Novel UV-B Phototherapy With a Light-Emitting Diode Device Prevents Atherosclerosis by Augmenting Regulatory T-Cell Responses in Mice.

BACKGROUND: Ultraviolet B (UV-B) irradiation is an effective treatment for human cutaneous disorders and was shown to reduce experimental atherosclerosis by attenuating immunoinflammatory responses. The aim of this study was to clarify the effect of specific wavelengths of UV-B on atherosclerosis and the underlying mechanisms focusing on immunoinflammatory responses. METHODS AND RESULTS: Based on light-emitting diode technology, we developed novel devices that can emit 282 nm UV-B, which we do not receive from natural sunlight, 301 nm UV-B, and clinically available 312 nm UV-B. We irradiated 6-week-old male atherosclerosis-prone Apoe-/- (apolipoprotein E-deficient) mice with specific wavelengths of UV-B and evaluated atherosclerosis and immunoinflammatory responses by performing histological analysis, flow cytometry, biochemical assays, and liquid chromatography/mass spectrometry-based lipidomics. Irradiation of 282 nm UV-B but not 301 or 312 nm UV-B significantly reduced the development of aortic root atherosclerotic plaques and plaque inflammation. This atheroprotection was associated with specifically augmented immune responses of anti-inflammatory CD4+ Foxp3 (forkhead box P3)+ regulatory T cells in lymphoid tissues, whereas responses of other immune cells were not substantially affected. Analysis of various lipid mediators revealed that 282 nm UV-B markedly increased the ratio of proresolving to proinflammatory lipid mediators in the skin. CONCLUSIONS: We demonstrated that 282 nm UV-B irradiation effectively reduces aortic inflammation and the development of atherosclerosis by systemically augmenting regulatory T-cell responses and modulating the balance between proresolving and proinflammatory lipid mediators in the skin. Our findings indicate that a novel 282 nm UV-B phototherapy could be an attractive approach to treat atherosclerosis.

The Gut Microbiota Profile in Heart Failure Patients: A Systematic Review.

BACKGROUND AND AIMS: Traditional cardiovascular risk factors are established predictors of heart failure (HF). However, the human gut microbiota is suggested to potentially interact with the cardiovascular system through the "gut-heart axis", which induces inflammation and contributes to HF pathogenesis. This systematic review aims to confirm the interconnection between the gut microbiome in HF patients. METHODS: Peer-reviewed human studies comparing the gut microbiota profile in adult patients with HF and healthy controls (HCs) up to April 18, 2022, were searched in Ovid MEDLINE, Ovid EMBASE, SCOPUS, and the Cochrane Library. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: A total of nine studies, including 317 HF patients and 510 HCs, were included in the review. Decreased gut microbiota richness and similar microbial diversity (alpha diversity), and significantly different gut microbiota composition (beta diversity) were observed between HF patients and HCs. In comparison to HCs, HF patients had a greater abundance of Actinobacteria, Proteobacteria, and Synergistetes phyla; Enterococcus, Escherichia, Klebsiella, Lactobacillus, Streptococcus, and Veilonella genera and Ruminococcus gnavus, Streptococcus sp., and Veilonella sp. species. In contrast, there was decreased abundance of Firmicutes phylum; Blautia, Eubacterium, Faecalibacterium, and Lachnospiraceae FCS020 genera; and Dorea longicatena, Eubacterium rectale, Faecalibacterium prausnitzii, Oscillibacter sp., and Sutterella wadsworthensis species in HF patients. CONCLUSIONS: Gut microbiota diversity, richness, and composition in HF patients differ significantly from the healthy population. Overall, short-chain fatty acid (SCFA)-producing gut microbiota was depleted in HF patients. However, different underlying comorbidities, environments, lifestyles, and dietary choices could affect gut microbiota heterogeneity.

Depletion of Foxp3+ regulatory T cells augments CD4+ T cell immune responses in atherosclerosis-prone hypercholesterolemic mice.

Compelling evidence suggests a crucial role for Foxp3+ regulatory T cells (Tregs) in the control of atherosclerosis. Although suppression of pro-inflammatory CD4+ T cell immune responses is supposed to be important for athero-protective action of Foxp3+ Tregs, few studies have provided direct evidence for this protective mechanism. We investigated the impact of Foxp3+ Treg depletion on CD4+ T cell immune responses and the development of atherosclerosis under hypercholesterolemia. We employed DEREG (depletion of regulatory T cells) mice on an atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr -/-) background, which carry a diphtheria toxin (DT) receptor under the control of the foxp3 gene locus. In these mice, DT injection led to efficient depletion of Foxp3+ Tregs in spleen, lymph nodes and aorta. Depletion of Foxp3+ Tregs augmented CD4+ effector T cell immune responses and aggravated atherosclerosis without affecting plasma lipid profile. Notably, the proportion of pro-inflammatory IFN-γ-producing T cells were increased in spleen and aorta following Foxp3+ Treg depletion, implying that Foxp3+ Tregs efficiently regulate systemic and aortic T cell-mediated inflammatory responses under hypercholesterolemia. Unexpectedly, Foxp3+ Treg depletion resulted in an increase in anti-inflammatory IL-10-producing T cells, which was not sufficient to suppress the augmented proinflammatory T cell immune responses caused by reduced numbers of Foxp3+ Tregs. Our data indicate that Foxp3+ Tregs suppress pro-inflammatory CD4+ T cell immune responses to control atherosclerosis under hypercholesterolemia.

Takotsubo Cardiomyopathy: A Brief Review.

Takotsubo cardiomyopathy is a reversible cardiomyopathy with a unique morphological feature of the left ventricle characterized by an apical ballooning appearance known for approximately known 25 years. Catecholamine drive plays an essential role in the pathogenesis and pathophysiology of Takotsubo cardiomyopathy; hence, it is also called stress cardiomyopathy. Physical stress could also have an impact and leads to a greater variety of characteristics in Takotsubo cardiomyopathy. Supportive and symptomatic medication remains the mainstay therapy with priority to improving the function of the left ventricle for several days and full recovery in 3-4 weeks. Due to its similarity with myocardial infarction, Takotsubo cardiomyopathy requires careful diagnosis and management for the best possible outcome.

Cytotoxic T Lymphocyte-Associated Antigen-4 Protects Against Angiotensin II-Induced Kidney Injury in Mice.

Background: Chronic inflammation caused by pathogenic immune response is crucial in the pathogenesis of kidney disease. In particular, T-cell-mediated adaptive immune responses evoke pathogenic immunoinflammatory responses and contribute to kidney injury (KI). Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a potent negative regulator of T-cell immune responses, protects against immunoinflammatory diseases of the arteries such as atherosclerosis and abdominal aortic aneurysm. However, the role of this molecule in kidney disease remains undetermined. Methods and Results: To examine the effects of CTLA-4 overexpression on angiotensin II (AngII)-induced KI, we induced KI in CTLA-4 transgenic/apolipoprotein E-deficient (CTLA-4-Tg/Apoe -/-) mice or Apoe -/- mice fed a high-cholesterol diet by continuously infusing AngII. Overexpression of CTLA-4 ameliorated the development of AngII-induced KI and fibrosis. Moreover, CTLA-4-Tg/Apoe -/- mice had decreased expression of pro-inflammatory molecules in the kidney. Conclusions: CTLA-4 overexpression has a protective effect on AngII-induced KI, and increasing CTLA-4 may be a novel therapeutic strategy to prevent the progression of kidney disease.

CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice.

Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E-deficient (Apoe-/-) mice or control Apoe-/- mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4+ T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c+ dendritic cells in lymphoid tissues. CTLA-4-Tg/Apoe-/- mice had reduced accumulation of macrophages and CD4+ T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.

Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis.

BACKGROUND: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. METHODS: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. RESULTS: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei. CONCLUSIONS: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

Ultraviolet B Exposure Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Expanding CD4+Foxp3+ Regulatory T Cells.

BACKGROUND: Pathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA. METHODS AND RESULTS: We used an angiotensin II-induced AAA model in apolipoprotein E-deficient mice fed a high-cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB-irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II-infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB-irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+CD44highCD62Llow T cells in para-aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells. CONCLUSIONS: Our data suggest that UVB-dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA.

Impact of CD14++CD16+ monocytes on plaque vulnerability in diabetic and non-diabetic patients with asymptomatic coronary artery disease: a cross-sectional study.

BACKGROUND: Previously, we have reported that daily glucose fluctuations could affect coronary plaque vulnerability, but the underlying mechanisms remained unclear. This study sought to investigate the impact of CD14++CD16+ monocytes on plaque vulnerability, as assessed by virtual histology intravascular ultrasound (VH-IVUS), as well as their relationship to fluctuating glucose levels in patients with asymptomatic coronary artery disease (CAD). METHODS: Fifty-one patients with asymptomatic CAD, who were undergoing lipid-lowering therapy and underwent VH-IVUS evaluation for angiographically mild to moderate lesions, were enrolled in the study. Standard VH-IVUS parameters, including the percentage volume of the necrotic core (%NC) within the plaque and the presence of a virtual histology thin-cap fibroatheroma (VH-TCFA), were then evaluated. Additionally, monocyte subsets were assessed by flow cytometry, and daily glucose fluctuations were analyzed by measuring the mean amplitude of glycemic excursion (MAGE). RESULTS: Among 82 plaques from 22 diabetes mellitus (DM) patients and 29 non-DM patients, 15 VH-TCFAs were identified. CD14++CD16+ monocyte counts significantly correlated with both  %NC and the presence of VH-TCFA (%NC: r = 0.339, p = 0.002; VH-TCFA: p = 0.003). Multivariate logistic regression analysis revealed that CD14++CD16+ monocyte counts were independently associated with VH-TCFA (odds ratio = 1.029, p = 0.004). Furthermore, CD14++CD16+ monocyte counts were significantly correlated with the MAGE score in the non-DM patients (r = 0.544, p = 0.005). CONCLUSIONS: CD14++CD16+ monocyte levels are associated with coronary plaque vulnerability and can serve as a biomarker for VH-TCFA in patients with CAD undergoing lipid-lowering therapy. In patients without DM, glucose fluctuations may alter the balance of monocyte subsets. Trial registration UMIN Registry number: UMIN000021228.

Galectin-3: a novel biomarker for the prognosis of heart failure.

Heart failure (HF) is still a global burden which carries substantial risk of morbidity and mortality. Thus, appropriate approach of diagnosis and layering the prognosis of HF are of great importance. In this paper we discuss and review a novel biomarker, which is called galectin-3 and already approved by Food and Drugs Administration (FDA) as a prediction tool for HF. Galectin-3, which is secreted by macrophages under the influence of mediators like osteopontin, has been known for its significant role in mediating cardiac fibrosis and inflammation. Numerous studies have shown galectin-3 as a novel prognostic biomarker with high predictive value for cardiovascular mortality and re-hospitalization in HF patients. However, there are also other contradictive studies displayed galectin-3 inferiority against other existed HF prognostic biomarkers like NT-proBNP and ST2. Nevertheless, galectin-3 has some advantages such as more stability and resistance against hemodynamic loading and unloading state, and also it could act as an early indicator of cardiac fibrosis, ventricular remodeling, and renal impairment in HF patients.

Regulatory T Cell Immunity in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder involving innate and adaptive immunity process. Effector T cell (Teff) responses promote atherosclerotic disease, whereas regulatory T cells (Tregs) have been shown to play a protective role against atherosclerosis by down-regulating inflammatory responses which include multiple mechanisms. Compelling experimental data suggest that shifting the Treg/Teff balance toward Tregs may be a possible therapeutic approach for atherosclerotic disease, although the role of Tregs in human atherosclerotic disease has not been fully elucidated. In this review, we discuss recent advances in our understanding of the roles of Tregs and Teffs in experimental atherosclerosis, as well as human coronary artery disease.

Oral administration of the lactic acid bacterium Pediococcus acidilactici attenuates atherosclerosis in mice by inducing tolerogenic dendritic cells.

The intestinal microbiota appears to play an important role in the development of atherosclerosis. We investigated the effect of the probiotic lactic acid bacterium Pediococcus acidilactici R037 on atherosclerosis using apolipoprotein E-deficient (ApoE -/-) mice. Six-week-old ApoE -/- mice were orally administered R037 six times a week. Mice treated with R037 for 12 weeks exhibited markedly attenuated atherosclerotic lesions in the aortic root (2.3 ± 0.15 × 105 µm2 vs. 3.3 ± 0.29 × 105 µm2, respectively; P < 0.01; n = 15-17 each group). The expression of Ki-67 in CD4+ T cells, the population of interferon γ-producing CD4+ T cells in the spleen, and pro-inflammatory cytokine production from splenic lymphocytes were significantly decreased in R037-treated mice. Interestingly, splenic dendritic cells (DCs) isolated from R037-treated mice suppressed CD4+ T-cell proliferation and pro-inflammatory cytokine production ex vivo, suggesting that R037 treatment induced tolerogenic DCs. Programmed cell death ligand 1 expression in DCs was significantly enhanced in R037-treated mice, which might explain the immunosuppressive effect of DCs at least in part. These results indicate that R037 attenuates atherosclerosis by inducing tolerogenic DCs, which suppress Th1-driven inflammation and the proliferative activity of CD4+ T cells. Our findings may provide a novel therapeutic approach for the prevention of atherosclerosis based on dietary supplementation with probiotics.

The New Mayo Clinic Risk Score Characteristics in Acute Coronary Syndrome in Patients Following Percutaneous Coronary Intervention.

Background: Mortality and major adverse cardiac events (MACE) frequently occur after percutaneous coronary intervention (PCI). Therefore, the ability to predict such events through an established risk stratification method is of great importance. The present study was aimed at determining the risk stratification of mortality and MACE in post-PCI patients at the intensive cardiac care unit of Cipto Mangunkusumo Hospital (CMH) using 7 variables of the New Mayo Clinic Risk Score (NMCRS). Method: This cross-sectional study drew upon secondary data gathered from the medical records of 313 patients that underwent PCI at the intensive cardiac care unit (ICCU) of CMH between August 1st, 2013, and August 31st, 2014. The primary end point was all-cause mortality and MACE. Seven variables in the NMCRS, namely age, left ventricular ejection fraction, serum creatinine, preprocedural cardiogenic shock, myocardial infarction, and peripheral arterial disease, were evaluated. Results: The mortality and MACE incidence rates in the post-PCI patients were 3.8% (95%CI: 2.6-5.0) and 8.3% (95% CI: 6.6-10.0), respectively. Regarding the NMCRS stratification, elderly patients with lower left ventricular ejection fraction, increased serum creatinine, preprocedural cardiogenic shock, myocardial infarction, and peripheral arterial disease had higher mortality and MACE incidence rates among the post-PCI patients. The mortality and MACE incidence rates significantly increased in the post-PCI patients with a higher NMCRS. Conclusion: Patients with a higher NMCRS had a tendency toward higher mortality and MACE incidence rates following PCI.

Hepatopulmonary Syndrome: A Brief Review.

Hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease characterized by arterial hypoxemia. Mechanisms related to this event are diffusion-perfusion flaw, ventilation-perfusion (V/Q) mismatch, and direct arteriovenous shunts. Diagnosis of HPS is based on the presence of liver disease or portal hypertension, increased alveolar-arterial (A-a) PO2, and intrapulmonary vascular dilatations (IPVD). Lung transplantation (LT) remains the most effective therapy for HPS. In spite of its poor prognosis, we could improve the quality of life and survival rate of patients.

Diagnostic approach to cardiac amyloidosis.

Amyloidosis is a relatively rare disease that may be underdiagnosed and could affect the entire human body. Many organs may be affected, which could increase the morbidity and mortality. Cardiac involvement is the leading cause of poor prognosis. Patients with cardiac amyloidosis are usually admitted with heart failure. The clinical presentation varies greatly, and using the correct approach is important in identifying cardiac amyloidosis. A 51-year-old man was diagnosed with chronic heart failure. He had increased brain natriuretic peptide levels, a low ejection fraction, and left and right ventricular hypertrophy with granular sparkling as seen by echocardiography. These findings led us to perform a cardiac biopsy that confirmed the diagnosis of cardiac amyloidosis. Further investigation revealed that the patient had amyloid light-chain type amyloidosis due to multiple myeloma. He is now undergoing the 3rd phase of chemotherapy. Congo-red stain is usually used by physicians to histologically confirm amyloidosis, with which apple-green birefringence indicates amyloid deposits. Other stains such as direct fast scarlet (DFS) and hematoxylin-eosin (HE) can also confirm the presence of amyloid deposits. In the present case, DFS and HE were used, both of which suggested amyloid deposits surrounding myocardial cells. The use of a combination of stains can increase the diagnostic sensitivity and specificity of amyloidosis. However, the typical echocardiographic appearances would be enough to diagnose cardiac amyloidosis when it is impossible for the patient to undergo a cardiac biopsy, if an additional histological specimen from another tissue such as abdominal fat confirms amyloidosis.