Principle and design of clinical efficacy observation of extracorporeal cardiac shock wave therapy for patients with myocardial ischemia-reperfusion injury: A prospective randomized controlled trial protocol.

BACKGROUND: Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life threatening event with a poor prognosis due to myocardial ischemia/reperfusion injury despite coronary revascularization. Extracorporeal cardiac shock wave (ECSW) is a safe, effective and non-invasive new method for the treatment of cardiovascular diseases. The current results show that extracorporeal cardiac shock wave provides a new treatment option for patients with severe and advanced coronary heart disease. However, there are relatively few clinical studies on the application of in vitro cardiac shock waves in patients with myocardial ischemia-reperfusion injury. We hypothesized that extracorporeal cardiac shock therapy would also be effective in reducing clinical endpoints in patients with STEMI reperfusion. OBJECTIVE: This study is order to provide a new therapeutic method for patients with myocardial ischemia-reperfusion injury and reveal the possible mechanism of ECSW for ischemia-reperfusion injury. METHODS AND MATERIALS: CEECSWIIRI is a single-center, prospective randomized controlled trial that plans to enroll 102 eligible patients with acute ST-segment elevation myocardial infarction reperfusion. Eligible patients with STEMI reperfusion will be randomly divided into external cardiac shock therapy (ECSW) trial group and blank control group. The blank control group will receive optimal drug therapy, and the experimental group will receive optimal drug therapy combined with ECSW. The shock wave treatment plan will be 3-month therapy, specifically 1 week of treatment per month, 3 weeks of rest, 3 times of ECSW in each treatment week, respectively on the first day, the third day and the fifth day of the treatment week, lasting for 3 months and follow-up for 2 years. The primary endpoint will be to assess the 2-year improvement in all-cause death, re-hospitalization due to cardiovascular disease, major unintentional cerebrovascular events, including cardiogenic death, myocardial infarction, heart failure, arrhythmia, emergency coronary revascularization, and stroke in patients with STEMI reperfusion. Secondary endpoints will include improvements in angina pectoris, quality of life, cardiac structure and function, coronary microcirculation, and endothelial progenitor cell-derived miR-140-3p in relation to survival outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov.org PRS:NCT05624203; Date of registration: November 12, 2022.

Gut microbiome-based noninvasive diagnostic model to predict acute coronary syndromes.

Background: Previous studies have shown that alterations in the gut microbiota are closely associated with Acute Coronary Syndrome (ACS) development. However, the value of gut microbiota for early diagnosis of ACS remains understudied. Methods: We recruited 66 volunteers, including 29 patients with a first diagnosis of ACS and 37 healthy volunteers during the same period, collected their fecal samples, and sequenced the V4 region of the 16S rRNA gene. Functional prediction of the microbiota was performed using PICRUSt2. Subsequently, we constructed a nomogram and corresponding webpage based on microbial markers to assist in the diagnosis of ACS. The diagnostic performance and usefulness of the model were analyzed using boostrap internal validation, calibration curves, and decision curve analysis (DCA). Results: Compared to that of healthy controls, the diversity and composition of microbial community of patients with ACS was markedly abnormal. Potentially pathogenic genera such as Streptococcus and Acinetobacter were significantly increased in the ACS group, whereas certain SCFA-producing genera such as Blautia and Agathobacter were depleted. In addition, in the correlation analysis with clinical indicators, the microbiota was observed to be associated with the level of inflammation and severity of coronary atherosclerosis. Finally, a diagnostic model for ACS based on gut microbiota and clinical variables was developed with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.963 (95% CI: 0.925-1) and an AUC value of 0.948 (95% CI: 0.549-0.641) for bootstrap internal validation. The calibration curves of the model show good consistency between the actual and predicted probabilities. The DCA showed that the model had a high net clinical benefit for clinical applications. Conclusion: Our study is the first to characterize the composition and function of the gut microbiota in patients with ACS and healthy populations in Southwest China and demonstrates the potential effect of the microbiota as a non-invasive marker for the early diagnosis of ACS.

ASK1 promotes apoptosis of normal and malignant plasma cells.

Although the overproduction of immunoglobulins by short-lived plasma cells accompanying an immune response links with their apoptosis, how long-lived plasma cells adapt to ensure their longevity in this context is obscure. Here, we show that apoptosis signal-regulating kinase 1 (ASK1) contributes to apoptosis of plasma cells because ASK1 activity was induced during differentiation of short-lived plasma cells, and, when produced by ASK1-deficient mice, these cells survived better than those of control mice. Moreover, antigen-specific long-lived plasma cells generated by immunization accumulated in ASK1-deficient mice, suggesting ASK1 also plays a negative role in survival of long-lived plasma cells. In malignant plasma cells, ASK1 transcription was directly suppressed by B lymphocyte-induced maturation protein-1 (Blimp-1). The expression of ASK1 and Blimp-1 showed an inverse correlation between normal human mature B cells and bone marrow plasma cells from patients with multiple myeloma (MM). Suppression of ASK1 is crucial for cell survival because its enforced expression in MM cells caused apoptosis in vitro and lowered MM load in a xenograft animal model; furthermore, alteration of ASK1 activity affected MM cell survival. Our findings indicate a novel mechanism underlying the regulation of survival in normal and malignant plasma cells by ASK1.

Involvement of histone demethylase LSD1 in Blimp-1-mediated gene repression during plasma cell differentiation.

Plasma cell differentiation is orchestrated by the transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1), which silences the gene expression program of mature B cells. The molecular mechanism underlying Blimp-1 suppression of mature B-cell gene expression is not fully understood. Here we report that a proline-rich domain in Blimp-1 directly interacts with LSD1, a histone lysine demethylase. Both LSD1 knockdown and expression of Blimp-1 lacking the proline-rich domain derepressed the activities of Blimp-1-dependent luciferase reporters. Disruption of the Blimp-1 interaction with LSD1 or reduced LSD1 expression attenuated antibody production, demonstrating the biological significance of this interaction. Finally, using chromatin immunoprecipitation, we showed that Blimp-1 binding to its target sites is accompanied by LSD1 binding to those same sites and that LSD1 binding correlates with histone modifications of accessible chromatin. These findings provide further insights into the molecular mechanism of the silencing of mature B-cell genes by Blimp-1 in plasma cell differentiation.

Induction of apoptosis in plasma cells by B lymphocyte-induced maturation protein-1 knockdown.

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1-dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells.