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The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.
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Imunidade Adaptativa , Linfócitos B , Doenças Cardiovasculares , Humanos , Linfócitos B/imunologia , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/terapia , Imunidade Inata , Aterosclerose/imunologia , Aterosclerose/terapia , Sobrevivência CelularRESUMO
BACKGROUND: Coronary microvascular dysfunction (CMD) after percutaneous coronary intervention (PCI) is prognostically important and may also be a cause of persistent angina. The stent balloon inflation technique or material properties may influence the degree of CMD post-PCI. METHODS: Thirty-six patients with stable angina attending for elective PCI were randomized to either slow drug eluting stent (DES) implantation technique (DES slow group): +2 atm. every 5 s., maintained for a further 30 s or a standard stent implantation technique (DES std group): rapid inflation and deflation. PressureWire X with thermodilution at rest and hyperemia and optical coherence tomography (OCT) were performed pre- and post-PCI. Combined primary endpoints were changes in index of microvascular resistance (delta IMR) and coronary flow reserve (delta CFR) following PCI. The secondary endpoints included differences in cardiac troponin I (delta cTnI) at 6 h post-PCI, Seattle angina questionnaire (SAQ) at 1, 3, 6, and 12 months and OCT measures of stent results immediately post-PCI and at 3 months. RESULTS: Both groups were well matched, with similar baseline characteristics and OCT-defined plaque characteristics. Delta IMR was significantly better in the DES slow PCI arm with a median difference of -4.14 (95% CI -10.49, -0.39, p = 0.04). Delta CFR was also numerically higher with a median difference of 0.47 (95% CI -0.52, 1.31, p = 0.46). This did not translate to improved delta median cTnI (1.5 (34.8) vs. 0 (27.5) ng/L, p = 0.75) or median SAQ score at 3 months, (85 (20) vs. 95 (17.5), p = 0.47). CONCLUSION: Slow stent implantation is associated with less CMD after elective PCI in patients with stable angina.
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Regulatory T cells and type-2 innate lymphoid cells represent 2 subsets of immune cells, which have been shown in preclinical models to be important in atherosclerosis and myocardial repair. Regulatory T cells play a crucial role in immune homeostasis and tolerance via their interactions with effector T cells, dendritic cells, and monocytes/macrophages. They also utilize and secrete inhibitory cytokines, including interleukin 10 and transforming growth factor ß, to regulate or suppress pathogenic immune responses. Type-2 innate lymphoid cells have an important role in type-2 immune responses and tissue repair through secreting interleukins 5 and 13, as well as a variety of biological mediators and growth factors. Intriguingly, interleukin-2 has emerged as a common cytokine, which can be harnessed to upregulate both cell types, and also has important translational consequences as clinical trials are ongoing for its use in cardiovascular disease. Here, we briefly review the biology of these regulatory immune cell types, discuss the preclinical and clinical evidence for their functions in cardiovascular disease, examine the prospects for clinical translation and current ongoing trials, and finally, postulate how overlap in the mechanisms of upregulation may be leveraged in future treatments for patients.
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Imunidade Adaptativa , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Imunidade Inata , Interleucina-2/uso terapêutico , Animais , Humanos , Interleucina-13/imunologia , Interleucina-5/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
OBJECTIVE: NR4A orphan receptors have been well studied in vascular and myeloid cells where they play important roles in the regulation of inflammation in atherosclerosis. NR4A1 (nerve growth factor IB) is among the most highly induced transcription factors in B cells following BCR (B-cell receptor) stimulation. Given that B cells substantially contribute to the development of atherosclerosis, we examined whether NR4A1 regulates B-cell function during atherogenesis. Approach and Results: We found that feeding Ldlr-/- mice a Western diet substantially increased Nr4a1 expression in marginal zone B (MZB) cells compared with follicular B cells. We then generated Ldlr-/- mice with complete B- or specific MZB-cell deletion of Nr4a1. Complete B-cell deletion of Nr4a1 led to increased atherosclerosis, which was accompanied by increased T follicular helper cell-germinal center axis response, as well as increased serum total cholesterol and triglycerides levels. Interestingly, specific MZB-cell deletion of Nr4a1 increased atherosclerosis in association with an increased T follicular helper-germinal center response but without any impact on serum cholesterol or triglyceride levels. Nr4a1-/- MZB cells showed decreased PDL1 (programmed death ligand-1) expression, which may have contributed to the enhanced T follicular helper response. CONCLUSIONS: Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells.
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Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Linfócitos B/metabolismo , Deleção de Genes , Tecido Linfoide/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Animais , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Linfócitos B/patologia , Modelos Animais de Doenças , Progressão da Doença , Tecido Linfoide/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de SinaisRESUMO
BACKGROUND: Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. METHODS: We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time-Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). RESULTS: There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G - 0.23 s (0.27) versus group GT - 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: - 20.83 mmHg s (24.54 vs. - 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine - 2.0 ng/ml (- 117.1, 14.8) versus - 0.5 ng/ml (- 19.6, 9.4); p = 0.60. CONCLUSION: The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. TRIAL REGISTRATION: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.
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Adenosina/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Transdução de Sinais , Teofilina/administração & dosagemRESUMO
BACKGROUND: To determine whether the presence of "coarse" fibrillatory waves (Fw) seen on surface ECGs of patients with persistent atrial fibrillation (AF) predict maintenance of sinus rhythm (SR) at 6 weeks after electrical cardioversion (ECV). METHODS: Preprocedure ECGs from 94 consecutive patients with persistent AF scheduled to undergo ECV at a single centre were classified as having coarse Fw (≥0.1 mV) or fine Fw (<0.1 mV) in leads II or V1 . The primary outcome was ECG rhythm at 6-week clinical follow-up. Demographic and echocardiographic data were also collected. RESULTS: Thirty-two patient ECGs (34%) had coarse Fw on baseline ECG in either or both leads II or V1 with no significant differences in baseline demographics compared to those patients with fine Fw. At 6 weeks post-ECV, in the coarse Fw group 72% of patients maintained SR vs. 42% in the fine Fw group (χ2 , p = .006) with the odds ratio (OR) of maintaining SR at 6 weeks in the presence of coarse Fw being 3.5 (95% CI: 1.4-8.9, p = .007). Across the overall study population, there were no other significant univariate predictors of SR at 6 weeks post-ECV. CONCLUSION: Classifying persistent AF using the maximal Fw amplitude on a surface ECG is a simple and reproducible method of predicting medium-term success of ECV, independent of traditional risk factors.
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Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Cardioversão Elétrica/métodos , Eletrocardiografia/métodos , Idoso , Fibrilação Atrial/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIMS: While acute cardiovascular complications of COVID-19 are well-described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19. METHODS AND RESULTS: Twenty-one participants (mean age 47 [SD 13] years, 71% female) with long COVID (n=17), raised troponin (n=2), or unexplained new-onset heart failure (n=2), who did not have pre-existing heart conditions or recent steroid/immunosuppression treatment were enrolled a mean 346 (SD 191) days after COVID-19 infection in a prospective observational study. Cardiac MRI and blood sampling for deep immunophenotyping using mass cytometry by time of flight and measurement of proteomic inflammatory markers was performed. Nine of 21 (43%) participants had MRI abnormalities (MRI(+)), including non-ischaemic patterns of late gadolinium enhancement and/or visually overt myocardial oedema in 8 people. One patient had mildly impaired biventricular function without fibrosis or oedema, and 2 had severe left ventricular impairment. MRI(+) individuals had higher blood CCL3, CCL7, FGF-23 and CD4 Th2 cells, and lower CD8 T effector memory (TEM) cells, than MRI(-). Cluster analysis revealed lower expression of inhibitory receptors PD1 and TIM3 in CD8 TEM cells from MRI(+) patients than MRI(-) patients, and functional studies of CD8 T αß cells showed higher proportions of cytotoxic granzyme B+ secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a LASSO regression model (composite AUC 0.96, 95%CI 0.88-1.0). CCL7 was correlated with diffuse myocardial fibrosis/oedema detected by quantitative T1 mapping (r=0.47, p=0.04). CONCLUSION: COVID-19 related cardiac injury in symptomatic patients with non-ischaemic myocarditis-like MRI abnormalities is associated with immune dysregulation, including decreased peripheral CD8 TEM cells and increased CCL7, persisting long after the initial infection.
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AIMS: The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis. METHODS AND RESULTS: We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet-induced Tfh. CONCLUSION: Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective 'natural' IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.
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Aterosclerose , Interleucina-18 , Humanos , Camundongos , Animais , Imunoglobulina M , Linfócitos B , Aterosclerose/genética , Aterosclerose/prevenção & controle , Colesterol , Linfócitos T Auxiliares-IndutoresRESUMO
Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.
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Interleucina-10 , Interleucina-2 , Humanos , Interleucina-2/efeitos adversos , Interleucina-10/metabolismo , Linfócitos B , Plasmócitos , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismoRESUMO
AIMS: In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI). METHODS AND RESULTS: Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset. Four escalating doses (200, 500, 700, and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% confidence interval 93.8-98.8%) depletion of circulating B cells within 30 min of starting the infusion. Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P < 0.001). B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets. Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up. CONCLUSIONS: A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy. CLINICAL TRIAL REGISTRATION: NCT03072199 at https://www.clinicaltrials.gov/.
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Pesquisa Biomédica , Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Estudos Prospectivos , Rituximab/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Resultado do TratamentoRESUMO
Background Post-percutaneous coronary intervention (PCI) fractional flow reserve ≥0.90 is an accepted marker of procedural success, and a cutoff of ≥0.95 has recently been proposed for post-PCI instantaneous wave-free ratio. However, stability of nonhyperemic pressure ratios (NHPRs) post-PCI is not well characterized, and transient reactive submaximal hyperemia post-PCI may affect their precision. We performed this study to assess stability and reproducibility of NHPRs post-PCI. Methods and Results Fifty-seven patients (age, 63.77±10.67 years; men, 71%) underwent hemodynamic assessment immediately post-PCI and then after a recovery period of 10, 20, and 30 minutes and repeated at 3 months. Manual offline analysis was performed to derive resting and hyperemic pressure indexes (Pd/Pa resting pressure gradient, mathematically derived instantaneous wave-free ratio, resting full cycle ratio, and fractional flow reserve) and microcirculatory resistances (basal microvascular resistance and index of microvascular resistance). Transient submaximal hyperemia occurring post-PCI was demonstrated by longer thermodilution time at 30 minutes compared with immediately post-PCI; mean difference of thermodilution time was 0.17 seconds (95% CI, 0.07-0.26 seconds; P=0.04). Basal microcirculatory resistance was also higher at 30 minutes than immediately post-PCI; mean difference of basal microvascular resistance was 10.89 mm Hg.s (95% CI, 2.25-19.52 mm Hg.s; P=0.04). Despite this, group analysis confirmed no significant differences in the values of resting whole cycle pressure ratios (Pd/Pa and resting full cycle ratio) as well as diastolic pressure ratios (diastolic pressure ratio and mathematically derived instantaneous wave-free ratio). Whole cardiac cycle NHPRs demonstrated the best overall stability post-PCI, and 1 in 5 repeated diastolic NHPRs crossed the clinical decision threshold. Conclusions Whole cycle NHPRs demonstrate better reproducibility and clinical precision post-PCI than diastolic NHPRs, possibly because of less perturbation from predominantly diastolic reactive hyperemia and left ventricular stunning. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03502083; Unique identifier: NCT03502083 and URL: https://clinicaltrials.gov/ct2/show/NCT03076476; Unique identifier: NCT03076476.
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Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Hiperemia , Intervenção Coronária Percutânea , Idoso , Pressão Sanguínea , Cateterismo Cardíaco , Angiografia Coronária , Vasos Coronários , Feminino , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the artery wall. Regulatory T cells (Tregs) limit inflammation and promote tissue healing. Low doses of interleukin (IL)-2 have the potential to increase Tregs, but its use is contraindicated for patients with ischemic heart disease. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation trial, we tested low-dose subcutaneous aldesleukin (recombinant IL-2), given once daily for 5 consecutive days. In study part A, the primary end point was safety, and patients with stable ischemic heart disease were randomly assigned to receive placebo or to one of five dose groups (range, 0.3 to 3.0 × 106 IU daily). In study part B, patients with acute non-ST elevation myocardial infarction or unstable angina were randomly assigned to receive placebo or to one of two dose groups (1.5 and 2.5 × 106 IU daily). The coprimary end points were safety and the dose required to increase circulating Tregs by 75%. Single-cell RNA-sequencing of circulating immune cells was used to provide a mechanistic assessment of the effects of aldesleukin. RESULTS: Forty-four patients were randomly assigned to either study part A (n=26) or part B (n=18). In total, 3 patients withdrew before dosing, 27 received active treatment, and 14 received placebo. The majority of adverse events were mild. Two serious adverse events occurred, with one occurring after drug administration. In parts A and B, there was a dose-dependent increase in Tregs. In part B, the estimated dose to achieve a 75% increase in Tregs was 1.46 × 106 IU (95% confidence interval, 1.06 to 1.87). Single-cell RNA-sequencing demonstrated the engagement of distinct pathways and cellcell interactions. CONCLUSIONS: In this phase 1b/2a study, low-dose IL-2 expanded Tregs without adverse events of major concern. Larger trials are needed to confirm the safety and to further evaluate the efficacy of low-dose IL-2 as an anti-inflammatory therapy for patients with ischemic heart disease. (Funded by the Medical Research Council, the British Heart Foundation, and others; ClinicalTrials.gov number, NCT03113773)
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Interleucina-2 , Interleucina-2/análogos & derivados , Isquemia Miocárdica , Linfócitos T Reguladores , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/tratamento farmacológico , Método Duplo-Cego , Masculino , Pessoa de Meia-Idade , Feminino , Proteínas RecombinantesRESUMO
Background Adenosine is used to treat no-reflow in the infarct-related artery (IRA) during ST-segment-elevation myocardial infarction intervention. However, the physiological effect of adenosine in the IRA is variable. Coronary steal-a reduction of blood flow to the distal coronary bed-can occur in response to adenosine and this is facilitated by collaterals. We investigated the effects of adenosine on coronary flow reserve (CFR) in patients presenting with ST-segment-elevation myocardial infarction to better understand the physiological mechanism underpinning the variable response to adenosine. Methods and Results Pressure-wire assessment of the IRA after percutaneous coronary intervention was performed in 93 patients presenting with ST-segment-elevation myocardial infarction to calculate index of microvascular resistance, CFR, and collateral flow index by pressure. Modified collateral Rentrop grade to the IRA was recorded, as was microvascular obstruction by cardiac magnetic resonance imaging. Coronary steal (CFR <0.9), no change in flow (CFR=0.9-1.1), and hyperemic flow (CFR >1.1) after adenosine occurred in 19 (20%), 15 (16%), and 59 (63%) patients, respectively. Patients with coronary steal had higher modified Rentrop score to the IRA (1 [0, 1.75] versus 0 [0, 1], P<0.001) and a higher collateral flow index by pressure (0.25±0.10 versus 0.15±0.10, P=0.004) than the hyperemic group. The coronary steal group also had significantly higher index of microvascular resistance (61.68 [28.13, 87.04] versus 23.93 [14.67, 37.00], P=0.006) and had more disease (stenosis >50%) in the donor arteries (52.63% versus 22.03%, P=0.02) than the hyperemic group. Conclusions Adenosine-induced coronary steal may be responsible for a reduction in coronary flow reserve in a proportion of patients presenting with ST-segment-elevation myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03145194. URL: https://www.isrctn.com; Unique identifier: ISRCTN3176727.
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Circulação Coronária , Reserva Fracionada de Fluxo Miocárdico , Microcirculação , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Resistência Vascular , Adenosina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Angiografia Coronária , Vasos Coronários/fisiopatologia , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
BACKGROUND: Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development. OBJECTIVES: ILC2s also reside in the pericardium but their role in postischemic injury is unknown. METHODS: We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS). RESULTS: We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine. CONCLUSIONS: ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.
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Síndrome Coronariana Aguda , Interleucina-2 , Linfócitos , Infarto do Miocárdio , Recuperação de Função Fisiológica , Animais , Feminino , Síndrome Coronariana Aguda/tratamento farmacológico , Tecido Adiposo/imunologia , Interleucina-2/metabolismo , Interleucina-2/uso terapêutico , Linfócitos/fisiologia , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Recuperação de Função Fisiológica/imunologia , Função VentricularRESUMO
Atherosclerosis has long been known as an inflammatory disease. However, whether targeting inflammation improves outcomes was unproven until the recent results of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). In this review, we reflect on why it has taken a long time to prove the inflammatory hypothesis of atherosclerosis and derive important lessons for the future. In particular, we discuss the off-target immune-modulatory effects of approved cardiovascular therapies, review the attempted anti-inflammatory therapies including the recently published CIRT (Cardiovascular Inflammation Reduction Trial), and discuss the likely reasons for their failures. We further build on CANTOS to review the immune-modulatory therapies for atherosclerosis currently in trials, and discuss the likelihood of their added value as well as the potential hazard associated with their use. We finally argue for a critical approach to the use of animal models, coupled with the use of humans as model organisms to accelerate the identification of the most appropriate targets.