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Hereditary transthyretin amyloid (ATTRv) cardiomyopathy (CM) is caused by mutations in the TTR gene. TTR mutations contribute to TTR tetramer destabilization and dissociation, leading to excessive deposition of insoluble amyloid fibrils in the myocardium and finally resulting in cardiac dysfunction. In this article, we report a case of a Chinese patient with transthyretin mutation p.D58Y and provide detailed information on cardiac amyloidosis, including transthoracic echocardiography, cardiac magnetic resonance, and SPECT imaging for the first time. Our report aims to provide a better understanding of ATTR genotypes and phenotypes.

BackgroundAccording to some recent observational studies, the gut microbiota influences atherosclerosis via the gut microbiota-artery axis. However, the causal role of the gut microbiota in atherosclerosis remains unclear. Therefore, we used a Mendelian randomization (MR) strategy to try to dissect this causative link.MethodsThe biggest known genome-wide association study (GWAS) (n = 13,266) from the MiBioGen collaboration was used to provide summary data on the gut microbiota for a two-sample MR research. Data on atherosclerosis were obtained from publicly available GWAS data from the FinnGen consortium, including cerebral atherosclerosis (104 cases and 218,688 controls), coronary atherosclerosis (23,363 cases and 187,840 controls), and peripheral atherosclerosis (6631 cases and 162,201 controls). The causal link between gut microbiota and atherosclerosis was investigated using inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode approaches, among which inverse variance weighting was the main research method. Cochran’s Q statistic was used to quantify the heterogeneity of instrumental variables (IVs), and the MR Egger intercept test was used to assess the pleiotropy of IVs.ResultsInverse-variance-weighted (IVW) estimation showed that genus Ruminiclostridium 9 had a protective influence on cerebral atherosclerosis (OR = 0.10, 95% CI: 0.01–0.67, P = 0.018), while family Rikenellaceae (OR = 5.39, 95% CI: 1.50–19.37, P = 0.010), family Streptococcaceae (OR = 6.87, 95% CI: 1.60–29.49, P = 0.010), genus Paraprevotella (OR = 2.88, 95% CI: 1.18–7.05, P = 0.021), and genus Streptococcus (OR = 5.26, 95% CI: 1.28–21.61, P = 0.021) had pathogenic effects on cerebral atherosclerosis. For family Acidaminococcaceae (OR = 0.87, 95% CI: 0.76–0.99, P = 0.039), the genus Desulfovibrio (OR = 0.89, 95% CI: 0.80–1.00, P = 0.048), the genus RuminococcaceaeUCG010 (OR = 0.80, 95% CI: 0.69–0.94, P = 0.006), and the Firmicutes phyla (OR = 0.87, 95% CI: 0.77–0.98, P = 0.023) were protective against coronary atherosclerosis. However, the genus Catenibacterium (OR = 1.12, 95% CI: 1.00–1.24, P = 0.049) had a pathogenic effect on coronary atherosclerosis. Finally, class Actinobacteria (OR = 0.83, 95% CI: 0.69–0.99, P = 0.036), family Acidaminococcaceae (OR = 0.76, 95% CI: 0.61–0.94, P = 0.013), genus Coprococcus2 (OR = 0.76, 95% CI: 0.60–0.96, P = 0.022), and genus RuminococcaceaeUCG010 (OR = 0.65, 95% CI: 0.46–0.92, P = 0.013), these four microbiota have a protective effect on peripheral atherosclerosis. However, for the genus Lachnoclostridium (OR = 1.25, 95% CI: 1.01–1.56, P = 0.040) and the genus LachnospiraceaeUCG001 (OR = 1.22, 95% CI: 1.04–1.42, P = 0.016), there is a pathogenic role for peripheral atherosclerosis. No heterogeneity was found for instrumental variables, and no considerable horizontal pleiotropy was observed.ConclusionWe discovered that the presence of probiotics and pathogens in the host is causally associated with atherosclerosis, and atherosclerosis at different sites is causally linked to specific gut microbiota. The specific gut microbiota associated with atherosclerosis identified by Mendelian randomization studies provides precise clinical targets for the treatment of atherosclerosis. In the future, we can further examine the gut microbiota’s therapeutic potential for atherosclerosis if we have a better grasp of the causal relationship between it and atherosclerosis.

Abstract Background Both the crystalline and soluble forms of cholesterol increase macrophage secretion of interleukin 1β (IL-1β), aggravating the inflammatory response in atherosclerosis (AS). However, the link between cholesterol and regulatory T cells (Tregs) remains unclear. This study aimed to investigate the effect of cholesterol treatment on Tregs. Methods Differentiation of induced Tregs (iTregs) was analyzed using flow cytometry. The expression of hypoxia-inducible factor-1a (HIF-1a) and its target genes was measured by western blotting and/or RT-qPCR. Two reporter jurkat cell lines were constructed by lentiviral transfection. Mitochondrial function and the structure of natural Tregs (nTregs) were determined by tetramethylrhodamine (TMRM) and mitoSOX staining, Seahorse assay, and electron microscopy. The immunoregulatory function of nTregs was determined by nTreg-macrophage co-culture assay and ELISA. Results Cholesterol treatment suppressed iTreg differentiation and impaired nTreg function. Mechanistically, cholesterol induced the production of mitochondrial reactive oxygen species (mtROS) in naïve T cells, inhibiting the degradation of HIF-1α and unleashing its inhibitory effects on iTreg differentiation. Furthermore, cholesterol-induced mitochondrial oxidative damage impaired the immunosuppressive function of nTregs. Mixed lymphocyte reaction and nTreg-macrophage co-culture assays revealed that cholesterol treatment compromised the ability of nTregs to inhibit pro-inflammatory conventional T cell proliferation and promote the anti-inflammatory functions of macrophages. Finally, mitoTEMPO (MT), a specific mtROS scavenger, restored iTreg differentiation and protected nTreg from further deterioration. Conclusion Our findings suggest that cholesterol may aggravate inflammation within AS plaques by acting on both iTregs and nTregs, and that MT may be a promising anti-atherogenic drug.

Summary: Emerging evidence supports that intestinal microbial metabolite short-chain fatty acids (SCFAs) increase the pool of regulatory T cells (Tregs) in the colonic lamina propria (cLP) and protect against nonintestinal inflammatory diseases, such as atherosclerosis and post-infarction myocardial inflammation. However, whether and how SCFAs protect the inflamed aortas of subjects with abdominal aortic aneurysm (AAA) remains unclear. Here, the authors revealed the protective effect of SCFAs on AAA in mice and the expansion of Tregs in the cLP, and propionate exerted Treg-dependent protection against AAA by promoting the recirculation of cLP-Tregs through colonic draining lymph nodes (dLNs) to the inflamed aorta.

BackgroundUntil now, few articles have revealed the potential roles of innate lymphoid cells (ILCs) in cardiovascular diseases. However, the infiltration of ILC subsets in ischemic myocardium, the roles of ILC subsets in myocardial infarction (MI) and myocardial ischemia-reperfusion injury (MIRI) and the related cellular and molecular mechanisms have not been described with a sufficient level of detail.MethodIn the current study, 8-week-old male C57BL/6J mice were divided into three groups: MI, MIRI and sham group. Single-cell sequencing technology was used to perform dimensionality reduction clustering of ILC to analyze the ILC subset landscape at a single-cell resolution, and finally flow cytometry was used to confirm the existence of the new ILC subsets in different disease groups.ResultsFive ILC subsets were found, including ILC1, ILC2a, ILC2b, ILCdc and ILCt. It is worth noting that ILCdc, ILC2b and ILCt were identified as new ILC subclusters in the heart. The cellular landscapes of ILCs were revealed and signal pathways were predicted. Furthermore, pseudotime trajectory analysis exhibited different ILC statuses and traced related gene expression in normal and ischemic conditions. In addition, we established a ligand–receptor–transcription factor–target gene regulatory network to disclose cell communications among ILC clusters. Moreover, we further revealed the transcriptional features of the ILCdc and ILC2a subsets. Finally, the existence of ILCdc was confirmed by flow cytometry.ConclusionCollectively, by characterizing the spectrums of ILC subclusters, our results provide a new blueprint for understanding ILC subclusters’ roles in myocardial ischemia diseases and further potential treatment targets.

Abstract In addition to maintaining immune tolerance, Foxp3+ regulatory T cells (Tregs) perform specialized functions in tissue homeostasis and remodeling. However, whether Tregs in aortic aneurysms have a tissue‐specific phenotype and function is unclear. Here, a special group of Tregs that potentially inhibit abdominal aortic aneurysm (AAA) progression are identified and functionally characterized. Aortic Tregs gradually increase during the process of AAA and are mainly recruited from peripheral circulation. Single‐cell TCR sequencing and bulk RNA sequencing demonstrate their unique phenotype and highly expressed trefoil factor 1 (Tff1). Foxp3cre/creTff1flox/flox mice are used to clarify the role of Tff1 in AAA, suggesting that aortic Tregs secrete Tff1 to regulate smooth muscle cell (SMC) survival. In vitro experiments confirm that Tff1 inhibits SMC apoptosis through the extracellular signal‐regulated kinase (ERK) 1/2 pathway. The findings reveal a tissue‐specific phenotype and function of aortic Tregs and may provide a promising and novel approach for the prevention of AAA.

Cardiovascular disease (CVD) remains the leading cause of mortality globally. Circular RNAs (circRNAs) have attracted extensive attention for their roles in the physiological and pathological processes of various cardiovascular diseases (CVDs). In this review, we briefly describe the current understanding of circRNA biogenesis and functions and summarize recent significant findings regarding the roles of circRNAs in CVDs. These results provide a new theoretical basis for diagnosing and treating CVDs.

Overactivated inflammatory responses contribute to adverse ventricular remodeling after myocardial infarction (MI). Regulatory B cells (Bregs) are a newly discovered subset of B cells with immunomodulatory roles in many immune and inflammation-related diseases. Our study aims to determine whether the expansion of Bregs exerts a beneficial effect on ventricular remodeling and explore the mechanisms involved. Here, we showed that adoptive transfer of Bregs ameliorated ventricular remodeling in a murine MI model, as demonstrated by improved cardiac function, decreased scar size and attenuated interstitial fibrosis without changing the survival rate. Reduced Ly6Chi monocyte infiltration was found in the hearts of the Breg-transferred mice, while the infiltration of Ly6Clo monocytes was not affected. In addition, the replenishment of Bregs had no effect on the myocardial accumulation of T cells or neutrophils. Mechanistically, Bregs reduced the expression of C-C motif chemokine receptor 2 (CCR2) in monocytes, which inhibited proinflammatory monocyte recruitment to the heart from the peripheral blood and mobilization from the bone marrow. Breg-mediated protection against MI was abrogated by treatment with an interleukin 10 (IL-10) antibody. Finally, IL-10 neutralization reversed the effect of Bregs on monocyte migration and CCR2 expression. The present study suggests a therapeutic value of Bregs in limiting ventricular remodeling after MI through decreasing CCR2-mediated monocyte recruitment and mobilization. [ABSTRACT FROM AUTHOR]

Aims Recently, interleukin (IL)-9was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. Methods and results IL-9Rwas expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/-mice fed a western diet for 10 weekswere administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4+IL-9+ T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. Conclusion Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Abstract Background  RNA interference (RNAi) is now being exploited as a powerful tool for gene knockdown. Recently, we had shown that inducible co-stimulator (ICOS) was up-regulated in experimental autoimmune uveoretinitis (EAU). The aim of this study was to investigate whether intravitreal injection of small interfering RNA (siRNA) plasmid, targeting ICOS, suppresses the ongoing experimental autoimmune uveoretinitis (EAU) in rats. Methods  Oligonucleotide targeting ICOS was cloned into linearized pRNAT-U6.1/Neo eukaryotic expression vector to construct the recombinant plasmid (pRNAT-U6.1/Neo-ICOS). After transfecting activated rat T cells with the recombinant plasmid, ICOS mRNA and protein expression levels were determined by real-time RT-PCR and Western blot analysis respectively. Rats were immunized with IRBP R16 peptide emulsified in complete Freund’s adjuvant (CFA) and given an intravitreal injection of pRNAT-U6.1/Neo-ICOS on day 6 after immunization. After 13days of immunization, the ICOS protein expression and CD4 + ICOS + T cells were identified in retinae through Western blot analysis and flow cytometry respectively. Intraocular inflammation was assessed by the scores of the clinical and histological appearances. Delayed-type hypersensitivity (DTH) and lymphocyte proliferation were detected to evaluate the systemic effect of intravitreal injection of pRNAT-U6.1/Neo-ICOS. Result  The recombinant plasmid (pRNAT-U6.1/Neo-ICOS) for the ICOS siRNA was successfully constructed. In vitro studies using the recombinant plasmid has showed the down-regulation of ICOS gene expression both at the mRNA and protein levels. Clinical and pathological scores showed that ocular inflammation of pRNAT-U6.1/Neo-ICOS-treated eyes was markedly less than that of vehicle-treated eyes. The expression of ICOS protein and the amount of CD4 + ICOS + T cells in retinae significantly decreased by intravitreal injection of the recombinant plasmid, whereas delayed-type hypersensitivity response and lymphocyte proliferation were not impaired in rats treated with the recombinant plasmid. Conclusion  Intravitreal injection of siRNA plasmid targeting ICOS effectively down-regulated the expression of ICOS, and was highly effective in suppressing the ongoing process of EAU without any side-effects on systemic cellular immunity. [ABSTRACT FROM AUTHOR]

CD4+ T cells are abnormally activated in patients with dilated cardiomyopathy (DCM) and might be associated with the immunopathogenesis of the disease. However, the underlying mechanisms of CD4+ T cell activation remain largely undefined. Our aim was to investigate whether the dysregulation of microRNAs (miRNAs) was associated with CD4+ T cell activation in DCM. CD4+Tcells fromDCMpatients showed increased expression levels of CD25 and CD69 and enhanced proliferation in response to anti-CD3/28, indicating an activated state. miRNA profiling analysis of magnetically sorted CD4+Tcells revealed a distinct pattern of miRNA expression in CD4+ T cells from DCM patients compared with controls. The level of miRNA-451a (miR-451a) was significantly decreased in the CD4+ T cells of DCM patients compared with that of the controls. The transfection of T cells with an miR-451a mimic inhibited their activation and proliferation, whereas an miR-451a inhibitor produced the opposite effects. Myc was directly inhibited by miR-451a via interaction with its 3+-UTR, thus identifying it as an miR-451a target inTcells. The knockdown of Myc suppressed the activation and proliferation of T cells, and the expression of Myc was significantly up-regulated at themRNA level in CD4+ T cells from patients with DCM. A strong inverse correlation was observed between the Myc mRNA expression and miR-451a transcription level. Our data suggest that the down-regulation of miR-451a contributes to the activation and proliferation of CD4+ T cells by targeting the transcription factor Myc in DCM patients and may contribute to the immunopathogenesis of DCM. [ABSTRACT FROM AUTHOR]