSP1 axis regulates CaMKII activation and exacerbates Dox‐induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.

Diabetic cardiomyopathy (DCM) is a chronic microvascular complication of diabetes that is generally defined as ventricular dysfunction occurring in patients with diabetes and unrelated to known causes. Several mechanisms have been proposed to contribute to the occurrence and persistence of DCM, in which oxidative stress and autophagy play a non‐negligible role. Diabetic cardiomyopathy is involved in a variety of physiological and pathological processes. The 5′ adenosine monophosphate‐activated protein kinase/nuclear factor‐erythroid 2‐related factor 2 (AMPK/Nrf2) are expressed in the heart, and studies have shown that asiaticoside (ASI) and activated AMPK/Nrf2 have a protective effect on the myocardium. However, the roles of ASI and AMPK/Nrf2 in DCM are unknown. The intraperitoneal injection of streptozotocin (STZ) and high‐fat feed were used to establish the DCM models in 100 C57/BL mice. Asiaticoside and inhibitors of AMPK/Nrf2 were used for intervention. Cardiac function, oxidative stress, and autophagy were measured in mice. DCM mice displayed increased levels of oxidative stress while autophagy levels declined. In addition, AMPK/Nrf2 was activated in DCM mice with ASI intervention. Further, we discovered that AMPK/Nrf2 inhibition blocked the protective effect of ASI by compound C and treatment with ML‐385. The present study demonstrates that ASI exerts a protective effect against DCM via the potential activation of the AMPK/Nrf2 pathway. Asiaticoside is a potential therapeutic target for DCM.

Although reperfusion is the most effective therapy for patients with acute myocardial infarction, reperfusion injury limits the therapeutic effects of early reperfusion. Oxidative stress plays a crucial role in myocardial ischaemia/reperfusion (I/R) injury. Melatonin, a circulating hormone, is well‐known as an antioxidant in cardiovascular diseases. In this short communication, we show that melatonin significantly improves post‐ischaemic cardiac function, reduces infarct size and decreases oxidative stress. Furthermore, melatonin markedly increases AMPK activation and Nrf2 nuclear translocation. Nevertheless, these melatonin‐induced changes are abrogated by compound C. In addition, ML‐385, an Nrf2 inhibitor, also withdraws the antioxidative effects of melatonin but has little effect on AMPK activation. In conclusion, our results demonstrate that melatonin alleviates myocardial I/R injury by inhibiting oxidative stress via the AMPK/Nrf2 signalling pathway.

This study was designed to investigate whether berbamine (BA)‐induced cardioprotective effects were related to 5′ adenosine monophosphate‐activated protein kinase (AMPK)/nuclear factor erythroid 2‐related factor (Nrf2) signaling and changes in the mitochondria in myocardial ischemia/reperfusion (I/R) injury. C57/BL6 mice were exposed to BA (10 mg/kg/d), with or without administration of the AMPK specific inhibitor compound C (5 mg/kg/d) or the Nrf2 specific inhibitor ML‐385 (30 mg/kg/d), and then subjected to a myocardial I/R operation. As expected, BA significantly improved post‐ischemic cardiac function, reduced infarct size and apoptotic cell death, decreased oxidative stress, and improved the mitochondrial state. Furthermore, BA markedly increased AMPK activation, Nrf2 nuclear translocation, and the levels of NAD(P)H quinone dehydrogenase and heme oxygenase‐1. Nevertheless, these BA‐induced changes were abrogated by compound C. In addition, ML‐385 also canceled the cardioprotective effects of BA but had little effect on AMPK activation. Our results demonstrate that BA alleviates myocardial I/R injury and the mitochondrial state by inhibiting apoptosis and oxidative stress via the AMPK/Nrf2 signaling pathway.

Objectives. The purpose of this study was to review the experiences with transcatheter closure of mitral PVL after surgical valve replacement. Background. Transcatheter closure of paravalvular leak (PVL) is an intricate alternative to surgical closure. But it represents one of the most intricate procedures in the field of structural heart interventions, especially for patients with mitral PVL. Methods. From January 2015 through January 2019, 35 patients with mitral PVL after valve replacement underwent transcatheter closure. We reviewed the catheter techniques, perioperative characteristics, and prognosis. The median follow-up was 26 (348) months. Results. Acute procedural success was achieved in 33/35 (94.3) patients. Twenty-five patients had single mitral prosthetic valve replacements; 10 had combined aortic and mitral prosthetic valve replacements previously; 28 had mechanical valves; and 7 had bioprosthetic valves. All percutaneous procedures were performed with local anesthesia except for seven transapical cases with general anesthesia. Multiple approaches were used: transfemoral, transapical, and transseptal via an arteriovenous loop. Multiple devices were deployed. There were no hospital deaths. The procedural time was 67300 (124±62) minutes. Fluoroscopic time was 1750 (23.6±12.1) minutes. The hospital stay was 517 (8.3±3.2) days. Complications included recurrent hemolysis, residual regurgitation, acute renal insufficiency, and anemia. Twenty-seven (77.1) patients improved by 1 New York Heart Association functional class at the 1-year follow-up. Conclusions. Transcatheter mitral PVL closure requires complex catheter techniques. However, this minimally invasive treatment could provide reliable outcomes and shorter hospital stays in selected patients. This trial is registered with NCT02917980.

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