Identification of key potential risk areas and key potential failure modes in hemodialysis rooms by the FMEA method following routine prevention and control of the COVID-19 pandemic.

Hemodialysis is an important part of nosocomial infection prevention and control (IPC). This study aimed to identify the key potential risk areas and failure modes in hemodialysis rooms in hospitals and put forward a series of improvement measures to prevent and control the spread of the coronavirus disease 2019 (COVID-19). Hemodialysis patients are highly susceptible to COVID-19 and usually have a high incidence of severe illness and mortality after infection with COVID-19. Therefore, IPC in hemodialysis patients is of crucial strategic significance. Based on 30 domain experts' interviews and careful analysis of prevention and control documents, we constructed a comprehensive failure system for a model that identifies the potential risks for nosocomial COVID-19 infection in the hemodialysis room. Subsequently, a thorough risk assessment of the potential failure factors identified in our model was conducted. The failure key factors corresponding to the human element in medical waste (garbage) disposal (C2) are verified to be the highest risk factors. They are as follows: The cleaning staff did not dispose of different types of medical waste (garbage) (C21), did not wear masks according to the regulations (C22), and lacked knowledge and norms of nosocomial IPC (C23). This study provides valuable insights for hospital decision-makers on the potential failure factors related to COVID-19 infections in hemodialysis rooms. By working with hospital infection specialists, the suggested improvement measures can help reduce the risk of virus exposure among hospital medical staff, patients, and cleaning staff.

Identification of key potential infection processes and risk factors in the computed tomography examination process by FMEA method under COVID-19.

PURPOSE: To identify the key infection processes and risk factors in Computed Tomography (CT) examination process within the standard prevention and control measures for the COVID-19 epidemic, aiming to mitigate cross-infection occurrences in the hospital. METHOD: The case hospital has assembled a team of 30 experts specialized in CT examination. Based on the CT examination process, the potential failure modes were assessed from the perspective of severity (S), occurrence probability (O), and detectability (D); they were then combined with corresponding risk prevention measures. Finally, key infection processes and risk factors were identified according to the risk priority number (RPN) and expert analysis. RESULTS: Through the application of RPN and further analysis, four key potential infection processes were identified, including "CT request form (A1)," "during the scan of CT patient (B2)," "CT room and objects disposal (C2)," and "medical waste (garbage) disposal (C3)". In addition, eight key risk factors were also identified, including "cleaning personnel does not wear masks normatively (C32)," "nurse does not select the vein well, resulting in extravasation of the peripheral vein for enhanced CT (B25)," "patient cannot find the CT room (A13)," "patient has obtained a CT request form but does not know the procedure (A12)," "patient is too unwell to continue with the CT scan (B24)," "auxiliary staff (or technician) does not have a good grasp of the sterilization and disinfection standards (C21)," "auxiliary staff (or technician) does not sterilize the CT machine thoroughly (C22)," and "cleaning personnel lacks of knowledge of COVID-19 prevention and control (C33)". CONCLUSION: Hospitals can publicize the precautions regarding CT examination through various channels, reducing the incidence of CT examination failure. Hospitals' cleaning services are usually outsourced, and the educational background of the staff employed in these services is generally not high. Therefore, during training and communication, it is more necessary to provide a series of scope and training programs that are aligned with their understanding level. The model developed in this study effectively identifies the key infection prevention process and critical risk factors, enhancing the safety of medical staff and patients. This has significant research implications for the potential epidemic of major infectious diseases.

Heart failure classification using deep learning to extract spatiotemporal features from ECG.

BACKGROUND: Heart failure is a syndrome with complex clinical manifestations. Due to increasing population aging, heart failure has become a major medical problem worldwide. In this study, we used the MIMIC-III public database to extract the temporal and spatial characteristics of electrocardiogram (ECG) signals from patients with heart failure. METHODS: We developed a NYHA functional classification model for heart failure based on a deep learning method. We introduced an integrating attention mechanism based on the CNN-LSTM-SE model, segmenting the ECG signal into 2 to 20 s long segments. Ablation experiments showed that the 12 s ECG signal segments could be used with the proposed deep learning model for superior classification of heart failure. RESULTS: The accuracy, positive predictive value, sensitivity, and specificity of the NYHA functional classification method were 99.09, 98.9855, 99.033, and 99.649%, respectively. CONCLUSIONS: The comprehensive performance of this model exceeds similar methods and can be used to assist in clinical medical diagnoses.

Application of failure mode and effect analysis in ICU admission of potentially COVID-19 infected patients.

BACKGROUND: To analyze the admission and treatment process of potentially COVID-19-infected patients in the intensive care unit under normalization, prevention, and control of the pandemic. METHODS: A multidisciplinary team was assembled to develop a flowchart of potentially COVID-19-infected patients admitted to the intensive care unit and identify potential failure steps and modes throughout the process using the failure mode and effect analysis method. Through risk priority number (RPN) analysis of each failure mode, those with the highest impact on nosocomial infection were identified, and the priority of implementation was determined. Related corrective measures have been developed to continuously improve clinical practice and management. RESULTS: Eighty potential failure modes were identified, and 8 potential failure modes were identified with RPNs greater than 100. These high RPNs of the failure modes were associated with careless inquiries of epidemiological histories by nurses, inadequate implementation of management standards by nursing assistants, and exposure of attending physicians to potentially risky environments. Finally, 18 general corrective measures are proposed. CONCLUSIONS: Application of the failure mode and effect analysis method for quality improvement is a powerful tool for predicting potential failures in the process and can suggest corrective measures that could help avoid nosocomial infection during a pandemic.

Evaluation and improvement of workplace vertical violence of nursing interns based on the Importance-Performance Analysis method.

Purpose: To analyze the key factors related to workplace vertical violence among nursing interns in China and to propose strategies to improve the nursing practice environment. Methods: A cross-sectional study was conducted using the Importance-Performance Analysis (IPA) method to analyze the key factors and significance of workplace vertical violence for nursing interns. The data were obtained by administering a workplace vertical violence survey, designed specifically for this study, to 120 nursing interns at a tertiary general hospital in Zhejiang Province, China. Results: The results demonstrated that the variables "I was ordered to do something beyond my ability and lacked guidance (C3)," "Errors in work have been repeatedly emphasized, spread, or exaggerated (C8)," "I was unjustly criticized (C9)," "I was withheld or blocked information purposefully (C1)," and "I was belittled at work (C2)" were the most crucial variables for determining the presence of workplace vertical violence of nursing interns. Moreover, they are priority improvement variables. Conclusion: Managers must prioritize the use of relevant resources during internships to minimize false reinforcement and unfair criticism. Efforts should focus on improving information sharing, emphasizing the role of nursing interns in clinical work, providing better guidance when arranging for nursing interns to do work that exceeds their capacity, reducing workplace vertical violence, and improving nursing intern practice environments.

Cardiac proteomic profiling suggests that hypertrophic and dilated cardiomyopathy share a common pathogenetic pathway of the calcium signalling pathway.

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are classified as different diseases but have many similar pathogenic genes and clinical symptoms. Previous research has focused on mutated genes. This study was conducted to identify key molecular mechanisms and explore effective therapeutic targets. METHODS: Myocardial tissue was harvested from patients with HCM (n = 3) or DCM (n = 4) during surgery. Hearts donated by healthy traffic accident victims were treated as controls (n = 4). Total proteins were extracted for liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were annotated via GO and KEGG analyses. Selected distinguishing protein abundance was confirmed by western blotting. RESULTS: Compared with the control group, there were 121 and 76 DEPs in the HCM and DCM groups, respectively. GO terms for these two comparisons are associated with contraction-related components and actin binding. Additionally, the most significantly upregulated and downregulated proteins were periostin and tropomyosin alpha-3 chain in both comparisons. Moreover, when comparing the HCM and DCM groups, we found 60 significant DEPs, and the GO and KEGG terms are related to the calcium signalling pathway. Expression of the calcium regulation-related protein peptidyl-prolyl cis-trans isomerase (FKBP1A) was significantly upregulated in multiple samples. CONCLUSION: HCM and DCM have many mutual pathogenetic pathways. Calcium ion-related processes are among the most significant factors affecting disease development. For HCM and DCM, research on regulating linchpin protein expression or interfering with key calcium-related pathways may be more beneficial than genetic research.

MicroRNA-21: A Critical Pathogenic Factor of Diabetic Nephropathy.

Diabetic nephropathy (DN), one of the most common and intractable microvascular complications of diabetes, is the main cause of terminal renal disease globally. MicroRNA-21 (miR-21) is a kind of miRNA early identified in human circulation and tissues. Mounting studies have demonstrated that miR-21 plays an important role in the development and progression of DN. This collaborative review aimed to present a first attempt to capture the current evidence on the relationship between miR-21 and DN. After a systematic search, 29 relevant studies were included for comprehensively and thoroughly reviewing. All these eligible studies reported that miR-21 was up-regulated in DN, whether in serum or renal tissues of human or animal models. MiR-21 exhibited its pathogenic roles in DN by forming a complex network with targeted genes (e.g. MMP-9, Smad7, TIMP3, Cdk6, FOXO1, IMP3, and MMP2) and the signaling cascades (e.g. Akt/TORC1 signaling axis, TGF-ß/NF-κB signaling pathways, TGF-ß/SMAD pathway, CADM1/STAT3 signaling, and AGE-RAGE regulatory cascade), which resulted in epithelial-to-mesenchymal transition, extracellular matrix deposition, cytoskeletal remodeling, inflammation, and fibrosis. This review highlights that miR-21 is a pivotal pathogenic factor in the development of DN. It may serve as an attractive potential diagnostic, prognostic, and predictive biomarker for DN in clinical practice after further confirmation of the clinicopathological features and molecular mechanisms of miR-21-mediated DN.

Acute stress disorder in patients with accidental traumatic fractures: What can we do.

AIM: To evaluate the potential influencing factors of acute stress disorder (ASD) in patients with accidental traumatic fractures to provide evidence for clinical nursing care. DESIGN: A retrospective study. METHODS: Patients with traumatic fractures treated in our hospital from 1 January 2020 to 30 November 2021 were included. The characteristics of ASD and no ASD patients were assessed. RESULTS: A total of 468 patients with traumatic fractures were included, the incidence of ASD was 28.20%. Logistic regression analysis showed that age ≤50 years (OR2.918, 95% CI1.994 ~ 3.421), female (OR2.074, 95% CI1.489 ~ 3.375), AIS-ISS at admission ≥20 (OR3.981, 95% CI2.188 ~ 5.091), VAS at admission≥7 (OR2.804, 95% CI2.027 ~ 3.467), introverted personality (OR1.722, 95%CI1.314 ~ 2.432) and CD-RISC at admission≤60 (OR3.026, 95% CI2.338 ~ 4.769) were the risk factors of ASD in patients with traumatic fractures (all p < .05). CONCLUSIONS: The development of ASD in patients with traumatic fractures is affected by multiple factors. Medical workers should take early and timely management and nursing measures for related risk factors to reduce the occurrence of ASD.

Roles of ARID1A variations in colorectal cancer: a collaborative review.

Colorectal cancer (CRC), a common malignancy, is one of the leading cause of cancer death in adults. AT-rich interaction domain 1A (ARID1A), a critical portion of the SWItch/sucrose non-fermentation (SWI/SNF) chromatin remodeling complexes, shows one of the most frequent mutant genes across different human cancer types. Deleterious variations of ARID1A has been recognized to be correlated the tumorigenesis and the poor prognosis of CRC. Here, we summarize recent advances in the clinical implications and molecular pathogenesis of ARID1A variations in CRC. According to independent data of 23 included studies, ARID1A is mutated in 3.6-66.7%. Consistently, all of the 23 relevant studies report that ARID1A functions as a specific tumor suppressor in CRC. Clinically, ARID1A variation status serves as a biomarker for survival prognosis and various therapies for CRC. Mechanistically, the pathophysiologic impacts of ARID1A variations on CRC may be associated with the co-occurrence variations of other genes (i.e., TP53, KRAS, APC, FBXW7, and PIK3CA) and the regulation of several signaling pathways being affected (i.e., WNT signaling, Akt signaling, and MEK/ERK pathway), leading to cell cycle arrest, chromatin remodeling, chromosome organization, and DNA hypermethylation of the cancer cells. The present review highlights ARID1A serving as a potent tumor suppressor and an important prognostic factor in CRC. ARID1A variations hint towards a promising tool for diagnostic tumor profiling and individualized therapeutic targets for CRC in the future.

Hypoxia-primed monocytes/macrophages enhance postinfarction myocardial repair.

Background: Oxygen supplementation in myocardial infarction (MI) remains controversial. Inflammation is widely believed to play a central role in myocardial repair. A better understanding of these processes may lead to the design of novel strategies complementary to MI treatment. Methods: To investigate the role of hypoxia in inflammation and myocardial repair after acute MI, we placed MI mice in a tolerable mild hypoxia (10% O2) chamber for 7 days and then transferred the mice to ambient air for another 3 weeks. Results: We found that the cumulative survival rate of the MI mice under hypoxia was significantly higher than that under oxygen supplementation. Hypoxia promoted postinfarction myocardial repair. Importantly, we found that hypoxia modulated the phenotypic transition of blood monocytes from pro-inflammatory to pro-reparative in a timely manner, leading to the subsequent discontinuation of inflammation in myocardial tissues and promotion of myocardial repair post-MI. Specifically, cultured bone marrow-derived macrophages (BMDMs) primed by hypoxia in vitro exhibited improved reparative capacities and differed from M1 and M2 macrophages through the AMPKα2 signaling pathway. The deletion of AMPKα2 in monocytes/macrophages prevented the phenotypic transition induced by hypoxia and could not promote myocardial repair after MI when transplanted into the myocardium. Conclusions: Taken together, our work demonstrates that hypoxia promotes postinfarction myocardial repair by modulating the blood monocyte/macrophage phenotypic transition from pro-inflammatory to pro-reparative in a timely manner through the AMPKα2 signaling pathway. Hypoxia priming might be an attractive translational strategy for MI treatment by amplifying immune cells during early inflammation and subsequent resolution and repair.

Mid-term follow-up of aortic valve replacement for bicuspid aortic valve.

OBJECTIVE: The purpose of this study was to evaluate the mid-term outcome of aortic valve replacement for bicuspid aortic valve and tricuspid aortic valve and the related risk factors. METHODS: From January 2014 to June 2019, 177 tricuspid aortic valve patients and 101 bicuspid aortic valve patients who underwent aortic valve replacement in our hospital were collected. 1:1 propensity score matching analysis was used to control the bias in patient selection. The perioperative and follow-up data between the two groups were compared. Independent risk factors which were associated with the continued dilatation of the ascending aorta were identified by univariate or multivariate logistic regression analysis. RESULTS: After the matching procedure, 160 patients were included in the analysis (80 in each group). Baseline characteristics, intraoperative, and perioperative outcomes were similar between the two groups (all p > 0.05). Moreover, 67 patients in the tricuspid aortic valve group and 70 in the bicuspid aortic valve group completed the follow-up. The ascending aorta change, annual change rate, and the proportion of continuous dilation of ascending aorta in bicuspid aortic valve group were significantly higher than those in the tricuspid aortic valve group (p < 0.05). Multivariate logistic regression analysis showed that type 1 in bicuspid aortic valve (OR 5.173; 95% CI 1.772, 15.101; p = 0.003), aortic regurgitation (OR 3.673; 95% CI 1.133, 11.908; p = 0.030), and aortic valve stenosis with regurgitation (OR 6.489; 95% CI 1.726, 24.404; p = 0.006) were independent risk factors for the continued dilatation of the ascending aorta in all AV patients. Furthermore, the multivariate logistic regression analysis showed that type 1 in bicuspid aortic valve (OR 5.157; 95% CI 1.053, 25.272; p = 0.043), age ≥ 40 years (OR 6.956; 95% CI 1.228, 39.410; p = 0.028), and aortic regurgitation (OR 4.322; 95% CI 1.174, 15.911; p = 0.028) were independent risk factors for the continued dilatation of the ascending aorta in bicuspid aortic valve patients. CONCLUSION: Compared with tricuspid aortic valve patients, the ascending aorta of bicuspid aortic valve patients is more likely to continue to enlarge after aortic valve replacement. Type 1 in bicuspid aortic valve, age ≥ 40 years, and aortic regurgitation were the independent risk factors.

AMPKα2 deficiency exacerbates hypoxia-induced pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation.

Increased evidence indicates that adenosine monophosphate-activated protein kinase (AMPK) plays a vital role in vascular homeostasis, especially under hypoxia, and protects against the progression of pulmonary hypertension (PH). However, the role of AMPK in the pathogenesis of PH remains to be clarified. In the present study, we confirmed that a loss of AMPKα2 exacerbated the development of PH by using hypoxia-induced PH model in AMPKα2 -/- mice. After a 4-week period of hypoxic exposure, AMPKα2 -/- mice exhibited more severe pulmonary vascular remodeling and pulmonary vascular smooth muscle cell (SMC) proliferation when compared with wild type (WT) mice. In vitro, AMPKα2 knockdown promoted the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. This phenomenon was accompanied by upregulated Skp2 and downregulated p27kip1 expression and was abolished by rapamycin, an inhibitor of mTOR. These results indicate that AMPKα2 deficiency exacerbates hypoxia-induced PH by promoting PASMC proliferation via the mTOR/Skp2/p27kip1 signaling axis. Therefore, enhanced AMPKα2 activity might underlie a novel therapeutic strategy for the management of PH.

KLF15 is a protective regulatory factor of heart failure induced by pressure overload.

The aim of the present study was to investigate the protective effect of Kruppel­like factor 15 (KLF15) overexpression on heart failure (HF) induced by left ventricular (LV) pressure overload in mice. Wild­type (WT) mice and cardiac­specific KLF15­overexpressed transgenic (TG) mice were selected as research subjects, and an LV pressure overload model was constructed by ascending aortic constriction surgery. Changes in cardiac morphology and function, and ultrastructure and molecular expression were observed via M­mode echocardiography, histological and immunohistochemical staining, ELISA and western blotting at 2 and 6 weeks of LV overload. WT and TG mice subjected to 2 weeks of overload displayed adaptive LV hypertrophy characterized by ventricular thickness, cardiomyocyte size, ejection fraction and fractional shortening of heart­lung weight ratio and KLF15, and increases in vascular endothelial growth factor (VEGF) expression without other pathological changes. WT mice subjected to 6 weeks of overload displayed enlargement of the LV chamber, severe interstitial remodeling, and HW/LW, cardiac capillary and heart function decline, accompanied by downregulated expression of KLF15 and VEGF, and upregulated expression of connective tissue growth factor, phosphorylated p38 (p­p38) and phosphorylated Smad3 (p­Smad3). In contrast, TG mice exhibited improved resistance to 6 weeks of overload and a slighter molecular expression response compared with WT mice. KLF15 was revealed to be a critical factor regulating the expression of CTGF, VEGF, p­p38 and p­Smad3, and could alleviate the progression from adaptive LV hypertrophy to decompensatory cardiac insufficiency.

Multinucleated polyploid cardiomyocytes undergo an enhanced adaptability to hypoxia via mitophagy.

AIMS: There is a large subpopulation of multinucleated polyploid cardiomyocytes (M*Pc CMs) in the adult mammalian heart. However, the pathophysiological significance of increased M*Pc CMs in heart disease is poorly understood. We sought to determine the pathophysiological significance of increased M*Pc CMs during hypoxia adaptation. METHODS AND RESULTS: A model of hypoxia-induced cardiomyocyte (CM) multinucleation and polyploidization was established and found to be associated with less apoptosis and less reactive oxygen species (ROS) production. Compared to mononucleated diploid CMs (1*2c CMs), tetraploid CMs (4c CMs) exhibited better mitochondria quality control via increased mitochondrial autophagy (mitophagy). RNA-seq revealed Prkaa2, the gene for AMPKα2, was the most obviously up-regulated autophagy-related gene. Knockdown of AMPKα2 increased apoptosis and ROS production and suppressed mitophagy in 4c CMs compared to 1*2c CMs. Rapamycin, an autophagy activator, alleviated the adverse effect of AMPKα2 knockdown. Furthermore, silencing PINK1 also increased apoptosis and ROS in 4c CMs and weakened the adaptive superiority of 4c CMs. Finally, AMPKα2-/- mutant mice exhibited exacerbation of apoptosis and ROS production via decreases in AMPKα2-mediated mitophagy in 4c CMs compared to 1*2c CMs during hypoxia. CONCLUSIONS: Compared to 1*2c CMs, hypoxia-induced 4c CMs exhibited enhanced mitochondria quality control and less apoptosis via AMPKα2-mediated mitophagy. These results suggest that multinucleation and polyploidization allow CM to better adapt to stress via enhanced mitophagy. In addition, activation of AMPKα2 may be a promising target for myocardial hypoxia-related diseases.

Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of ß-catenin.

Cardiomyocyte (CM) loss is a characteristic of various heart diseases, including ischaemic heart disease. Cardiac regeneration has been suggested as a promising strategy to address CM loss. Although many studies of regeneration have focused mainly on mononucleated or diploid CM, the limitations associated with the cytokinesis of polyploid and multinucleated CMs remain less well known. Here, we show that ß-catenin, a key regulator in heart development, can increase cytokinesis in polyploid multinucleated CMs. The activation of ß-catenin increases the expression of the cytokinesis-related factor epithelial cell transforming 2 (ECT2), which regulates the actomyosin ring and thus leads to the completion of cytokinesis in polyploid CMs. In addition, hypoxia can induce polyploid and multinucleated CMs by increasing factors related to the G1-S-anaphase of the cell cycle, but not those related to cytokinesis. Our study therefore reveals that the ß-catenin can promote the cytokinesis of polyploid multinucleated CMs via upregulation of ECT2. These findings suggest a potential field of polyploid CM research that may be exploitable for cardiac regeneration therapy.

Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress.

Sirtuin 1 (Sirt1) exerts its cardioprotective effects in various cardiovascular diseases via multiple cellular activities. However, the therapeutic implications of Sirt1 in hypoxic cardiomyocytes and the underlying mechanisms remain elusive. The present study investigated whether Sirt1 regulates autophagy and apoptosis in hypoxic H9C2 cardiomyocytes and in an experimental hypoxic mouse model. Right ventricular outflow tract biopsies were obtained from patients with cyanotic or acyanotic congenital heart diseases. Adenovirus Ad­Sirt1 was used to activate Sirt1 and Ad­Sh­Sirt1 was used to inhibit Sirt1 expression in H9C2 cells, in order to investigate the effect of Sirt1 on cellular autophagy and apoptosis. SRT1720, a pharmacological activator of Sirt1 and EX­527, a Sirt1 antagonist, were administered to mice to explore the role of Sirt1 in hypoxic cardiomyocytes in vivo. The levels of autophagy and apoptosis­related proteins were evaluated using western blotting. Apoptosis was investigated by TUNEL staining and Annexin V/7­aminoactinomycin D flow cytometry analysis. Heart tissue samples from cyanotic patients exhibited increased autophagy and apoptosis, as well as elevated Sirt1 levels, compared with the noncyanotic control samples. The data from the western blot analysis revealed that Sirt1 promoted autophagic flux and reduced apoptosis in hypoxic H9C2 cells. In addition, Sirt1 activated AMP­activated protein kinase (AMPK), and the AMPK inhibitor Compound C abolished the effect of Sirt1 on autophagy activation. Further exploration of the mechanism revealed that Sirt1 protects hypoxic cardiomyocytes from apoptosis, at least in part, through inositol requiring kinase enzyme 1α (IRE1α). Consistent with the in vitro results, treatment with the Sirt1 activator SRT1720 activated AMPK, inhibited IRE1α, enhanced autophagy, and decreased apoptosis in the heart tissues of normoxic mice compared with the hypoxia control group. Opposite changes were observed in hypoxic mice treated with the Sirt1 inhibitor EX­527. These results suggested that Sirt1 promoted autophagy via AMPK activation and reduced hypoxia­induced apoptosis via the IRE1α pathway, to protect cardiomyocytes from hypoxic stress.

miRNA-mRNA crosstalk in myocardial ischemia induced by calcified aortic valve stenosis.

Aortic valve stenosis is the most common cause of morbidity and mortality in valvular heart disease in aged people. Both microRNA (miRNA) and mRNA are potential targets for the diagnosis and therapeutic intervention of myocardial ischemia induced by calcified aortic valve stenosis (CAVS), with unclear mechanisms. Here, 3 gene expression profiles of 47 male participants were applied to generate shared differentially expressed genes (DEGs) with significant major biological functions. Moreover, 20 hub genes were generated by a Weighted Genes Co-Expression Network Analysis (WGCNA) and were cross-linked to miRNA based on miRanda/miRwalk2 databases. Integrated miRNA/mRNA analysis identified several novel miRNAs and targeted genes as diagnostic/prognostic biomarkers or therapeutic targets in CAVS patients. In addition, the clinical data suggested that myocardial hypertrophy and myocardial ischemia in CAVS patients are likely associated with hub genes and the upstream regulatory miRNAs. Together, our data provide evidence that miRNAs and their targeted genes play an important role in the pathogenesis of myocardial hypertrophy and ischemia in patients with CAVS.

Melatonin alleviates hypoxia-induced cardiac apoptosis through PI3K/Akt pathway.

Hypoxia-induced apoptosis is an inevitable problem in cyanotic congenital heart disease. In the present study, we investigated effects of melatonin on hypoxic cardiomyocytes in vitro and in vivo, and explored its underlying mechanism. H9C2 cells were subjected to hypoxia for 48 hours. Mice were subjected to hypoxia treatment (10% O2) for 4 weeks. Cell viability was detected by the cell counting kit-8 assay. Cellular apoptosis was assessed by Annexin V/7 AAD assay. Western blotting was employed to determine the expression of Bcl-2, Bax, cleaved caspase 3, phosphorylation of PI3K, and AKT. Melatonin increased cell viability and alleviated apoptosis in hypoxic H9C2 cells and cardiomyocytes of hypoxia-treated mice. Melatonin pretreatment increased Bcl-2 and decreased cleaved caspase 3 and Bax levels. Moreover, melatonin activated the PI3K/Akt pathway. The protective effects of melatonin were abolished by a PI3K/Akt-inhibitor, LY294002. Our results demonstrated that melatonin confers cardioprotection by inhibiting apoptosis through the activation of PI3K/Akt signaling pathway in hypoxic cardiomyocytes.

AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia.

Mitochondrial biogenesis is one of the generally accepted regulatory mechanisms in the heart under chronic hypoxia. The precise quantity and quality control of mitochondria is critical for the survival and function of cardiomyocytes. Mitochondrial autophagy, also known as mitophagy, which selectively eliminates dysfunctional and unwanted mitochondria, is the most important type of mitochondrial quality control. However, the detailed molecular mechanisms of mitophagy in cardiomyocytes have been largely undefined. The present study investigated the role of adenosine 5'­monophosphate­activated protein kinase (AMPK) in mitophagy regulation in cardiomyocytes under chronic hypoxia. H9c2 cells were cultured under hypoxic conditions (1% O2) for different time periods. Mitochondrial biogenesis was confirmed and hypoxia was found to induce the collapse of mitochondrial membrane potential (ΛΨm) and increase the number of dysfunctional mitochondria. As expected, mitochondrial autophagy was increased significantly in cardiomyocytes exposed to hypoxic conditions for 48 h. AMPK was activated under hypoxia. Notably, when the activation of AMPK was enhanced by the AMPK agonist AICAR, mitochondrial autophagy was increased accordingly. By contrast, when AMPK activation was blocked, mitochondrial autophagy was decreased and cardiomyocyte apoptosis was increased. In conclusion, in the present study, mitophagy was activated and played a crucial role in cardioprotection under chronic hypoxia. AMPK was involved in mitophagy regulation, thereby providing a potential therapeutic target for heart diseases associated with chronic hypoxia.