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2.
Arterioscler Thromb Vasc Biol ; 39(11): 2386-2401, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31644355

RESUMO

OBJECTIVE: The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal. CONCLUSIONS: Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY.

3.
Cardiovasc Res ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549149

RESUMO

Recent evidence suggests a link between periodontitis (PD) and hypertension, but the nature of this association remains unclear. The overall aim of this review was to critically appraise the evidence linking these two common disorders. Systematic search was conducted for studies published up to December 2018. Prevalence of hypertension in patients with PD (moderate/severe groups) vs. those without PD (non-PD) was the primary outcome. Additional outcomes included adjusted mean difference in systolic (SBP) and diastolic (DBP) blood pressure (BP) levels in PD vs. non-PD, assessment of biomarkers in PD and hypertension, and BP changes after periodontal therapy. From 81 studies selected, 40 were included in quantitative meta-analyses. Diagnoses of moderate-severe PD [odds ratio (OR) = 1.22; 95% confidence interval (CI): 1.10-1.35] and severe PD (OR = 1.49; 95% CI: 1.09-2.05) were associated with hypertension. Prospective studies confirmed PD diagnosis increased likelihood of hypertension occurrence (OR = 1.68; 95% CI: 0.85-3.35). Patients with PD exhibited higher mean SBP [weighted mean difference (WMD) of 4.49 mmHg; 95% CI: 2.88-6.11] and DBP (2.03 mmHg; 95% CI: 1.25-2.81) when compared with non-PD. Lastly, only 5 out of 12 interventional studies confirmed a reduction in BP following periodontal therapy, ranging from 3 to 12.5 mmHg of SBP and from 0 to 10 mmHg of DBP. PD is associated with increased odds of hypertension (SORT C) and higher SBP/DBP levels. The evidence suggesting that PD therapy could reduce BP is inconclusive. Although additional research is warranted on this association, these results suggest that oral health assessment and management of PD could not only improve oral/overall health and quality of life but also be of relevance in the management of patients with hypertension.

4.
Front Immunol ; 10: 1979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552015

RESUMO

Abdominal Aortic Aneurysm (AAA) is a major cause of cardiovascular mortality. Adverse changes in vascular phenotype act in concert with chronic inflammation to promote AAA progression. Perivascular adipose tissue (PVAT) helps maintain vascular homeostasis but when inflamed and dysfunctional, can also promote vascular pathology. Previous studies suggested that PVAT may be an important site of vascular inflammation in AAA; however, a detailed assessment of leukocyte populations in human AAA, their anatomic location in the vessel wall and correlation to AAA size remain undefined. Accordingly, we performed in depth immunophenotyping of cells infiltrating the pathologically altered perivascular tissue (PVT) and vessel wall in AAA samples at the site of maximal dilatation (n = 51 patients). Flow cytometry revealed that T cells, rather than macrophages, are the major leukocyte subset in AAA and that their greatest accumulations occur in PVT. Both CD4+ and CD8+ T cell populations are highly activated in both compartments, with CD4+ T cells displaying the highest activation status within the AAA wall. Finally, we observed a positive relationship between T cell infiltration in PVT and AAA wall. Interestingly, only PVT T cell infiltration was strongly related to tertiles of AAA size. In summary, this study highlights an important role for PVT as a reservoir of T lymphocytes and potentially as a key site in modulating the underlying inflammation in AAA.

5.
Cardiovasc Res ; 115(12): e125-e126, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544943
6.
Eur Heart J ; 40(35): 2931-2932, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31520580
7.
Eur Heart J ; 40(42): 3459-3470, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504461

RESUMO

AIMS: Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension. METHODS AND RESULTS: We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of -11.1 mmHg; 95% CI 6.5-15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension. CONCLUSION: A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.

8.
Cardiovasc Res ; 115(11): e109-e110, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31436830
9.
Curr Hypertens Rep ; 21(9): 68, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321561

RESUMO

PURPOSE OF REVIEW: In recent years, a vast body of evidence has accumulated indicating the role of the immune system in the regulation of blood pressure and modulation of hypertensive pathology. Numerous cells of the immune system, both innate and adaptive immunity, have been indicated to play an important role in the development and maintenance of hypertension. The purpose of this review was to summarize the role of adaptive immunity in experimental models of hypertension (genetic, salt-sensitive, and Angiotensin (Ang) II induced) and in human studies. In particular, the role of T and B cells is discussed. RECENT FINDINGS: In response to hypertensive stimuli such as Ang II and high salt, T cells become pro-inflammatory and they infiltrate the brain, blood vessel adventitia and periadventitial fat, heart, and the kidney. Pro-inflammatory T cell-derived cytokines such as IFN-γ and TNF-α (from CD8+ and CD4+Th1) and IL-17A (from the γδ-T cell and CD4+Th17) exacerbate hypertensive responses mediating both endothelial dysfunction and cardiac, renal, and neurodegenerative injury. The modulation of adaptive immune activation in hypertension has been attributed to target organ oxidative stress that leads to the generation of neoantigens, including isolevuglandin-modified proteins. The role of adaptive immunity is sex-specific with much more pronounced mechanisms in males than that in females. Hypertension is also associated with B cell activation and production of autoantibodies (anti-Hsp70, anti-Hsp65, anti-Hsp60, anti-AT1R, anti-α1AR, and anti-ß1AR). The hypertensive responses can be inhibited by T regulatory lymphocytes (Tregs) and their anti-inflammatory IL-10. Adaptive immunity and its interface with innate mechanisms may represent valuable targets in the modulation of blood pressure, as well as hypertension-related residual risk.

10.
Cardiovasc Res ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31250885

RESUMO

AIMS: Transient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel+kinase) that influences cellular Mg2+ homeostasis and vascular signaling. However the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis. METHODS AND RESULTS: TRPM7-deficient mice with deletion of the kinase domain (TRPM7+/Δkinase) were studied and molecular mechanisms investigated in TRPM7+/Δkinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGFß) and cytokines (IL-6, IL-10, IL-12, TNFα) and phosphorylation of the pro-inflammatory signaling molecule Stat1, were increased in TRPM7+/Δkinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/Δkinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/Δkinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intravital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil:endothelial attachment and transmigration of leukocytes in TRPM7+/Δkinase mice. TRPM7+/Δkinase BMDMs had increased levels of galectin-3, IL-10 and IL-6. In co-culture systems, TRPM7+/Δkinase macrophages increased expression of fibronectin, PCNA, and TGFß in cardiac fibroblasts from wildtype mice, effects ameliorated by MgCl2 treatment. Conclusions. We identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.

11.
Clin Rheumatol ; 38(9): 2473-2481, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31076943

RESUMO

INTRODUCTION: Difficult-to-treat rheumatoid arthritis (RA) is a significant clinical problem despite no clear definition. We aimed to provide clinical characteristics and associated comorbidities of RA patients in relation to disease control. METHODS: RA characteristics and physician-recorded comorbidities were analyzed in a sample of 1937 RA patients. Patients treated for RA for 5.2 y (IQR, 2.1-11.3) were classified as difficult-to-control when presenting with DAS28-ESR > 3.2 despite previous use of at least 2 csDMARDs. A comparison of demographic and RA-related characteristics between difficult-to-treat and low disease activity patients (DAS28-ESR ≤ 3.2) was performed. Comorbidity burden was assessed by calculating Rheumatic Diseases Comorbidity Index (RDCI). Logistic regression model was constructed for difficult-to-control disease. RESULTS: Hypertension (46.9% (95%CI, 44.7-49.2)), coronary artery disease (CAD) (18.5% (95%CI, 16.8-20.3)), and diabetes (14.4% (95%CI, 12.9-16.0)) were the most prevalent conditions in RA patients. When compared with the adequate control group, difficult-to-control patients were increasingly burdened with hypertension (52.7% (95%CI, 47.5-57.8) vs. 42.0% (95%CI, 36.6-47.6); p = 0.006), cardiovascular diseases (24.2% (95%CI, 20.1-28.9) vs. 11.1% (95%CI, 8.0-15.1); p < 0.001), respiratory system diseases (7.0% (95%CI, 4.8-10.2) vs. 3.3% (95%CI, 1.8-5.9); p = 0.03) and gastroduodenal ulcers (2.3% (95%CI, 1.2-4.4) vs. 0.3% (95%CI, 0.1-1.8); p = 0.04). Patients with higher RDCI had lower chance to obtain low disease activity (OR 0.69 (95%CI, 0.61-0.79); p < 0.001). In multivariate analysis, RDCI was independently associated with difficult-to-control disease (OR 1.46 (95%CI, 1.21-1.76); p < 0.001). CONCLUSIONS: RA patients suffer from a variety of comorbidities. Cardiovascular and respiratory system diseases occur twice as often in difficult-to-control patients. RDCI may provide a valuable tool in evaluating a risk for difficult-to-control RA. Key Points • Hypertension, coronary artery disease and diabetes are the most prevalent comorbidities in rheumatoid arthritis. • Cardiovascular and respiratory tract diseases as well as gastroduodenal ulcers are more common among difficult-to-control patients, when compared with subjects with adequately controlled RA. • Rheumatic Diseases Comorbidity Index is an independent predictor for difficult-to-control RA.

12.
Kardiol Pol ; 77(7-8): 661-669, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31144674

RESUMO

Aspirin decreases the risk of recurrent thrombotic events in patients with coronary artery disease or peripheral artery disease but the risk of recurrent events remains high. Long­term dual antiplatelet therapy or the combination of aspirin and warfarin further reduces the risk of recurrent events, but at the cost of increased bleeding, and neither of these treatments reduce mortality. The COMPASS (Cardiovascular Outcomes in People Using Anticoagulation Strategies) randomized controlled trial involving 27 395 patients from 602 sites in 33 countries (Poland: 9 sites, 518 patients) tested whether low­dose anticoagulant therapy with the coagulation factor Xa inhibitor rivaroxaban given alone or combined with aspirin reduced thrombotic risk compared with aspirin in patients with apparently stable chronic coronary and/or peripheral artery disease. In patients treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily, compared with aspirin alone, the primary outcome of the composite of cardiovascular death, stroke, or myocardial infarction was decreased by 24% (hazard ratio, 0.76; 95% confidence interval, 0.66 to 0.86; P <0.001), and mortality by 18% at the cost of a 70% increase in major bleeding but no significant increase in fatal or intracranial bleeding. Results were consistent in patients with coronary artery disease or peripheral artery disease, and the greatest absolute benefit was evident in the highest risk patients, including those with polyvascular disease, mild or moderate heart failure, chronic kidney disease, or diabetes. These results establish the combination of low­dose rivaroxaban and aspirin as a highly effective treatment to decrease morbidity and mortality rates in patients with atherosclerotic vascular disease..

13.
Front Immunol ; 10: 849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068936

RESUMO

Atherosclerosis is a complex inflammatory pathology underpinning cardiovascular diseases (CVD), which are the leading cause of death worldwide. The interplay between vascular stromal cells and immune cells is fundamental to the progression and outcome of atherosclerotic disease, however, the majority of in vitro studies do not consider the implications of these interactions and predominantly use mono-culture approaches. Here we present a simple and robust methodology involving the co-culture of vascular endothelial (ECs) and smooth muscle cells (SMCs) alongside an inflammatory compartment, in our study containing THP-1 macrophages, for studying these complex interactions. Using this approach, we demonstrate that the interaction between vascular stromal and immune cells produces unique cellular phenotypes and soluble mediator profiles not observed in double-cell 2D cultures. Our results highlight the importance of cellular communication and support the growing idea that in vitro research must evolve from mono-culture systems to provide data more representative of the multi-cellular environment found in vivo. The methodology presented, in comparison with established approaches, has the advantage of being technically simple whilst enabling the isolation of pure populations of ECs, SMCs and immune cells directly from the co-culture without cell sorting. The approach described within would be applicable to those studying mechanisms of vascular inflammation, particularly in relation to understanding the impact cellular interaction has on the cumulative immune-vascular response to atherogenic or inflammatory stimuli.

14.
Cardiovasc Res ; 115(6): e61-e62, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077586
15.
Eur Heart J ; 40(30): 2492-2494, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30929007
16.
Cardiovasc Res ; 2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-30980670

RESUMO

AIMS: Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T cell activation in the arterial wall remain poorly understood. METHODS AND RESULTS: Here, we have identified naïve T cells in the aorta of wild-type and T-cell receptor (TCR) transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with both kinetics and frequency of T-cell activation found to be similar to splenic and lymphoid T cells. Aortic homing of naïve T cells is regulated at least in part by the P-selectin glycosylated ligand-1 (PSGL-1) receptor. In experimental atherosclerosis the aorta supports CD4+ T cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion. CONCLUSIONS: Our results demonstrate that the aorta can support T cell priming and that naïve T cells traffic between the circulation and vessel wall. These data underpin the paradigm that local priming of T cells specific for plaque antigens contributes to atherosclerosis progression.

17.
Nat Rev Immunol ; 19(8): 517-532, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30992524

RESUMO

Hypertension affects 30% of adults and is the leading risk factor for heart attack and stroke. Traditionally, hypertension has been regarded as a disorder of two systems that are involved in the regulation of salt-water balance and cardiovascular function: the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). However, current treatments that aim to limit the influence of the RAAS or SNS on blood pressure fail in ~40% of cases, which suggests that other mechanisms must be involved. This Review summarizes the clinical and experimental evidence supporting a contribution of immune mechanisms to the development of hypertension. In this context, we highlight the immune cell subsets that are postulated to either promote or protect against hypertension through modulation of cardiac output and/or peripheral vascular resistance. We conclude with an appraisal of knowledge gaps still to be addressed before immunomodulatory therapies might be applied to at least a subset of patients with hypertension.

18.
Br J Pharmacol ; 176(6): 753-756, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30815852

RESUMO

The controversial plan for scientific research publications to be published in compliant Open Access Journals or on compliant Open Access Platforms is discussed. The article has been co-published with permission in European Heart Journal and British Journal of Pharmacology. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article.

20.
Eur Heart J ; 40(12): 949-952, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30799489
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