Regulatory T Cells in Pathological Cardiac Hypertrophy: Mechanisms and Therapeutic Potential.

BACKGROUND: Pathological cardiac hypertrophy is linked to immune-inflammatory injury, and regulatory T cells (Tregs) play a crucial role in suppressing immune-inflammatory responses. However, the precise role of Tregs in pathological cardiac hypertrophy remains unclear. OBJECTIVE: To summarize the current knowledge on the role and mechanisms of Tregs in pathological cardiac hypertrophy and explore their perspectives and challenges as a new therapeutic approach. RESULTS: Treg cells may play an important protective role in pressure overload (hypertension, aortic stenosis), myocardial infarction, metabolic disorders (diabetes, obesity), acute myocarditis, cardiomyopathy (hypertrophic cardiomyopathy, storage diseases), and chronic obstructive pulmonary disease-related pathological cardiac hypertrophy. Although some challenges remain, the safety and efficacy of Treg-based therapies have been confirmed in some clinical trials, and engineered antigen-specific Treg cells may have better clinical application prospects due to stronger immunosuppressive function and stability. CONCLUSION: Targeting the immune-inflammatory response via Treg-based therapies might provide a promising and novel future approach to the prevention and treatment of pathological cardiac hypertrophy.

Lipoprotein(a), a Lethal Player in Calcific Aortic Valve Disease.

Calcified aortic valve disease (CAVD) is the most common valvular cardiovascular disease with increasing incidence and mortality. The primary treatment for CAVD is surgical or transcatheter aortic valve replacement and there remains a lack of effective drug treatment. Recently, lipoprotein (a) (Lp(a)) has been considered to play a crucial role in CAVD pathophysiology. Multiple studies have shown that Lp(a) represents an independent risk factor for CAVD. Moreover, Lp(a) mediates the occurrence and development of CAVD by affecting aortic valve endothelial dysfunction, indirectly promoting foam cell formation through oxidized phospholipids (OxPL), inflammation, oxidative stress, and directly promotes valve calcification. However, there is a lack of clinical trials with Lp(a) reduction as a primary endpoint. This review aims to explore the relationship and mechanism between Lp(a) and CAVD, and focuses on the current drugs that can be used as potential therapeutic targets for CAVD.

Direct Oral Anticoagulants Combined with Antiplatelet Therapy in the Treatment of Coronary Heart Disease: An Updated Meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) combined with antiplatelet therapy for acute coronary syndrome (ACS) may reduce ischemic events, but there is no consensus on bleeding risk. Moreover, the effect of DOACs on stable coronary artery disease (CAD) needs to be elucidated. We conducted a meta-analysis to summarize the efficacy and safety of DOACs combined with antiplatelet therapy in the treatment of stable CAD and ACS. METHODS: We searched PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials, then performed a systematic review of all 17 randomized controlled trials. RESULTS: For patients with stable CAD, DOACs combined with antiplatelet therapy significantly reduced the rate of major adverse cardiovascular events (MACE) (risk ratio; 95% confidence interval: 0.88; 0.81-0.95) and ischemic stroke (0.62; 0.50-0.77), with a relatively low risk of major bleeding (1.72; 1.42-2.07). For patients with ACS, the combination of DOACs reduced the risk of MACE (0.91; 0.85-0.97), myocardial infarction (MI) (0.90; 0.83-0.98), and ischemic stroke (0.75; 0.58-0.97), accompanied by increased non-fatal bleeding events and intracranial hemorrhage (3.42; 1.76-6.65). Results were similar when restricting the analysis to phase III studies except for the rate of stroke in patients with ACS. CONCLUSIONS: Combination therapy reduced the incidence of MI in ACS patients, but the risk of bleeding from intracranial hemorrhaging outweighs the benefit of MACE driven by MI. That is due to combination therapy having no positive impact on mortality; thus, the benefit-risk balance may be more favorable  in patients with stable CAD.

Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction.

Mitochondria are important organelles in eukaryotic cells. Normal mitochondrial homeostasis is subject to a strict mitochondrial quality control system, including the strict regulation of mitochondrial production, fission/fusion and mitophagy. The strict and accurate modulation of the mitochondrial quality control system, comprising the mitochondrial fission/fusion, mitophagy and other processes, can ameliorate the myocardial injury of myocardial ischaemia and ischaemia-reperfusion after myocardial infarction, which plays an important role in myocardial protection after myocardial infarction. Further research into the mechanism will help identify new therapeutic targets and drugs for the treatment of myocardial infarction. This article aims to summarize the recent research regarding the mitochondrial quality control system and its molecular mechanism involved in myocardial infarction, as well as the potential therapeutic targets in the future.

Methotrexate can prevent cardiovascular events in patients with rheumatoid arthritis: An updated meta-analysis.

AIMS: The incidence of cardiovascular events (CVEs) in patients with rheumatoid arthritis (RA) is higher than that in people without RA. This may be because inflammation promotes the progression of atherosclerosis. Anti-inflammatory drugs might reduce the occurrence of CVEs in patients with RA. Methotrexate (MTX) is a conventional synthetic anti-rheumatic drug that is widely used in the treatment of RA. We performed a meta-analysis to determine whether MTX can prevent CVEs in RA patients. Then, we discussed the possibility of using MTX to prevent recurred CVEs in patients with coronary heart disease (CHD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library using the key words "methotrexate," "cardiovascular," "acute coronary syndrome," "coronary heart disease," "myocardial infarction," "angina pectoris," and "rheumatoid arthritis." The efficacy outcome was defined as a composite of CVEs, including stable angina, acute coronary syndrome, stroke, heart failure, and cardiac death. RESULTS: A total of 10 studies and 195,416 RA patients were included in our meta-analysis, and the effect size of relative risk (RR) was pooled using a fixed effect model. The results showed that MTX prevented CVEs in RA patients (RR: 0.798, 95% CI 0.726-0.876, P = .001, I2 = 27. 9%). CONCLUSION: MTX can prevent CVEs in RA patients, but there is not sufficient evidence for using MTX to treat patients with CHD.

The role and research progress of the balance and interaction between regulatory T cells and other immune cells in obesity with insulin resistance.

Metabolic homoeostasis in adipose tissue plays a major role in obesity-related insulin resistance (IR). Regulatory T (Treg) cells have been recorded to regulate metabolic homoeostasis in adipose tissue. However, their specific mechanism is not yet known. This review aims to present the role of Treg cells and other immune cells in obesity-associated IR, focusing on the balance of numbers and functions of Treg cells and other immune cells as well as the crucial role of their interactions in maintaining adipose tissue homoeostasis. Th1 cells, Th17 cells, CD8+ T cells, and pro-inflammatory macrophages mediate the occurrence of obesity and IR by antagonizing Treg cells, while anti-inflammatory dendritic cells, eosinophils and type 2 innate lymphoid cells (ILC2s) regulate the metabolic homoeostasis of adipose tissue by promoting the proliferation and differentiation of Treg cells. γ δ T cells and invariant natural killer T (iNKT) cells have complex effects on Treg cells, and their roles in obesity-associated IR are controversial. The balance of Treg cells and other immune cells can help maintain the metabolic homoeostasis of adipose tissue. Further research needs to explore more specific molecular mechanisms, thus providing more precise directions for the treatment of obesity with IR.

Circular RNA in cardiovascular disease: Expression, mechanisms and clinical prospects.

Circular RNAs (circRNAs) are a group of covalently closed, endogenous, non-coding RNAs, which exist widely in human tissues including the heart. Increasing evidence has shown that cardiac circRNAs play crucial regulatory roles in cardiovascular diseases (CVDs). In this review, we aimed to provide a systemic understanding of circRNAs with a special emphasis on the cardiovascular system. We have summarized the current research on the classification, biogenesis and properties of circRNAs as well as their participation in the pathogenesis of CVDs. CircRNAs are conserved, stable and have specific spatiotemporal expression; thus, they have been accepted as a potential diagnostic marker or an incremental prognostic biomarker for CVDs.

Advances in the role and mechanism of BAG3 in dilated cardiomyopathy.

The B cell lymphoma 2-associated anthanogene (BAG3) is an anti-apoptotic co-chaperone protein. Previous reports suggest that mutations in BAG3 are associated with dilated cardiomyopathy. This review aims to summarize the current understanding of the relationship between BAG3 mutations and dilated cardiomyopathy, primarily focusing on the role and protective mechanism of BAG3 in cardiomyocytes from individuals with dilated cardiomyopathy. The results of published studies show that BAG3 is critically important for reducing cardiomyocyte apoptosis, maintaining protein homeostasis, regulating mitochondrial stability, modulating myocardial contraction, and reducing cardiac arrhythmia, which suggests an indispensable protective mechanism of BAG3 in dilated cardiomyopathy. The significant role of BAG3 in protecting cardiomyocytes provides a new direction for the diagnosis and treatment of dilated cardiomyopathy. However, further research is required to explore the molecular mechanisms that regulate BAG3 expression, to identify a novel therapy for patients with dilated cardiomyopathy.

Sex differences in survival after out-of-hospital cardiac arrest: a meta-analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of sudden cardiac death worldwide. Researchers have found significant pathophysiological differences between females and males and clinically significant sex differences related to medical services. However, conflicting results exist and there is no uniform agreement regarding sex differences in survival and prognosis after OHCA. Therefore, we investigated the relationship between the prognosis of OHCA and sex factors. METHODS: We comprehensively searched the PubMed, Embase, and Cochrane databases and obtained a total of 1042 articles, from which 33 studies were selected for inclusion. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS: The meta-analysis included 1,268,664 patients. Compared with males, females were older (69.7 years vs. 65.4 years, p < 0.05) and more frequently suffered OHCA without witnesses (58.39% vs 62.70%, p < 0.05). Females were less likely to receive in-hospital interventions than males. There was no significant difference between females and males in the survival from OHCA to hospital admission (OR 0.99, 95% CI 0.89-1.1). However, females had lower chances for survival from hospital admission to discharge (OR 0.59, 95% CI 0.48-0.73), overall survival to hospital discharge (OR 0.73, 95% CI 0.62-0.86), and favorable neurological outcomes (OR 0.62, 95% CI 0.47-0.83) compared with males. CONCLUSIONS: Our results indicate that the overall discharge survival rate of females is lower than that of males, and females face a poor prognosis of the nervous system. This is likely related to the pathophysiological characteristics of females, more conservative treatment measures compared with males, and different post-resuscitation care. However, these findings should be interpreted with caution due to the presence of several confounding factors.

A Soluble Epoxide Hydrolase Inhibitor Upregulated KCNJ12 and KCNIP2 by Downregulating MicroRNA-29 in a Mouse Model of Myocardial Infarction.

BACKGROUND: Soluble epoxide hydrolase inhibitors (sEHi) have anti-arrhythmic effects, and we previously found that the novel sEHi t-AUCB (trans-4[-4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid) significantly inhibited ventricular arrhythmias after myocardial infarction (MI). However, the mechanism is unknown. It's known that microRNA-29 (miR-29) participates in the occurrence of arrhythmias. In this study, we investigated whether sEHi t-AUCB was protective against ischemic arrhythmias by modulating miR-29 and its target genes KCNJ12 and KCNIP2. METHODS: Male 8-week-old C57BL/6 mice were divided into five groups and fed distilled water only or distilled water with t-AUCB of different dosages for seven days. Then, the mice underwent MI or sham surgery. The ischemic region of the myocardium was obtained 24 hours after MI to detect miR-29, KCNJ12, and KCNIP2 mRNA expression levels via real-time PCR and KCNJ12 and KCNIP2 protein expression levels via western blotting. RESULTS: MiR-29 expression levels were significantly increased in the ischemic region of MI mouse hearts and the mRNA and protein expression levels of its target genes KCNJ12 and KCNIP2 were significantly decreased. T-AUCB prevented these changes dose-dependently. CONCLUSION: The sEHi t-AUCB regulates the expression levels of miR-29 and its target genes KCNJ12 and KCNIP2, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmia.

Efficacy and Safety of Inorganic Nitrate Versus Placebo Treatment in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is a lack of effective treatments. In this meta-analysis, we assessed the efficacy and safety of inorganic nitrate in patients with HFpEF. METHODS AND RESULTS: We systematically searched PubMed, Embase, and the Cochrane Library from the inception of the database through March 2020. We included randomized controlled trials that compared the efficacy and safety of inorganic nitrate with a placebo in the treatment of patients with HFpEF. The primary outcome of the meta-analysis was exercise capacity (measured as a change in peak oxygen uptake). We also assessed the effect of inorganic nitrate on diastolic function (measured as changes in E/A and E/e', assessed by echocardiography), quality of life (estimated using the Kansas City Cardiomyopathy Questionnaire), and rest and exercise hemodynamics (measured by invasive cardiac catheterization). In the pooled data analysis, there were no significant differences in peak oxygen uptake (mL/kg/min) [mean difference (MD), 0.25; 95% CI, - 0.07 to 0.57], diastolic function [E/A-standardized mean difference (SMD), 0.51; 95% CI, - 0.17 to 1.20; or E/e'-SMD, 0.02; 95% CI, - 0.23 to 0.27], or quality of life. However, a significant change was observed in the rest and exercise hemodynamics between the inorganic nitrate and placebo treatment in HFpEF patients. No study has reported the effect of inorganic nitrate on hospitalization and mortality of patients with HFpEF. CONCLUSIONS: In patients with HFpEF, the use of inorganic nitrate is not associated with improvements in exercise capacity, diastolic function, and quality of life but is associated with significant changes in rest and exercise hemodynamics.

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating low-density lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.