CircUsp9x/miR-599/stim1 axis regulates proliferation and migration in vascular smooth muscle cells induced by oxidized-low density lipoprotein.

Circular RNAs (circRNAs) regulate the function of vascular smooth muscle cells (VSMCs) in atherosclerosis (AS) progression. We aimed to explore the role of circUSP9X in oxidized low-density lipoprotein (ox-LDL)-induced VSMCs. Cell proliferation was assessed using cell counting kit-8 and EDU assays. Cell migration was evaluated using Transwell and wound healing assays. The interaction between circUSP9X or STIM1 and miR-599 was analyzed using dual-luciferase reporter and RNA pull-down assays. Their levels were examined using quantitative real-time PCR. CircUSP9X and STIM1 expression was increased, whereas miR-599 expression was reduced in the serum of patients with AS and ox-LDL-stimulated VSMCs. Overexpression of circUSP9X facilitated the proliferation and migration of VSMCs induced by ox-LDL. CircUSP9X sponged miR-599, which targeted STIM1. MiR-599 reversed the effects induced by circUSP9X, and STIM1 reversed the effects induced by miR-599. Taken together, CircUSP9X promoted proliferation and migration in ox-LDL-treated VSMCs via the miR-599/STIM1 axis, providing a theoretical basis for the role of circUSP9X/miR-599/STIM1 axis in AS.

Identification of prognostic and diagnostic signatures for cancer and acute myocardial infarction: multi-omics approaches for deciphering heterogeneity to enhance patient management.

Patients diagnosed with cancer face an increased risk of cardiovascular events in the short term, while those experiencing acute myocardial infarction (AMI) have a higher incidence of cancer. Given limitations in clinical resources, identifying shared biomarkers offers a cost-effective approach to risk assessment by minimizing the need for multiple tests and screenings. Hence, it is crucial to identify common biomarkers for both cancer survival and AMI prediction. Our study suggests that monocyte-derived biomarkers, specifically WEE1, PYHIN1, SEC61A2, and HAL, hold potential as predictors for cancer prognosis and AMI. We employed a novel formula to analyze mRNA levels in clinical samples from patients with AMI and cancer, resulting in the development of a new risk score based on expression profiles. By categorizing patients into high-risk and low-risk groups based on the median risk score, we observed significantly poorer overall survival among high-risk patients in cancer cohorts using Kaplan-Meier analysis. Furthermore, calibration curves, decision curve analysis (DCA), and clinical impact curve analyses provided additional evidence supporting the robust diagnostic capacity of the risk score for AMI. Noteworthy is the shared activation of the Notch Signaling pathway, which may shed light on common high-risk factors underlying both AMI and cancer. Additionally, we validated the differential expression of these genes in cell lines and clinical samples, respectively, reinforcing their potential as meaningful biomarkers. In conclusion, our study demonstrates the promise of mRNA levels as biomarkers and emphasizes the significance of further research for validation and refinement.

Low T3 syndrome predicts more adverse events in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder that clinically manifests with sudden death and progressive heart failure. Moreover, thyroid dysfunction is associated with increased cardiovascular morbidity and mortality risks. Therefore, this study aimed to clarify whether thyroid hormones could serve as an independent predictor of adverse events in patients with HCM. METHODS: The cohort consisted of 782 patients with HCM who had thyroid hormones baseline data and were admitted to the Affiliated Hospital of Jiaxing University. Patients were divided into two groups according to serum levels of free triiodothyronine (fT3): the normal fT3 and low triiodothyronine (T3) syndrome groups. Low T3 syndrome was defined as fT3 < 2.43 pmol/L with a normal thyroid-stimulating hormone (TSH) level. Patients whose TSH levels were abnormally high or abnormally low were excluded from this study. The primary endpoint was the occurrence of sudden cardiac death (SCD) events, and the secondary endpoint was a composite of worsening heart failure (WHF) events, including heart failure death, cardiac decompensation, hospitalization for heart failure, and HCM-related stroke. The Kaplan-Meier and Cox regression were performed for the survival analysis. RESULTS: After a median follow-up of 52 months, 75 SCD events and 134 WHF events were recorded. The Kaplan-Meier survival curves showed that the cumulative incidence of SCD events and WHF events were significantly higher in patients with low T3 syndrome (log-rank p = .02 and log-rank p = .001, respectively). Furthermore, multivariate Cox regression analysis demonstrated that low T3 syndrome is a strong predictor of SCD events and WHF events (adjusted hazard ratio [HR: 1.53, 95% confidence interval [CI]: 1.13-2.24, p < .01; HR: 3.87, 95% CI: 2.91-4.98, p < .001, respectively). CONCLUSIONS: Low T3 syndrome is highly prevalent among patients with HCM and was independently associated with an increased risk of SCD events and WHF events. The routine assessment of serum fT3 levels may provide risk stratification in this population.

Time-restricted eating with calorie restriction on weight loss and cardiometabolic risk: a systematic review and meta-analysis.

The effect of time-restricted eating (TRE) has been summarized in previous studies, but its benefits in combination with calorie restriction (CR) still need to be determined. The present meta-analysis aimed to evaluate the efficacy of TRE with CR on weight loss and cardiometabolic risk. PubMed, Embase, Cochrane Library, and gray literature databases were searched from inception to October 18, 2022, for potential randomized controlled trial (RCT) studies based on predefined inclusion and exclusion criteria. Body weight and other cardiometabolic risk factors were described as weighted mean difference (WMD) with a 95% confidence interval (CI). Eight RCTs involving 579 participants were enrolled in the present analysis. The pooled results showed that TRE with CR reduced the body weight, fat mass, and waist circumference significantly (WMD: -1.40, 95% CI: -1.81 to -1.00, and I2: 0%; WMD: -0.73, 95% CI: -1.39 to -0.07, and I2: 0%; WMD: -1.87, 95% CI: -3.47 to -0.26, and I2: 67.25%, respectively). However, compared with CR alone, TRE plus CR exhibited no significant benefit on the blood pressure, glucose profile, and lipid profile. Subgroup analysis suggested that early TRE is more effective in weight loss (WMD: -1.42, 95% CI: -1.84 to -1.01, and I2: 0%) and improving fat mass (WMD: -1.06, 95% CI: -1.91 to -0.22, and I2: 0%) than delayed or broader TRE when combined with CR. Although the combination of TRE and CR can effectively decrease body weight, fat mass, and waist circumference, the long-term effects, particularly those on cardiometabolic risk in participants with chronic cardiovascular disease and diabetes, remain to be explored.

Machine learning-based mRNA signature in early acute myocardial infarction patients: the perspective toward immunological, predictive, and personalized.

Patients diagnosed with stable coronary artery disease (CAD) are at continued risk of experiencing acute myocardial infarction (AMI). This study aims to unravel the pivotal biomarkers and dynamic immune cell changes, from an immunological, predictive, and personalized viewpoint, by implementing a machine-learning approach and a composite bioinformatics strategy. Peripheral blood mRNA data from different datasets were analyzed, and CIBERSORT was used for deconvoluting human immune cell subtype expression matrices. Weighted gene co-expression network analysis (WGCNA) in single-cell and bulk transcriptome levels was conducted to explore possible biomarkers for AMI, with a particular emphasis on examining monocytes and their involvement in cell-cell communication. Unsupervised cluster analysis was performed to categorize AMI patients into different subtypes, and machine learning methods were employed to construct a comprehensive diagnostic model to predict the occurrence of early AMI. Finally, RT-qPCR on peripheral blood samples collected from patients validated the clinical utility of the machine learning-based mRNA signature and hub biomarkers. The study identified potential biomarkers for early AMI, including CLEC2D, TCN2, and CCR1, and found that monocytes may play a vital role in AMI samples. Differential analysis revealed that CCR1 and TCN2 exhibited elevated expression levels in early AMI compared to stable CAD. Machine learning methods showed that the glmBoost+Enet [alpha=0.9] model achieved high predictive accuracy in the training set, external validation sets, and clinical samples in our hospital. The study provided comprehensive insights into potential biomarkers and immune cell populations involved in the pathogenesis of early AMI. The identified biomarkers and the constructed comprehensive diagnostic model hold great promise for predicting the occurrence of early AMI and can serve as auxiliary diagnostic or predictive biomarkers.

Association Between Aromatase Inhibitors and Myocardial Infarction Morbidity in Women With Breast Cancer: A Meta-Analysis of Observational Studies.

BACKGROUND: The cardiovascular toxicity of aromatase inhibitors (AIs) for women with estrogen receptor-positive breast cancer is controversial. We aimed to evaluate the association between AIs and the risk of myocardial infarction (MI) in women with estrogen receptor-positive breast cancer based on real-world studies. METHOD: PubMed, Embase, and Cochrane Library were searched to identify studies that estimated the association between MI risk and AIs. A random-effects model was used to evaluate the hazard ratio (HR) and 95% confidence intervals (CIs) of the predefined outcomes. RESULTS: A total of 134 476 patients from eight cohort studies were enrolled in our analysis. For MI incidence, no significant difference was found between the users of AIs and non-users (HR: .98, 95% CI: .83-1.17). The subgroup analysis of patients without a history of cardiovascular disease (CVD) suggested a reduced risk of MI (HR: .86, 95% CI: .77-.96). No significant difference was found for ischemic stroke (HR: .93, 95% CI: .82-1.07) and heart failure (HR: 1.24, 95% CI: .92-1.66) between the two groups. CONCLUSION: Based on real-world data, AIs may be a safe treatment route for patients with estrogen receptor-positive breast cancer and those with a history of CVD. AIs caused a major decrease in MI in patients without CVD history. However, more in-depth investigations are needed to explore the association between AI use and the incidence of MI in the treatment of estrogen receptor-positive breast cancer.

Anxiety Predicts Poor Prognosis in Patients With Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is the prevalent inherited cardiomyopathy and a major contributor to sudden death and heart failure in young adults. Although depression has been associated with poor prognosis in patients with cardiovascular disease, the relationship between anxiety and HCM clinical outcomes has not been addressed. We aimed to determine the prevalence of anxiety symptoms in patients with HCM and the association between anxiety and adverse prognosis in this population. Methods: A total of 793 patients with HCM were prospectively enrolled and followed up for a mean of 4.1 years from March 2014 to January 2018. The primary endpoint was sudden cardiac death (SCD) events, and the secondary endpoint was HCM-related heart failure events. Anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) during outpatient visits or hospital stays. Results: Elevated scores on the HADS anxiety subscale (HADS-A ≥ 8) were defined as clinically significant anxiety. SCD and HCM-related heart failure events occurred in 76 and 149 patients, respectively, during the follow-up period. Kaplan-Meier survival curves demonstrated the significant association of anxiety with SCD events (log-rank P = 0.012) and HCM-related heart failure events (log-rank P = 0.001). Multivariable Cox regression analysis showed anxiety as a predictor of SCD events and HCM-related heart failure events (adjusted hazard ratio [HR] = 1.42, 95% confidence interval [CI] = 1.12-2.04, P = 0.03; adjusted HR = 2.9,2 95% CI = 1.73-4.03, P < 0.001), independent of conventional risk factors and depression. Besides, patients with comorbid anxiety and depression showed a fourfold higher risk of heart failure events and 3.5-fold higher risk of SCD versus those with neither (adjusted HR = 4.08, 95% CI = 2.76-5.91, P < 0.001; adjusted HR = 3.52, 95% CI = 2.24-4.67, P < 0.001, respectively). Conclusions: Anxiety was prevalent among Chinese patients with HCM, and it was independently associated with a higher risk of SCD and HCM-related heart failure events, particularly when comorbid with depression. Psychological assessment and intervention should be considered to alleviate anxiety symptoms in this population. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000040759.

Effect of a Novel Pocket Compression Device on Hematomas Following Cardiac Electronic Device Implantation in Patients Receiving Direct Oral Anticoagulants.

Background: A pocket hematoma is a well-recognized complication that occurs after pacemaker or defibrillator implantation. It is associated with increased pocket infection and hospital stay. Patients suffering from atrial fibrillation and undergoing cardiovascular electronic implantable device (CIED) surgery are widely prescribed and treated with direct oral anticoagulants (DOACs). In this study, the use of a novel compression device was evaluated to examine its ability to decrease the incidence of pocket hematomas following device implantation with uninterrupted DOACs. Methods: A total of 204 participants who received DOACs and underwent CIED implantation were randomized into an experimental group (novel compression device) and a control group (elastic adhesive tape with a sandbag). The primary outcome was pocket hematoma, and the secondary outcomes were skin erosions and patient comfort score. Grade 3 hematoma was defined as a hematoma that required anticoagulation therapy interruption, re-operation, or prolonged hospital stay. Results: The baseline characteristics of both groups had no significant differences. The incidence of grades 1 and 2 hematomas was significantly lower in the compression device group than in the conventional pressure dressing group (7.8 vs. 23.5 and 2.0 vs. 5.9%, respectively; P < 0.01). Grade 3 hematoma occurred in 2 of 102 patients in the experimental group and 7 of 102 patients in the control group (2.0 vs. 6.9%; P = 0.03). The incidence rates of skin erosion were significantly lower, and the patient comfort score was much higher in the compression device group than in the control group (P < 0.01). Multivariable logistic regression analysis showed that the use of novel compression device was a significant protective factor for pocket hematoma (OR = 0.42; 95% CI, 0.29-0.69, P = 0.01). Conclusions: The incidence of pocket hematomas and skin erosions significantly decreases when the proposed compression device is used for patients undergoing device implantation with uninterrupted DOACs. Thus, the length of hospital stay and re-operation rate can be reduced, and patient comfort can be improved. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2100049430.

Sleep Quality, Sleep Duration, and the Risk of Adverse Clinical Outcomes in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with varying underlying etiologies and occurs in ~5-10% of patients with acute myocardial infarction. Sleep disorders and short sleep duration are common phenomena experienced by patients with coronary heart disease and are associated with poor clinical outcomes. However, the association between sleep quality, sleep duration, and the MINOCA prognosis is less clear. Methods: We performed a prospective observational study of 607 patients with MINOCA between February 2016 and June 2018. The mean follow-up period was 3.9 years. Sleep quality and sleep duration were measured by the Chinese version of the Pittsburgh Sleep Quality Index. The primary endpoint was all-cause mortality, and the secondary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and heart failure hospitalization. Results: During the follow-up period, all-cause death occurred in 69 participants and 105 participants developed MACE. The Kaplan-Meier survival analysis demonstrated a significant association between poor sleep quality and all-cause mortality (log-rank P = 0.005) and MACE (log-rank P = 0.004). Multivariable Cox regression model indicated that poor sleep quality was an independent predictor of all-cause mortality as well as MACE [adjusted hazard ratio (HR) = 1.649; 95% confidence interval (CI), 1.124-2.790; P < 0.001; and adjusted HR = 1.432; 95% CI, 1.043-2.004; P = 0.003, respectively]. For sleep duration, short sleep duration (<6 h/d) was significantly associated with an increased risk of all-cause mortality and MACE (adjusted HR = 1.326; 95% CI, 1.103-1.812; P = 0.004; and adjusted HR = 1.443; 95% CI, 1.145-1.877; P < 0.001, respectively), whereas long sleep duration was not (>8 h/d). A poorer sleep profile (including poor sleep quality and short sleep duration) was associated with a 149.4% increased risk of death (HR = 2.494; 95% CI, 1.754-4.562; P < 0.001) and a 96.7% increased risk of MACE (HR = 1.967; 95% CI, 1.442-3.639; P < 0.001) than those with neither. Conclusion: Sleep disorders were common among Chinese patients with MINOCA. Poor sleep quality and short sleep duration were independently associated with an increased risk of all-cause mortality and MACE in the MINOCA population. Meanwhile, a poor sleep profile has an additive effect with regard to cardiovascular risks; in these populations, efforts should be made to improve both sleep quality and sleep duration for secondary cardiovascular prevention. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000040701.

Effects of Intermittent Compared With Continuous Energy Restriction on Blood Pressure Control in Overweight and Obese Patients With Hypertension.

Background and Aims: Weight-loss diets reduce body weight and improve blood pressure control in hypertensive patients. Intermittent energy restriction (IER) is an alternative to continuous energy restriction (CER) for weight reduction. We aimed to compare the effects of IER with those of CER on blood pressure control and weight loss in overweight and obese patients with hypertension during a 6-month period. Methods: Two hundred and five overweight or obese participants (BMI 28.7 kg/m2) with hypertension were randomized to IER (5:2 diet, a very-low-calorie diet for 2 days per week, 500 kcal/day for women and 600 kcal/day for men, along with 5 days of a habitual diet) compared to a moderate CER diet (1,000 kcal/day for women and 1,200 kcal/day for men) for 6 months. The primary outcomes of this study were changes in blood pressure and weight, and the secondary outcomes were changes in body composition, glycosylated hemoglobin A1c (HbA1c), and blood lipids. Results: Of the 205 randomized participants (118 women and 87 men; mean [SD] age, 50.2 [8.9] years; mean [SD] body mass index, 28.7 [2.6]; mean [SD] systolic blood pressure, 143 [10] mmHg; and mean [SD] diastolic blood pressure, 91 [9] mmHg), 173 completed the study. The intention-to-treat analysis demonstrated that IER and CER are equally effective for weight loss and blood pressure control: the mean (SEM) weight change with IER was -7.0 [0.6] kg vs. -6.8 [0.6] kg with CER, the mean (SEM) systolic blood pressure with IER was -7 [0.7] mmHg vs. -7 [0.6] mmHg with CER, and the mean (SEM) diastolic blood pressure with IER was -6 [0.5] mmHg vs. -5 [0.5] mmHg with CER, (diet by time P = 0.62, 0.39, and 0.41, respectively). There were favorable improvements in body composition, HbA1c, and blood lipid levels, with no differences between groups. Effects did not differ according to completer analysis. No severe hypoglycemia occurred in either group during the trial. Conclusions: Intermittent energy restriction is an effective alternative diet strategy for weight loss and blood pressure control and is comparable to CER in overweight and obese patients with hypertension. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000040468.

Association Between Depression and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

Background Hypertrophic cardiomyopathy (HCM) is considered to be the most common cause of sudden death in young people and is associated with an elevated risk of mood disorders. Depression has emerged as a critical risk factor for development and progression of coronary artery disease; however, the association between depression and HCM outcomes is less clear. We sought to examine the impact of depression on clinical outcomes in patients with HCM. Methods and Results Between January 2014 and December 2017, 820 patients with HCM were recruited and followed for an average of 4.2 years. End points were defined as sudden cardiac death (SCD) events and HCM-related heart failure events. A Chinese version of the Structured Clinical Interview followed the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition and was used to diagnose depression. During the follow-up period, SCD events occurred in 75 individuals (21.8 per 1000 person-years), and HCM-related heart failure events developed in 149 individuals (43.3 per 1000 person-years). Kaplan-Meier cumulative incidence curves showed a significant association of depression disorders with SCD events (log-rank P=0.001) and HCM-related heart failure events (log-rank P=0.005). A multivariate Cox regression analysis indicated that depression was an independent predictor of SCD events and HCM-related heart failure events (41.9 versus 21.7 per 1000 person-years; adjusted hazard ratio [HR], 1.9; 95% CI, 1.6-2.3; P<0.001; and 69.9 versus 38.6 per 1000 person-years; HR, 1.8; 95% CI, 1.6-2.1; P<0.001, respectively). Conclusions Depression is common among patients with HCM. The diagnosis of depression is significantly and independently associated with an increased risk of SCD events and heart failure events in patients with HCM.

Association Between Obstructive Sleep Apnea-Hypopnea Syndrome and Outcomes in Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease.

Background and Aims: Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) occurs in 5-10% of all patients with acute myocardial infarction. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is linked to increased cardiovascular morbidity and mortality, but the relationship of OSAHS and outcomes in patients with MINOCA remains unknown. We aimed to evaluate the association between OSAHS and clinical outcomes in patients with MINOCA. Methods: Between January 2015 and December 2016, we carried out a consecutive cohort study of 583 patients with MINOCA and followed them up for 3 years. An apnea-hypopnea index of ≥ 15 events per hour recorded by polysomnography was defined as the diagnostic criterion for OSAHS. The primary end point was all-cause mortality, and the second end point was major adverse cardiovascular or cerebrovascular events (MACCE), a composite of cardiac death, non-fatal myocardial infarction, heart failure, cardiovascular-related rehospitalization, and stroke. Results: All-cause mortality happened in 69 patients and MACCE occurred in 113 patients during the 3-year follow-up. Kaplan-Meier survival curves indicated the significant relationship of OSAHS with all-cause mortality (log-rank P = 0.012) and MACCE (log-rank P = 0.002). Multivariate Cox regression analysis indicated OSAHS as an independent predictor of all-cause mortality and MACCE [adjusted hazard ratio: 1.706; 95% confidence interval (CI): 1.286-2.423; P = 0.008; and adjusted hazard ratio: 1.733; 95% CI: 1.201-2.389; P < 0.001; respectively], independent of age, sex, cardiovascular risk factors and discharge medications. Conclusions: OSAHS is independently associated with increased risk of all-cause mortality and MACCE in patients with MINOCA. Intervention and treatment should be considered to alleviate OSAHS-associated risk.

Association between anxiety and clinical outcomes in Chinese patients with myocardial infarction in the absence of obstructive coronary artery disease.

BACKGROUND: Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) accounts for approximately 5% - 6% of acute myocardial infarction (AMI) patients. Anxiety symptoms are common in patients with coronary artery disease (CAD), and are associated with a poor prognosis. However, the association between anxiety and MINOCA outcomes is less clear. HYPOTHESIS: Anxiety will be associated with clinical outcomes in patients with MINOCA. METHODS AND RESULTS: Between November 2014 and December 2016, 620 hospitalized patients with MINOCA were recruited from a single center. Within 7 days of coronary angiography, anxiety was assessed using the Zung Self-Rating Anxiety Scale. The primary endpoint was all-cause mortality; secondary endpoint was any major adverse cardiovascular event (MACE). After 3 years, 87 deaths and 151 MACE had occurred. Kaplan-Meier curves indicated the unadjusted rates of all-cause mortality (log-rank P = .045) and MACE (log-rank P = .023) were significantly higher in the anxiety group compared with the control group of patients without anxiety. Multivariate Cox regression analysis showed that clinically significant anxiety was an independent prognostic factor for all-cause mortality as well as MACE (hazard ratio [HR] = 1.547; 95% confidence interval [CI], 1.006-2.380; P = .047; HR = 1.460; 95% CI, 1.049-2.031; P = .025; respectively). CONCLUSIONS: Anxiety is significantly and independently associated with an increased risk of all-cause mortality and MACE in patients with MINOCA.

Effect of exercise-based cardiac rehabilitation on clinical outcomes in patients with myocardial infarction in the absence of obstructive coronary artery disease (MINOCA).

BACKGROUND: Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is characterized by clinical evidence of myocardial infarction with nonobstructive coronary stenosis on angiography (stenosis < 50%). Studies on the effect that exercise-based cardiac rehabilitation (CR) has on outcomes in MINOCA patients are lacking. Therefore, the purpose of this study was to determine the effect of exercise-based CR on clinical outcomes in patients with MINOCA. METHODS: A total of 524 participants with MINOCA were recruited in this prospective cohort study from August 2014 to October 2016 and followed for three years. We randomly divided 524 patients into an exercise-based cardiac rehabilitation group (CR+) and a control group (CR-). The CR+ group followed a home-based exercise-training program three times a week during the three years of moderate continuous training (MCT; 65%-75% of peak heart rate) on a bicycle or treadmill. RESULTS: After one year of follow-up, the Short Form 36 (SF-36) survey showed apparent improvement in the mean physical health score in the CR+ group compared with the CR- group (P < 0.01). During the three-year follow-up, all-cause mortality occurred in 60 individuals, and major adverse cardiovascular events (MACE) happened in 136 individuals. Kaplan-Meier curves indicated a significant reduction in all-cause mortality (log-rank P < 0.05) and MACE (log-rank P < 0.01) in the CR+ group. A multivariate Cox regression analysis indicated that exercise-based CR was associated with a significant reduction in all-cause mortality (hazard ratio [HR] = 0.483; 95% confidence interval [CI], 0.279-0.818; P < 0.01) and MACE (HR = 0.574; 95% CI, 0.403-0.827; P < 0.001). CONCLUSIONS: A long-term exercise-based CR program was associated with superior physical health and a significant reduction in all-cause mortality and MACE in patients with MINOCA.

Long non-coding RNA NEAT1 modulates hypoxia/reoxygenation-induced cardiomyocyte injury via targeting microRNA-520a.

In the present study, a hypoxia/reoxygenation (H/R) model of cardiomyocytes was established to investigate the effects of long non-coding RNA (LncRNA) Nuclear Enriched Abundant Transcript 1 (NEAT1) and microRNA (miR)-520a on H/R-induced cardiomyocyte apoptosis. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were used to evaluate cell apoptosis. Luciferase activity assay was used to investigate whether miR-520a targets NEAT1. Results revealed that NEAT1 was significantly upregulated and miR-520a was downregulated in the ischemia/reperfusion myocardium and the cardiomyocytes that received H/R treatment. Further study demonstrated that knockdown of NEAT1 and overexpression of miR-520a serves a protective role against H/R-induced cardiomyocyte apoptosis. miR-520a directly targets NEAT1 and its expression level is negatively correlated with that of NEAT1. The findings suggested that NEAT1 and miR-520a may protect cardiomyocytes from apoptosis through regulating apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein, and altering cleaved caspase3 expression levels.

MicroRNA-98 attenuates cardiac ischemia-reperfusion injury through inhibiting DAPK1 expression.

Cardiovascular ischemic disease is a large class of diseases that are harmful to human health. The significant role of microRNAs (miRNAs) in terms of controlling cardiac injury has been reported in latest studies. MiR-98 is very important in regulating the apoptosis, the differentiation, the growth as well as the metastasis of cells. Nevertheless, the effect of miR-98 in the cardiac ischemia reperfusion (I/R) injury has rarely been investigated. In the current research, we found that the miR-98 expression was down-regulated in the cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and in the myocardium of the I/R rats. In addition, over-expression of miR-98 could significantly reduce the myocardial oxidative stress and ischemic injury as well as cell apoptosis. In agreement, similar findings were demonstrated in H9c2 cells subjected to H/R injury. Bioinformatic analysis using MiRanda and TargetScan and luciferase activity assay confirmed death-associated protein kinase 1 (DAPK1) as a direct target of miR-98. These findings suggest that miR-98 may be exploited as a novel molecular marker or therapeutic target for myocardial I/R injury. © 2018 IUBMB Life, 71(1):166-176, 2019.

miR-190 protects cardiomyocytes from apoptosis induced by H2O2 through targeting MAPK8 and regulating MAPK8/ERK signal pathway.

MicroRNAs (miRs) have been demonstrated to regulate physiological and pathological processes. Numerous miRsprotect against cardiomyocyte injury induced by oxidative stress. However, the function of miR-190 still remains unclear. Here, we determined the expression level of miR-190 in H9c2 cells under H2O2 treatment and found that miR-190 expression was significantly inhibited by H2O2. Further study indicated that miR-190 significantly reduced cell apoptosisand the LDH and MDA levels of H9c2 cells induced by H2O2. Luciferase activity assay, quantitative real-time-PCR, and Western blot demonstrated that miR-190 directly targets MAPK8. Rescue experiment confirmed this hypothesis. Further study has revealed that miR-190 protects H9c2 cells from oxidative stress injury through inhibiting the MAPK8/ERK signal pathway. In conclusion, these data suggest that miR-190 protects against oxidative stress injury of H9c2 cells induced by H2O2 through inhibiting MAPK8 expression and the MAPK8/ERK pathway. Our findings provide a potential therapeutic target to promote functional recovery after cardiac ischemia/reperfusion.

Sodium tanshinone IIA sulfonate protects rat myocardium against ischemia-reperfusion injury via activation of PI3K/Akt/FOXO3A/Bim pathway.

AIM: To investigate the mechanisms underlying the protective effects of sodium tanshinone IIA sulfonate (STS) in an ischemia-reperfusion (I/R)-induced rat myocardial injury model. METHODS: Male SD rats were iv injected with STS, STS+LY294002 or saline (NS) for 15 d. Then the hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. Cardiac function, infarction size and area at risk were assessed. Cell apoptosis was evaluated with TUNEL staining, DNA laddering and measuring caspase-3 activity. In addition, isolated cardiomyocytes of neonatal rats were pretreated with the above drugs, then exposed to H2O2 (200 mol/L) for 1 h. Cell apoptosis was detected using flow cytometric assay. The levels of p-Akt, p-FOXO3A and Bim were examined with immunoblotting. RESULTS: Compared to NS group, administration of STS (20 mg/kg) significantly reduced myocardial infarct size (40.28%±5.36% in STS group vs 59.52%±7.28% in NS group), and improved the myocardial function as demonstrated by the increased values of dp/dtmax, LVDP and coronary flow at different reperfusion time stages. Furthermore, STS significantly decreased the rate of apoptotic cells (15.11%±3.71% in STS group vs 38.21%±7.83% in NS group), and reduced caspase-3 activity to nearly a quarter of that in NS group. Moreover, STS significantly increased the phosphorylation of Akt and its downstream target FOXO3A, and decreased the expression of pro-apoptotic gene Bim. Co-treatment with the PI3K inhibitor LY294002 (40 mg/kg) partially countered the protective effects induced by STS treatment. In isolated cardiomyocytes, STS exerted similar protective effects as shown in the ex vivo I/R model. CONCLUSION: STS pretreatment reduces infarct size and improves cardiac function in an I/R-induced rat myocardial injury model via activation of Akt/FOXO3A/Bim-mediated signal pathway.

Glycyrrhizin protects rat heart against ischemia-reperfusion injury through blockade of HMGB1-dependent phospho-JNK/Bax pathway.

AIM: Glycyrrhizin (GL) has been found to inhibit extracellular HMGB1 cytokine's activity, and protect spinal cord, liver and brain against I/R-induced injury in experimental animals. The purpose of this study was to investigate the protective effect of GL in rat myocardial I/R-induced injury and to elucidate the underlying mechanisms. METHODS: Male adult Sprague-Dawley rats underwent a 30-min left coronary artery occlusion followed by a 24-h reperfusion. The rats were treated with glycyrrhizin or glycyrrhizin plus recombinant HMGB1 after 30 min of ischemia and before reperfusion. Serum HMGB1, TNF-α and IL-6 levels, and hemodynamic parameters were measured at the onset and different time points of reperfusion. At the end of the experiment, the heart was excised, and the infarct size and histological changes were examined. The levels of Bcl2, Bax and cytochrome c, as well as phospho-ERK1/2, phospho-JNK and phospho-P38 in the heart tissue were evaluated using Western blot analysis, and myocardial caspase-3 activity was measured colorimetrically using BD pharmingen caspase 3 assay kit. RESULTS: Intravenous administration of GL (10 mg/kg) significantly reduced the infarct size, but did not change the hemodynamic parameters at different time points during reperfusion. GL significantly decreased the levels of serum HMGB1, TNF-α and IL-6. GL changed the distribution of Bax and cytochrome c expression between the mitochondrial and cytosolic fractions in the heart tissue, resulting in inhibition of myocardial apoptosis. Moreover, expression of phospho-JNK, but not ERK1/2 and P38 was decreased by GL in the heart tissue. All of the effects produced by GL treatment were reversed by co-administration with the recombinant HMGB1 (100 µg). Intravenous administration of SP600125, a selective phospho-JNK inhibitor (0.5 mg/kg), attenuated HMGB1-dependent Bax translocation and the subsequent apoptosis. CONCLUSION: These results demonstrate that GL alleviates rat myocardial I/R-induced injury via directly inhibiting extracellular HMGB1 cytokine activity and blocking the phospho-JNK/Bax pathway.