Extracorporeal Cardiac Shock Wave-Induced Exosome Derived From Endothelial Colony-Forming Cells Carrying miR-140-3p Alleviate Cardiomyocyte Hypoxia/Reoxygenation Injury via the PTEN/PI3K/AKT Pathway

Background: Stem cell-derived exosomes have great potential in the treatment of myocardial ischemia–reperfusion injury (IRI). Extracorporeal cardiac shock waves (ECSW) as effective therapy, in part, could activate the function of exosomes. In this study, we explored the effect of ECSW-induced exosome derived from endothelial colony-forming cells on cardiomyocyte hypoxia/reoxygenation (H/R) injury and its underlying mechanisms.Methods: The exosomes were extracted and purified from the supernatant of endothelial colony-forming cells (ECFCs-exo). ECFCs-exo treated with shock wave (SW-exo) or without shock wave (CON-exo) were performed with high-throughput sequencing of the miRNA. H9c2 cells were incubated with SW-exo or CON-exo after H/R injury. The cell viability, cell apoptosis, oxidative stress level, and inflammatory factor were assessed. qRT-PCR was used to detect the expression levels of miRNA and mRNA in cells and exosomes. The PTEN/PI3K/AKT pathway-related proteins were detected by Western blotting, respectively.Results: Exosomes secreted by ECFCs could be taken up by H9c2 cells. Administration of SW-exo to H9c2 cells after H/R injury could significantly improve cell viability, inhibit cell apoptosis, and downregulate oxidative stress level (p < 0.01), with an increase in Bcl-2 protein and a decrease in Bax, cleaved caspase-3, and NF-κB protein (p < 0.05). Notably, miR-140-3p was found to be highly enriched both in ECFCs and ECFCs-exo treated with ECSW (p < 0.05) and served as a critical mediator. SW-exo increased miR-140-3p expression but decreased PTEN expression in H9c2 cells with enhanced phosphorylation of the PI3K/AKT signaling pathway. These cardioprotective effects of SW-exo on H/R injury were blunted by the miR-140-3p inhibitor. Dual-luciferase assay verified that miR-140-3p could directly target the 3′UTR of PTEN mRNA and exert a negative regulatory effect.Conclusion: This study has shown the potential of ECSW as an effective stimulation for the exosomes derived from ECFCs in vitro. SW-exo exerted a stronger therapeutic effect on H/R injury in H9c2 cells possibly via delivering exosomal miR-140-3p, which might be a novel promising strategy for the myocardial IRI.

Extracorporeal Cardiac Shock Waves Therapy Improves the Function of Endothelial Progenitor Cells After Hypoxia Injury via Activating PI3K/Akt/eNOS Signal Pathway

Background: Extracorporeal cardiac shock waves (ECSW) have great potential in the treatment of coronary heart disease. Endothelial progenitor cells (EPCs) are a class of pluripotent progenitor cells derived from bone marrow or peripheral blood, which have the capacity to migrate to ischemic myocardium and differentiate into mature endothelial cells and play an important role in neovascularization and endothelial repair. In this study, we investigated whether ECSW therapy can improve EPCs dysfunction and apoptosis induced by hypoxia and explored the underlying mechanisms.Methods: EPCs were separated from ApoE gene knockout rat bone marrow and identified using flow cytometry and fluorescence staining. EPCs were used to produce in vitro hypoxia-injury models which were then divided into six groups: Control, Hypoxia, Hypoxia + ECSW, Hypoxia + LY294002 + ECSW, Hypoxia + MK-2206 + ECSW, and Hypoxia + L-NAME + ECSW. EPCs from the Control, Hypoxia, and Hypoxia + ECSW groups were used in mRNA sequencing reactions. mRNA and protein expression levels were analyzed using qRT-PCR and western blot analysis, respectively. Proliferation, apoptosis, adhesion, migration, and angiogenesis were measured using CCK-8, flow cytometry, gelatin, transwell, and tube formation, respectively. Nitric oxide (NO) levels were measured using an NO assay kit.Results: Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that differentially expressed genes were enriched in cancer signaling, PI3K-Akt signaling, and Rap1 signaling pathways. We selected differentially expressed genes in the PI3K-Akt signaling pathway and verified them using a series of experiments. The results showed that ECSW therapy (500 shots at 0.09 mJ/mm2) significantly improved proliferation, adhesion, migration, and tube formation abilities of EPCs following hypoxic injury, accompanied by upregulation of p-PI3K, p-Akt, p-eNOS, Bcl-2 protein and NO, PI3K, and Akt mRNA expression, and downregulation of Bax and Caspase3 protein expression. All these effects of ECSW were eliminated using inhibitors specific to PI3K (LY294002), Akt (MK-2206), and eNOS (L-NAME).Conclusion: ECSW exerted a strong repaired effect on EPCs suffering inhibited hypoxia injury by inhibiting cell apoptosis and promoting angiogenesis, mainly through activating the PI3K/Akt/eNOS signaling pathway, which provide new evidence for ECSW therapy in CHD.

Successful treatment of severe electrolyte imbalance-induced cardiac arrest caused by adrenal tuberculosis with ECMO in the ED

Background Tuberculosis (TB) is a chronic infectious disease, common in China. TB bacteria can invade multiple organs throughout the body, but they rarely cause critical illness. We present a complex critically ill case in this report. Case presentation A 40-year-old man suffered sudden cardiac arrest during an emergency room visit. Spontaneous circulation resumed after emergency cardiopulmonary resuscitation (CPR), but recurrent ventricular fibrillation and refractory cardiac shock emerged. Thereafter, extracorporeal membrane oxygenation (ECMO) was implemented to maintain hemodynamic stability. Blood test results revealed that the patient had severe electrolyte imbalance and adrenal insufficiency. Further imaging examination showed multiple tuberculosis lesions throughout the body, including the lungs, adrenal glands, and lumbar spine. In the end, the patient was successfully moved from the ICU after weaning from ECMO and the ventilator, and then transferred to an infectious disease specialist hospital for standard anti-tuberculosis therapy. Conclusions ECMO has won the opportunity for the diagnosis and treatment of this young patient who suffered from a rare cause of cardiac arrest and finally achieved a good prognosis.

Successful Treatment of Severe Electrolyte Imbalance-Induced Cardiac Arrest Caused by Adrenal Tuberculosis With ECMO in The ED

Background Tuberculosis (TB) is a chronic infectious disease, common in China. TB bacteria can invade multiple organs throughout the body, but they rarely cause critical illness. We present a complex critically ill case in this report. Case presentation A 40-year-old man suffered sudden cardiac arrest during an emergency room visit. Spontaneous circulation resumed after emergency cardiopulmonary resuscitation (CPR), but recurrent ventricular fibrillation and refractory cardiac shock emerged. Thereafter, extracorporeal membrane oxygenation (ECMO) was implemented to maintain hemodynamic stability. Blood test results revealed that the patient had severe electrolyte imbalance and adrenal insufficiency. Further imaging examination showed multiple tuberculosis lesions throughout the body, including the lungs, adrenal glands, and lumbar spine. In the end, the patient was successfully moved from the ICU after weaning from ECMO and the ventilator, and then transferred to an infectious disease specialist hospital for standard anti-tuberculosis therapy. Conclusions ECMO has won the opportunity for the diagnosis and treatment of this young patient who suffered from a rare cause of cardiac arrest, and finally achieved a good prognosis.

Cardiac Shock Wave Therapy Ameliorates Myocardial Ischemia in Patients With Chronic Refractory Angina Pectoris: A Randomized Trial

Background: Cardiac shock wave therapy (CSWT) is a non-invasive new option for the treatment of chronic refractory angina pectoris (CRAP). This study aimed to evaluate the safety and efficiency of CSWT in the treatment of CRAP.Methods: Eighty-seven patients with CRAP were randomly allocated into CWST group (n = 46) and Control group (n = 41). Canadian Cardiovascular Society (CCS) grade of angina pectoris, Seattle Angina Questionnaire (SAQ) score, 6-min walk test (6MWT), weekly dosage of nitroglycerin, and myocardial perfusion on D-SPECT were determined at baseline and during the follow-up period. Adverse events were also evaluated.Results: CSWT was well-tolerated in the CSWT patients. CSWT significantly improved the CCS grade, SAQ score, and 6MWT (p < 0.05). Imaging examinations showed that the ischemic area was reduced after CSWT. However, no significant changes were observed in the Control group.Conclusions: CSWT may improve the myocardial perfusion and reduce clinical symptoms without increasing adverse effects in CRAP patients. It provides a non-invasive and safe clinical therapy for CRAP patients.Clinical Trial registration:www.ClinicalTrials.gov, identifier: NCT03398096.

Cardiac Shock Wave Therapy Improves Ventricular Function by Relieving Fibrosis Through PI3K/Akt Signaling Pathway: Evidence From a Rat Model of Post-infarction Heart Failure

Objection: Cumulative studies have identified the effectiveness of cardiac shock wave therapy (CSWT) in treating heart failure after acute myocardial infarction (AMI), but little have been discussed with regard to the beneficial effects of CSWT on anti-fibrosis along with the underlying mechanism. In this study, we investigated whether CSWT could reduce post-AMI fibrosis and further explored the molecular mechanism.Methods: Rat heart failure (HF) models induced by ligating the left anterior descending coronary artery were established and validated by echocardiography. Eligible animals were randomly categorized into five groups: the sham group, the HF group, the HF + CSWT group, the HF + LY294002 group, and the HF + CSWT + LY294002 group. The cardiac weight, serum level of BNP, NT-pro BNP and echocardiography parameters were measured to assess cardiac function in different groups. Masson's trichrome staining was used to assess the proportions of the fibrotic area. The expression level of CD34, αSMA was measured by RT-PCR, Immunohistochemistry and Immunofluorescent analyses and the level of PI3K/Akt was quantified by Immunohistochemistry and Western blotting.Results: The application of CSWT significantly improved cardiac function and reduced myocardial fibrosis and level of CD34 and αSMA, compared to the HF group. CSWT led to significant elevations of p-PI3K and p-Akt expression levels compared to that of the HF group and the inhibition of the PI3K/Akt pathway abolished the observed beneficial effects of CSWT.Conclusion: CSWT can facilitate the alleviation of cardiac fibrosis induced by AMI through the activation of PI3K/Akt signaling pathway.