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Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway plays a key role in myocardial ischemia-reperfusion (I/R) injury. Mammalian target of rapamycin (mTOR), a downstream target of PI3K/AKT signaling, is necessary and sufficient to protect the heart from I/R injury. Inhaled anesthetic sevoflurane is widely used in cardiac surgeries because its induction and recovery are faster and smoother than other inhaled anesthetics. Sevoflurane proved capable of inducing postconditioning effects in the myocardium. However, the underlying molecular mechanisms for sevoflurane-induced postconditioning (SPC) were largely unclear. In the present study, we demonstrated that SPC protects myocardium from I/R injury with narrowed cardiac infarct focus, increased ATP content, and decreased cardiomyocyte apoptosis, which are mainly due to the activation of PI3K/AKT/mTOR signaling and the protection of mitochondrial energy metabolism. Application of dactolisib (BEZ235), a PI3K/mTOR dual inhibitor, abolishes the up-regulation of pho-AKT, pho-GSK, pho-mTOR, and pho-p70s6k induced by SPC, hence abrogating the anti-apoptotic effect of sevoflurane and reducing SPC-mediated protection of heart from I/R injury. As such, this study proved that PI3K/AKT/mTOR pathway plays an important role in SPC induced cardiac protection against I/R injury.

Background and PurposeMyocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R) in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC) in myocardial I/R is through restored impaired autophagic flux.MethodsExcept for the sham control (SHAM) group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by hemodynamics and echocardiography. The activation of autophagy was evaluated by autophagosome accumulation, LC3 conversion and p62 degradation. Potential molecular mechanisms were investigated by immunoblotting, real-time PCR and immunofluorescence staining.ResultsSPC improved the hemodynamic parameters, cardiac dysfunction, histopathological and ultrastructural damages, and decreased myocardial infarction size after myocardial I/R injury (P < 0.05 vs. I/R group). Compared with the cases in I/R group, myocardial ATP and NAD+ content, mitochondrial function related genes and proteins, and the expressions of SOD2 and HO-1 were increased, while the expressions of ROS and Vimentin were decreased in the SPC group (P < 0.05 vs. I/R group). SPC significantly activated Akt/mTOR signaling, and inhibited the formation of Vps34/Beclin1 complex via increasing expression of Bcl2 protein (P < 0.05 vs. I/R group). SPC suppressed elevated expressions of LC3 II/I ratio, Beclin1, Atg5 and Atg7 in I/R rat, which indicated that SPC inhibited over-activation of autophagy, and promoted autophagosome clearance. Meanwhile, SPC significantly suppressed the decline of Opa1 and increases of Drp1 and Parkin induced by I/R injury (P < 0.05 vs. I/R group). Moreover, SPC maintained the contents of ATP by reducing impaired mitochondria.ConclusionSPC protects rat hearts against I/R injury via ameliorating mitochondrial impairment, oxidative stress and rescuing autophagic clearance.

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Background/Aims: A combination sevoflurane postconditioning (SPC) and remote ischemic preconditioning (RIPC) is proved effective in an ex vivo rat heart perfusion model. However, the combined effect of those two interventions is not tested in rat myocardial ischemia/reperfusion (I/R) model, and the underlying mechanisms remain to be elucidated. This study aimed to investigate the effect in vivo using a rat myocardial I/R model and illuminate the related mechanisms. Methods: Forty male Sprague-Dawley rats were randomly divided into the following 5 groups: i) sham-operated control; ii) I/R; iii) I/R + RIPC; iv) I/R + SPC; v) I/R + RIPC + SPC. The hemodynamic parameters were recorded at the end of reperfusion. The histological changes including the infarct size were assessed using Triphenyltetrazolium chloride (TTC) staining and H&E staining. In addition, the circulating levels of cardiac enzymes (CK-MB, hs-cTnT, and cTnT) inflammatory cytokines (IL-6, IL-8, and TNF-α) were detected. The expression levels of apoptosis-related proteins (C-Caspase 3, PARP, Bax, and Bcl-2), proinflammatory factors (TLR4, HMGB-1, MyD88, and p65), and IKB-α were measured by Western blot analysis. Real-time PCR was performed to detect mRNA levels of the proinflammatory factors. Results: Both SPC and RIPC significantly reduced the infarct size, cardiac enzyme release, inflammatory cytokine secretion, and proinflammatory factor expression, and increased IKB-α expression compared to I/R group. Furthermore, the combination of those two strategies had synergic infarct size limiting and anti-inflammatory effects. Conclusions: The finding of this study suggested that the combination of SPC and RIPC had a potentially cardioprotective effect through inhibiting TLR4/MyD88/NF-κB signaling.

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Background: Epidemiological studies have shown that atrial fibrillation (AF) is a potential cardiovascular complication of coronavirus disease 2019 (COVID-19). We aimed to perform a systematic review and meta-analysis to clarify the prevalence and clinical impact of AF and new-onset AF in patients with COVID-19.Methods: PubMed, Embase, the Cochrane Library, and MedRxiv up to February 27, 2021, were searched to identify studies that reported the prevalence and clinical impact of AF and new-onset AF in patients with COVID-19. The study was registered with PROSPERO (CRD42021238423).Results: Nineteen eligible studies were included with a total of 21,653 hospitalized patients. The pooled prevalence of AF was 11% in patients with COVID-19. Older (≥60 years of age) patients with COVID-19 had a nearly 2.5-fold higher prevalence of AF than younger (&lt;60 years of age) patients with COVID-19 (13 vs. 5%). Europeans had the highest prevalence of AF (15%), followed by Americans (11%), Asians (6%), and Africans (2%). The prevalence of AF in patients with severe COVID-19 was 6-fold higher than in patients with non-severe COVID-19 (19 vs. 3%). Furthermore, AF (OR: 2.98, 95% CI: 1.91 to 4.66) and new-onset AF (OR: 2.32, 95% CI: 1.60 to 3.37) were significantly associated with an increased risk of all-cause mortality among patients with COVID-19.Conclusion: AF is quite common among hospitalized patients with COVID-19, particularly among older (≥60 years of age) patients with COVID-19 and patients with severe COVID-19. Moreover, AF and new-onset AF were independently associated with an increased risk of all-cause mortality among hospitalized patients with COVID-19.

Background The associations between vitamin D and coronavirus disease 2019 (COVID-19) infection and clinical outcomes are controversial. The efficacy of vitamin D supplementation in COVID-19 is also not clear. Methods We identified relevant cohort studies that assessed the relationship between vitamin D, COVID-19 infection and associated death and randomized controlled trials (RCTs) that reported vitamin D supplementation on the outcomes in patients with COVID-19 by searching the PubMed, EMBASE, and medRxiv databases up to June 5th, 2021. Evidence quality levels and recommendations were assessed using the GRADE system. Results Eleven cohort studies with 536,105 patients and two RCTs were identified. Vitamin D deficiency (< 20 ng/ml) or insufficiency (< 30 ng/ml) was not associated with an significant increased risk of COVID-19 infection (OR for < 20 ng/ml: 1.61, 95% CI: 0.92–2.80, I2 = 92%) or in-hospital death (OR for < 20 ng/ml: 2.18, 95% CI: 0.91–5.26, I2 = 72%; OR for < 30 ng/ml: 3.07, 95% CI: 0.64–14.78, I2 = 66%). Each 10 ng/ml increase in serum vitamin D was not associated with a significant decreased risk of COVID-19 infection (OR: 0.92, 95% CI: 0.79–1.08, I2 = 98%) or death (OR: 0.65, 95% CI: 0.40–1.06, I2 = 79%). The overall quality of evidence (GRADE) for COVID-19 infection and associated death was very low. Vitamin D supplements did not significantly decrease death (OR: 0.57, I2 = 64%) or ICU admission (OR: 0.14, I2 = 90%) in patients with COVID-19. The level of evidence as qualified using GRADE was low. Conclusions Current evidence suggested that vitamin D deficiency or insufficiency was not significantly linked to susceptibility to COVID-19 infection or its associated death. Vitamin D supplements did not significantly improve clinical outcomes in patients with COVID-19. The overall GRADE evidence quality was low, we suggest that vitamin D supplementation was not recommended for patients with COVID-19.