Systemic Proinflammatory State Research Articles

The NLRP3-inflammasome inhibitor MCC950 improves cardiac function in a HFpEF mouse model

Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLRP3 inflammasome, contributes to the pathogenesis of HFpEF. This study aimed to investigate the potential cardiac protective effects of the selective NLRP3 inhibitor MCC950, in a mouse model of HFpEF. HFpEF was obtained in 18–22 months old female mice using high-fat diet (HFD) and angiotensin II (AngII) infusion. Mice developed HFpEF and comorbidities such as obesity, type 2 diabetes, and hypertension. MCC950 was added to HFD and groups were treated for four weeks until the study endpoint. MCC950 treatment resulted in lower plasma IL-18 levels (-47.3 %), illustrating target engagement. First, we observed that MCC950 treatment improved left ventricular function, demonstrated by enhanced global longitudinal strain (GLS, 3.9 %, P<0.01) and reverse peak longitudinal strain (RPLSR, +46.8 %, P<0.05). Second, MCC950 reduced cardiac hypertrophy (cardiomyocyte size -19.5 %, P<0.001) and fibrosis (-32.5 %, P<0.05), accompanied by lower expression of pro-fibrotic genes. Finally, MCC950 treatment reduced macrophage infiltration in left ventricular tissue and attenuated macrophage accumulation in visceral adipose tissue, even more as compared to caloric restriction. Overall, this suggests that NLRP3 inhibition could be a promising treatment for HFpEF patients with a pro-inflammatory profile, potentially improving heart function, systemic inflammation, and metabolic parameters.

Long-term monocyte activation after coronary artery bypass grafting: An exploratory prospective observational study

Major surgery such as coronary artery bypass grafting (CABG) is associated with an increased post-operative risk of atherosclerotic cardiovascular events. Cells of the innate immune system can adopt a long-lasting pro-inflammatory and atherogenic phenotype after brief exposure to exogenous or endogenous inflammatory stimuli, a process called “trained immunity”. We hypothesized that the surgery-induced inflammation leads to sustained alterations in monocyte function, which promote the subsequent occurrence of cardiovascular events. Blood from 13 patients undergoing elective CABG was obtained before, 3–7 days (median 4) after, and 6–8 weeks (median 6) weeks after surgery. At 3–7 days postoperatively, circulating C-reactive protein (CRP) concentration, leukocyte counts and ex vivo Peripheral Blood Mononuclear Cell (PBMC) IL-6, TNFα and IL-1Ra production after stimulation (with various inflammatory stimuli) were significantly increased. Simultaneously, there was a reduction in monocyte HLA-DR expression. 6–8 weeks after CABG there was an ongoing systemic pro-inflammatory state with higher CRP concentrations, increased stimulated ex vivo PBMC IL-6 production, changes in monocytes subsets, and a higher expression of CCR2 on monocytes compared to baseline. In conclusion, CABG induces a persistent systemic inflammatory reaction with a sustained activated monocyte phenotype. This might contribute to the increased atherosclerotic cardiovascular event risk observed in cardiac surgery patients.

Proinflammatory pattern in the lower airways of non-asthmatic obese adolescents

BackgroundObesity is known to be a pro-inflammatory condition affecting multiple organs. Obesity as a systemic pro-inflammatory state, might be associated with bronchial inflammation in non-smoking adolescents with a BMI ≥ 30 kg/m2 without evidence of concomitant chronic diseases. Materials and methodsWe studied non-asthmatic obese patients (n = 20; median age 15.8 years; BMI 35.0 kg/m2) compared to age matched healthy control subjects (n = 20; median age 17.5 years; BMI 21.5 kg/m2). Induced sputum differential cell counts and sputum mRNA levels were assessed for all study subjects. Serum levels of CRP, IL-6, and IL-8 were measured. Further, IL-5, IL-6, IL-8, IL-13, IL-17, TNF-α, IFN-γ, and IP-10 protein levels were analyzed in induced sputum was. ResultsSerum CRP levels, sputum inflammatory cell load and sputum eosinophils differed significantly between obese and non-obese subjects, for sputum neutrophils, a correlation was shown with BMI ≥ 30 kg/m2. Differences were also observed for sputum mRNA expression of IL6, IL8, IL13, IL17, IL23, and IFN-γ, as well as the transcription factors T-bet, GATA3, and FoxP3. ConclusionsIncreased bronchial inflammation, triggered by systemic or local inflammatory effects of obesity itself, may account for the higher rates of airway disease in obese adolescents.

Expression of a Novel Chimeric Inhibitory Receptor Attenuates CD19 CAR T Cells: A Promising Strategy for Toxicity Mitigation

Introduction Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective in patients with refractory/relapsed acute lymphoblastic leukemia and lymphoma but often trigger severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). For r/rALL patients, as many as 77% develop Grade 3-5 CRS and 40% Grade 3-5 ICANS. sCRS occurs when hyperactivated CAR T cells undergo exponential expansion accompanied by the release of excessive amounts of inflammatory cytokines. This leads to a systemic pro-inflammatory state that can cause hypotension, multi-organ failure and even death. Tocilizumab is the only FDA-approved drug for CRS and despite concurrent corticosteroids, often fails to control CRS. Attempts to improve safety have been proposed, but have significant limitations, such as permanent removal of CARs. New and innovative methods to mitigate toxicities are needed. The purpose of this study was to design and test the efficacy of a novel autoregulatory element in the form of a chimeric inhibitory receptor (CIR), that when engaged by a specific CRS-associated pro-inflammatory molecule would trigger inhibitory signaling within CAR T cells. We hypothesize that as cytokine levels increase following activation, these signals can be redirected through responsiveness of the CIR, leading to an attenuation of CAR activity. In this study, we have tested a CIR construct that couples the recognition of IFNγ to the signaling domain of the TIGIT inhibitory receptor. We co-expressed this CIR with a CD19.28ζ CAR to evaluate its ability to attenuate activation and cytokine production and to assess its cytotoxic activity. Methods An anti-IFNγ scFv followed by the transmembrane and intracellular domains of TIGIT were arranged in sequence with the truncated EGFR receptor followed by the CD19.28ζ FMC63 CAR with intervening T2A cleavage domains and cloned into a retroviral backbone. Transduction efficiency was assessed by staining with biotinylated CD19-Fc protein or biotinylated EGFR. Following expansion, memory and effector cell differentiation was evaluated by staining for CD45RO, CD45RA, CCR7, CD127, and CD95. Activation following stimulation with NALM-6 tumor cells was measured by staining for CD69, CD25, CD38, PD-1, and CD107a. Cytotoxicity was evaluated using bioluminescence. To mimic cell types present during CRS, we utilized a coculture assay that consists of CAR T cells, NALM-6 tumor cells, and either macrophages or dendritic cells (DC) differentiated from autologous CD14 + monocytes. Cocultures were incubated for 48 hr. and supernatants were collected for analyses by Luminex. Results CD19 CARs co-expressing a CIR composed of an anti-IFNγ scFv coupled to TIGIT inhibitory signaling expanded during the manufacturing process as well as T cells expressing only CD19 CAR and displayed normal levels of CAR expression. The presence of the CIR did not affect the differentiation profile of memory and effector subsets. CIR-expressing CD19 CARs exhibited robust tumor cell killing of NALM-6 targets equivalent to CD19 CARs. Next, CD19 CAR/CIR cells were pretreated with IFNγ for 24 hr. and then cultured with NALM-6 cells. Exposure to IFNγ resulted in a significant abrogation in cytotoxicity, which was eventually restored with time. Activation profile analysis of CARs equipped with CIR signaling after target stimulation revealed an overall diminution of CARs expressing multiple (4 or 5) activation markers relative to CD19 CARs. Importantly, CIR signaling resulted in significant reductions in the levels of effector, stimulatory, and inflammatory mediators including IFNγ, TNFα, GM-CSF, and IL-17. CARs expressing the CIR exhibited slower killing kinetics when challenged with sequential stimulations by fresh tumor cells. However, in vivo anti-tumor cell activity was not adversely affected as CAR/CIR T cells robustly eliminated disease in leukemia-bearing NSG mice. Lastly, using an in vitro CRS assay, we sought to determine if attenuated CAR T cells would be less potent in activating myeloid cells. We observed that monocyte-derived macrophage and DC activation by CD19 CAR/CIR T cells was reduced as evidenced by decreased secretion of proinflammatory cytokines and chemokines. Conclusion These results provide a compelling proof of concept of a novel self-regulating CAR T cell design with the potential to mitigate severe toxicities in patients.

Systemic inflammation index, disease severity, and mortality in patients with COVID-19: a systematic review and meta-analysis.

An excessive systemic pro-inflammatory state increases the risk of severe disease and mortality in patients with coronavirus disease 2019 (COVID-19). However, there is uncertainty regarding whether specific biomarkers of inflammation can enhance risk stratification in this group. We conducted a systematic review and meta-analysis to investigate an emerging biomarker of systemic inflammation derived from routine hematological parameters, the systemic inflammation index (SII), in COVID-19 patients with different disease severity and survival status. A systematic literature search was conducted in PubMed, Web of Science, and Scopus, between the 1st of December 2019 and the 15th of March 2023. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development and Evaluation, respectively (PROSPERO registration number: CRD42023420517). In 39 studies, patients with a severe disease or non-survivor status had significantly higher SII values on admission compared to patients with a non-severe disease or survivor status (standard mean difference (SMD)=0.91, 95% CI 0.75 to 1.06, p<0.001; moderate certainty of evidence). The SII was also significantly associated with the risk of severe disease or death in 10 studies reporting odds ratios (1.007, 95% CI 1.001 to 1.014, p=0.032; very low certainty of evidence) and in six studies reporting hazard ratios (1.99, 95% CI 1.01 to 3.92, p=0.047; very low certainty of evidence). Pooled sensitivity, specificity, and area under the curve for severe disease or mortality were 0.71 (95% CI 0.67 to 0.75), 0.71 (95% CI 0.64 to 0.77), and 0.77 (95% CI 0.73 to 0.80), respectively. In meta-regression, significant correlations were observed between the SMD and albumin, lactate dehydrogenase, creatinine, and D-dimer. Our systematic review and meta-analysis has shown that the SII on admission is significantly associated with severe disease and mortality in patients with COVID-19. Therefore, this inflammatory biomarker derived from routine haematological parameters can be helpful for early risk stratification in this group. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023420517.

Association between metabolome and neutrophil count in intrauterine fluid after insemination in the mare

Assessment of post-breeding endometritis is challenging in the mare. Correlation analysis of metabolite concentration in serum and intrauterine fluid with neutrophil count in intrauterine fluid after insemination was performed in 17 Spanish mares. After body condition score (BCS) was determined, a uterine edema score and intrauterine fluid diameter (IUF) were determined by ultrasonography at insemination and 8 hours afterwards, when a blood sample and low volume uterine lavage sample were collected. Neutrophils in the recovered fluid were counted using a Neubauer camera. In lavage supernatant fraction and in serum, metabolite determination by spectrophotometry was performed. Data were analyzed with PROC CORR (SAS) after log transformation of neutrophil count, oedema score and IUF. There was no association between edema or IUF at insemination and edema/IUF at lavage. The BCS tended to be positively associated with edema score (r=0.466, p=0.059) and IUF 8 hours after insemination (r=0.4562, p=0.066), but not at the time of insemination. Correlation analysis of BCS and neutrophil count did not reach significance (r=0.3928, p=0.118). Age tended to be positively associated with neutrophil count (r=0.4112, p=0.100) and was highly associated with urea concentrations in the IUF (r=6221, p=0.008). Edema at lavage was correlated with serum globulin concentrations (r=0.50911, P=0.03). The IUF was also correlated with serum albumin (r=0.5396, p=0.02),but no association with globulin was detected; instead IUF was correlated with serum glucose concentrations (r=0.4818, p=0.05). Neutrophil count was positively correlated with specific metabolites (cholesterol, urea, globulins), but not with glucose, triglycerides or albumin concentrations in the IUF. Neutrophil count was associated with serum globulin concentration (r=0.548, p=0.02), but no other correlations were found. The only metabolite that was correlated in serum and IUF was globulin (r=0.4777, p=0.05). Glucose and urea concentrations in the IUF were negatively associated with serum albumin (r= -0.6173, p=0.008 and r= - 0.4533, p=0.06 respectively). This is probably the first report showing an association between BCS and oedema score and intrauterine fluid after insemination, suggesting that in obese mares, clearance of physiological endometritis post-breeding is altered. The finding of the association between the oedema and neutrophil count with serum globulin concentrations, and the positive correlation of globulins in serum and uterine fluid suggest a systemic pro-inflammatory state that is present locally. Moreover, serum albumin was negatively correlated with glucose and urea in the uterine fluid. Overall, neutrophil count in low volume lavage obtained after breeding is consistent with the metabolome in uterine fluid and serum, and thus neutrophil count and serum globulin determination could be used as a diagnostic tool for post-breeding endometritis.

Microvascular impairment in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a cardiovascular disease characterized by diastolic dysfunction. Main risk factors include advanced age, sex (women being more susceptible), and comorbidities like obesity, type 2 diabetes, and renal dysfunction. The etiology of the disease is poorly known. Our pathophysiological hypothesis is that metabolic disorders and renal dysfunction induced by the risk factors generate a systemic pro-inflammatory state and hemodynamical changes that, accumulating with age, are responsible for endothelial dysfunction and pathological reorganization of the microvascular morphology, leading to diastolic dysfunction. The objective of the study was, using an HFpEF mouse model, to (1) identify the metabolic disorders and the renal dysfunction, (2) evaluate the pro-inflammatory state, (3) quantify the cardiac microvascular morphology, and (4) characterize the cardiac diastolic function. Experiments were done on 14-week-old female C57BL/Ks mice, predisposed to renal dysfunction, deficient for leptin receptors, and hence developing obesity and type 2 diabetes. 8-week-old male C57BL/6J mice, lacking HFpEF risk factors, were used as healthy control. Glycemia, triglyceridemia, cholesterolemia, and % pro-inflammatory cells were analyzed on blood samples. 3D imaging of glomeruli was done by light-sheet microscopy (LSM) on optically cleared kidneys. 3D imaging of the coronary capillary network was done by LSM on optically cleared hearts. Diastolic pressure, developed pressure, and relaxation rate was measured on Langendorff's isolated perfused hearts. Compared to controls, HFpEF mice showed increased plasmatic glucose, triglyceride, and cholesterol concentration, and increased monocyte and granulocyte %. Their kidneys had decreased glomerular volume, and compactness. The coronary capillary network was altered in the left and right ventricles. Isolated hearts showed left ventricle diastolic dysfunction. Our study suggests that risk factors induce diastolic dysfunction related to coronary microvascularisation morphological alteration via a systemic pro-inflammatory state. Further studies are needed to investigate hemodynamic alteration and endothelial dysfunction.

The effect of omega-3 polyunsaturated fatty acid intake on blood levels of omega-3s in people with chronic atherosclerotic disease: a systematic review.

Atherosclerosis is a systemic pro-inflammatory and pro-oxidative disease, accounting for approximately a third of deaths globally. It has been proposed that omega-3s, through their antioxidant and anti-inflammatory properties, mitigate atherosclerotic disease progression. However, due to the systemic pro-inflammatory and pro-oxidative state of atherosclerosis, it is proposed that patients with atherosclerotic disease may have higher omega-3 requirements than the average requirement, due to increased nutrient utilization in anti-inflammatory and anti-oxidant processes. The aim of this review was to determine what dose and duration of omega-3 supplementation is required to reach a therapeutic blood level of omega-3s (eicosapentaenoic acid ≥150 µg/mL or omega-3 index ≥8%) in people with chronic atherosclerotic disease. This systematic review comprehensively searched MEDLINE, Emcare, Scopus, and CINAHL using key search terms for atherosclerotic disease, omega-3, supplementation, and blood levels of omega-3s. Two reviewers independently screened 529 randomized controlled trials (RCTs) supplementing omega-3s in patients with chronic atherosclerotic disease. In total, 25 journal articles from 17 original RCTs were included and assessed quantitatively. Supplementation at 1.8 g to 3.4 g per day for a 3-month-6-month duration, and at 4.4 g and above for as little as 1 month-6 months were identified as the most effective dosage ranges for increasing blood levels of omega-3s to therapeutic levels in people with atherosclerotic disease. Consideration should be given to routine omega-3 supplementation and to increasing the omega-3 dietary recommendations and upper limits of daily intake to improve clinical outcomes and reduce the risk of cardiac mortality in this population.

Con: Modified Ultrafiltration Should Not Be Routinely Used in Adult Cardiac Surgery

CARDIOPULMONARY BYPASS (CPB) is known to induce a systemic proinflammatory state and may contribute to postoperative organ dysfunction, primarily through complement activation secondary to blood passing through an artificial extracorporeal circuit. 1 Hall RI Smith MS Rocker G. The systemic inflammatory response to cardiopulmonary bypass: Pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg. 1997; 85: 766-782 Crossref PubMed Google Scholar , 2 Wang W Huang HM Zhu DM et al. Modified ultrafiltration in paediatric cardiopulmonary bypass. Perfusion. 1998; 13: 304-310 Crossref PubMed Scopus (39) Google Scholar , 3 Thapmongkol S Masaratana P Subtaweesin T et al. The effects of modified ultrafiltration on clinical outcomes of adult and pediatric cardiac surgery. Asian Biomedicine. 2015; 9: 591-599 Crossref Scopus (4) Google Scholar Ultrafiltration may minimize some of the impact of the CPB-induced systemic inflammatory response. 4 Huang H Yao T Wang W et al. Continuous ultrafiltration attenuates the pulmonary injury that follows open heart surgery with cardiopulmonary bypass. Ann Thorac Surg. 2003; 76: 136-140 Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Traditionally, ultrafiltration may be conventional (CUF) or modified (MUF). Conventional ultrafiltration has been employed extensively during CPB, and involves hemoconcentration of both the priming volume and patient's blood volume at any point during CPB. 5 Darup J Bleese N Kalmar P et al. Hemofiltration during extracorporeal circulation (ECC). Thorac Cardiovasc Surg. 1979; 27: 227-230 Crossref PubMed Scopus (30) Google Scholar ,6 Klineberg PL Kam CA Johnson DC et al. Hematocrit and blood volume control during cardiopulmonary bypass with the use of hemofiltration. Anesthesiology. 1984; 60: 478-480 Crossref PubMed Scopus (19) Google Scholar In the early 1990s, Naik et al. introduced the concept of MUF 7 Elliott MJ. Ultrafiltration and modified ultrafiltration in pediatric open heart operations. Ann Thorac Surg. 1993; 56: 1518-1522 Abstract Full Text PDF PubMed Scopus (205) Google Scholar ,8 Andreasson S Gothberg S Berggren H et al. Hemofiltration modifies complement activation after extracorporeal circulation in infants. Ann Thorac Surg. 1993; 56: 1515-1517 Abstract Full Text PDF PubMed Scopus (88) Google Scholar ,9 Naik SK Knight A Elliott MJ. A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion. 1991; 6: 41-50 Crossref PubMed Scopus (164) Google Scholar in which the patient's blood volume is hemoconcentrated after separation from CPB. 10 Wang S Palanzo D Undar A. Current ultrafiltration techniques before, during and after pediatric cardiopulmonary bypass procedures. Perfusion. 2012; 27: 438-446 Crossref PubMed Scopus (40) Google Scholar Naik et al. postulated it may permit blood-free cardiac surgery. 11 Naik SK Knight A Elliott M. A prospective randomized study of a modified technique of ultrafiltration during pediatric open-heart surgery. Circulation. 1991; 84 (III422-31) PubMed Google Scholar Blood is typically removed from the arterial cannula and returned through the venous cannula. Others employ a modified technique in which blood is removed from the right atrium and infused into the aorta, potentially reducing concerns about cerebral shunting. 12 Myers GJ Leadon RB Mitchell LB et al. Simple modified ultrafiltration. Perfusion. 2000; 15: 447-452 Crossref PubMed Scopus (16) Google Scholar

Abstract 14808: Clinical Characteristics and Outcomes of Myocardial Infarction (MI) Among Patients With Chronic Kidney Disease (CKD): A National Inpatient Analysis

Introduction Cardiovascular disease, including myocardial infarction, is a common cause of morbidity and mortality among patients with chronic kidney disease (CKD), independent of other common cardiovascular disease risk factors. CKD has been linked to a systemic proinflammatory state contributing to myocardial and vascular remodeling resulting in atherosclerotic lesions, vascular calcification, and senescence. The clinical characteristics and outcomes of MI among patients with CKD has not been extensively studied nationally. Objectives To evaluate the clinical characteristics, including gender, race, and age; and outcomes, including in-hospital mortality (IHM), length of hospital stay (LOS), and complications post-MI among those with CKD. Methods Adults diagnosed with myocardial infarction and had background CKD were identified from the National In-Patient Sample (NIS) dataset for the year 2019 using the International Classification of Disease (ICD-10) codes. Weighted multivariable logistic regression models were used as appropriate. Various sociodemographic and clinical factors were adjusted for in the analysis. Results Of the 23,590 patients identified with MI and CKD; 65.1% were male, 69.6% were White, while the median age was 62 years (Inter-Quartile Range (IQR): 54-71) and 72 years (IQR: 63-81) in the non-CKD and CKD population respectively. The median LOS was 2 days (IQR: 2-4) and 3 days (IQR: 2-7) in the non-CKD and CKD group, respectively. The incidence of new intracardiac thrombus was lower at 0.2% among CKD patients vs. 0.4% among those without CKD (p: 0.108). Conversely, IHM was higher among those with CKD at 13.9% compared to those without CKD, who had an IHM of 6.7% (p: 0.0001). The incidence of heart failure was 49.3% among those with CKD, almost twice that of those without CKD at 23.6% (p: 0.0001). Conclusion This study highlights critical clinical characteristics and outcomes of MI in the CKD population. The results, especially regarding the age of onset of MI and the incidence of intracardiac thrombi, warrant further studies to unravel the reason(s) behind these findings.

HFpEF and Atrial Fibrillation: The Enigmatic Interplay of Dysmetabolism, Biomarkers, and Vascular Endothelial Dysfunction.

Heart failure with preserved ejection fraction (HFpEF) has a complex pathophysiology that encompasses systemic proinflammatory state and dysregulated levels of cardiometabolic and oxidative stress biomarkers. The prevalence of both HFpEF and atrial fibrillation (AF) is continuously rising, especially in the elderly. The aim of our study was to explore if there were any differences in biomarker levels and vascular function in the elderly patients with HFpEF with and without AF and to assess interconnections between clinically relevant biomarkers and cardiac and vascular function. This was a cross-sectional study of patients ≥ 65 years with HFpEF who were divided into 2 groups based on the presence or absence of AF. We have sonographically assessed echocardiographic parameters of left ventricular systolic and diastolic function and the peripheral vascular function parameters, namely, pulse wave velocity (PWV) and flow-mediated dilation (FMD). NT-proBNP, irisin, leptin, adiponectin, insulin-like growth factor 1 (IGF-1), and malondialdehyde (MDA) blood levels were determined. Fifty-two patients (mean age 80 ± 7 years, 67% females) were included. Patients with HFpEF and AF had significantly lower levels of irisin (median 4.75 vs. 13.5 ng/mL, p = 0.007), leptin (median 9.5 vs. 15.0 ng/L, p = 0.023), and MDA (median 293 vs. 450 ng/mL, p = 0.017) and significantly higher values of NT-proBNP (median 2365 vs. 529 ng/L, p < 0.001) but not vascular function parameters, as compared to HFpEF patients without AF. MDA was significantly correlated with diastolic function (r = 0.395, p = 0.007) and FMD (r = 0.394, p = 0.011), while adiponectin was inversely associated with FMD (r = -0.325, p = 0.038) and left ventricular ejection fraction (r = -0.319, p = 0.029). Our results have demonstrated that patients with HFpEF and AF have significantly lower leptin, irisin, and MDA levels compared to patients with HFpEF but without AF. These results offer new insights into the complexity of vascular function and cardiometabolic and oxidative stress biomarkers in the context of HFpEF, AF, and aging.

Assessment of cardiovascular risk with C-reactive protein in rheumatoid arthritis patients

Over the past decades, it has become increasingly accepted that the risk of cardiovascular (CV) morbidity and mortality is noticeably augmented in rheumatoid arthritis (RA) patients [1]. When compared to the general population, the mere existence of said condition increases CV death risk by up to 50% [2]. Furthermore, more than half of premature mortality in these patients is attributable to CV disease, which remains as their leading cause of death [2–4]. Therefore, RA, by itself, is now accepted as an independent cardiovascular risk factor, due to its inherent chronic and systemic pro-inflammatory state [1].

Transcutaneous Vagus Nerve Stimulation Ameliorates the Phenotype of Heart Failure With Preserved Ejection Fraction Through Its Anti-Inflammatory Effects.

A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction (HFpEF). Low-level transcutaneous vagus nerve stimulation (LLTS) suppresses inflammation in animals and humans, mediated by an α7nAchR (alpha7 nicotinic acetylcholine receptor)-dependent pathway. We examined the effects of LLTS on cardiac function, inflammation, and fibrosis in the presence of α7nAchR pharmacological blockade in a rat model of HFpEF. Dahl salt-sensitive rats at 7 weeks of age were treated with high-salt diet for 6 weeks to induce HFpEF, followed by 4 weeks of (1) LLTS, (2) LLTS with the α7nAchR blocker methyllycaconitine, (3) sham, and (4) olmesartan. Blood pressure, cardiac function by echocardiography, heart rate variability, and serum cytokines were measured at 13 and 17 weeks of age. Cardiac fibrosis, inflammatory cell infiltration, and gene expression were determined at 17 weeks. LLTS attenuated the increase in blood pressure; improved cardiac function; decreased inflammatory cytokines, macrophage infiltration, and fibrosis; and improved survival compared with other groups. Methyllycaconitine attenuated these effects, whereas olmesartan did not improve cardiac function or fibrosis despite maintaining similar blood pressure as LLTS. Heart rate variability was similarly improved in the LLTS and LLTS plus methyllycaconitine groups but remained low in the other groups. LLTS reversed the dysregulated inflammatory signaling pathways in HFpEF hearts. Neuromodulation with LLTS improved cardiac function in a rat model of HFpEF through its anti-inflammatory and antifibrotic effects. These results provide the basis for further clinical trials in humans.

Stevens-Johnson syndrome induced by carbamazepine and amitriptyline in diabetic patient: a case report

Stevens-Johnson syndrome (SJS) is systemic immune reactions (type IV hypersensitivity) that are usually present by blistering and erosions of skin and mucous membranes with involvement of multiple organ systems. The incidence of SJS is rare, with the common comorbidities are diabetes mellitus, epilepsy, hypertension, and stroke. This condition is associated with systemic proinflammatory state. Diabetes mellitus is a metabolic disorder that is characterized by abnormally elevated levels of blood glucose due to glucose intolerance, hyperglycemia, and impaired insulin secretion. Nowadays, pathogenesis of diabetes is considered to be dysregulation of immune factors that are recognized as important etiological components in the development of insulin resistance. We report a case of a 30-years-old man with fever and sore throat, who had type 2 diabetes mellitus (T2DM) and used carbamazepine and amitriptyline for diabetic neuropathy, then followed by redness and blistering on his lips, palates, face, and trunk which subsequently diagnosed with SJS.

Gut Microbiota and Sex Hormones: Crosstalking Players in Cardiometabolic and Cardiovascular Disease

The available evidence indicates a close connection between gut microbiota (GM) disturbance and increased risk of cardiometabolic (CM) disorders and cardiovascular (CV) disease. One major objective of this narrative review is to discuss the key contribution of dietary regimen in determining the GM biodiversity and the implications of GM dysbiosis for the overall health of the CV system. In particular, emerging molecular pathways are presented, linking microbiota-derived signals to the local activation of the immune system as the driver of a systemic proinflammatory state and permissive condition for the onset and progression of CM and CV disease. We further outline how the cross-talk between sex hormones and GM impacts disease susceptibility, thereby offering a mechanistic insight into sexual dimorphism observed in CVD. A better understanding of these relationships could help unravel novel disease targets and pave the way to the development of innovative, low-risk therapeutic strategies based on diet interventions, GM manipulation, and sex hormone analogues.

The contribution of the immune system to genitourinary fibrosis.

Fibrotic diseases of the genitourinary tract are devastating and incompletely understood pathologies. These diseases include urethral and ureteral strictures, retroperitoneal fibrosis, and Peyronie's disease. They can contribute to obstructive uropathy and sexual dysfunction. Poor understanding of the pathophysiology of these diseases severely limits our ability to prevent and treat them. Genitourinary fibrotic diseases likely represent related pathologies that share common underlying mechanisms involving wound healing in response to injury. These diseases share the common feature of extracellular matrix abnormalities-such as collagen deposition, transforming growth factor-β accumulation, and dysregulation of collagen maturation-leading to abnormal tissue stiffness. Given the association of many of these diseases with autoimmunity, a systemic pro-inflammatory state likely contributes to their associated fibrogenesis. Herein, we explore the immunologic contribution to fibrogenesis in several fibrotic diseases of the genitourinary system. Better understanding how the immune system contributes to fibrosis in these diseases may improve prevention and therapeutic strategies and elucidate the functions of immunologic contributors to fibrosis in general.

Targeting the Metabolic-Inflammatory Circuit in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality. The current mechanistic paradigm supports a comorbidity-driven systemic proinflammatory state that evokes microvascular and myocardial dysfunction. Crucially, diabetes and obesity are frequently prevalent in HFpEF patients; as such, we review the involvement of a metabolic-inflammatory circuit in disease pathogenesis. Experimental models of diastolic dysfunction and genuine models of HFpEF have facilitated discovery of underlying drivers of HFpEF, where metabolic derangement and systemic inflammation appear to be central components of disease pathophysiology. Despite a shared phenotype among these models, molecular signatures differ depending on type and combination of comorbidities present. Inflammation, oxidative stress, hypertension, and metabolic derangements have been positioned as therapeutic targets to suppress the metabolic-inflammatory circuit in HFpEF. However, the stratification of unique patient phenogroups within the collective HFpEF subgroup argues for specific interventions for distinct phenogroups.

Effect of SARS-CoV-2 Infection on Anti-HLA Antibodies and De Novo DSA Incidence in Lung Transplant Recipients

PurposeThe SARS-CoV-2 pandemic has brought many challenges into the field of transplantation. The infection itself leads to a broad activation of B-lymphocytes, which in combination with reduced immunosuppression and systemic pro-inflammatory state may possibly lead to an alloimmune response. The main objective of this retrospective single-center study was to evaluate the effect of SARS-CoV-2 infection on anti-HLA antibody dynamics and development of de novo donor specific antibodies (dnDSA) in lung transplant recipients (LTRs). We also aimed to determine the outcomes of treatment with convalescent plasma (CP) and mycophenolate mofetil (MMF) reduction.MethodsA cohort of 27 LTRs infected by SARS-CoV-2 was retrospectively analyzed. The median age of LTRs at infection was 45.4 years (IQR 26.8-59.5) and median time between transplantation and infection was 16.8 months (IQR 8.0-56.9). The inclusion criteria were history of SARS-CoV-2 infection and screening for anti-HLA antibodies (Luminex technology, One Lambda) before and after infection (median 84, IQR 29-239 days and median 55, IQR 32-90 days resp.).ResultsNo dnDSA were detected after SARS-CoV-2 infection. De novo class II anti-HLA antibodies with low mean fluorescence intensity (MFI) were observed in 1 patient (3.7%) treated with favipiravir and MMF discontinuation without receiving CP. The standard therapeutic regimen consisted of specific antiviral therapy (remdesivir n=15, 55.6%; favipiravir n=12, 44.4%), reduced or discontinued MMF (n=10, 37.0% and n=17, 63.0%, resp.) and administration of CP (n=18, 66.7%) (Table 1).ConclusionIn this retrospective study we did not observe a significant effect of SARS-CoV-2 infection, MMF reduction or CP treatment on anti-HLA antibody dynamics and dnDSA incidence in LTRs. Therefore, CP and MMF withdrawal may be considered as safe therapeutic options regarding antibody-mediated rejection in LTRs affected by SARS-CoV-2. Future studies in larger cohorts are needed to confirm the findings.

Cell Therapy in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is the most common cause of hospitalisation for heart failure. However, only limited effective treatments are available. Recent evidence suggests that HFpEF may result from a systemic proinflammatory state, microvascular endothelial inflammation and microvascular rarefaction. Formation of new microvasculature in ischaemic tissues is dependent on CD34+ cells, which incorporate into the newly developing vasculature and produce pro-angiogenic cytokines. In HFpEF patients, worsening of diastolic function appears to correlate with decreased numbers of CD34+ cells. Therefore, it is plausible that increasing the myocardial numbers of CD34+ cells could theoretically lead to improved microvascular function and improved diastolic parameters in HFpEF. In accordance with this hypothesis, recent pilot clinical data suggest that CD34+ cell therapy may indeed be associated with improved diastolic function and better functional capacity in HFpEF patients and could thus represent a promising novel therapeutic modality for this patient population.

Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders.

The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early as in utero fetal development and continuing through birth to late-stage adulthood, the crosstalk between the gut microbiome and brain is essential for modulating various metabolic, neurodevelopmental, and immune-related pathways. Conversely, microbial dysbiosis – defined as alterations in richness and relative abundances – of the gut is implicated in the pathogenesis of several chronic neurological and neurodegenerative disorders. Evidence from large-population cohort studies suggests that individuals with neurodegenerative conditions have an altered gut microbial composition as well as microbial and serum metabolomic profiles distinct from those in the healthy population. Dysbiosis is also linked to psychiatric and gastrointestinal complications – comorbidities often associated with the prodromal phase of Parkinson’s disease (PD) and Alzheimer’s disease (AD). Studies have identified potential mediators that link gut dysbiosis and neurological disorders. Recent findings have also elucidated the potential mechanisms of disease pathology in the enteric nervous system prior to the onset of neurodegeneration. This review highlights the functional pathways and mechanisms, particularly gut microbe-induced chronic inflammation, protein misfolding, propagation of disease-specific pathology, defective protein clearance, and autoimmune dysregulation, linking gut microbial dysbiosis and neurodegeneration. In addition, we also discuss how pathogenic transformation of microbial composition leads to increased endotoxin production and fewer beneficial metabolites, both of which could trigger immune cell activation and enteric neuronal dysfunction. These can further disrupt intestinal barrier permeability, aggravate the systemic pro-inflammatory state, impair blood–brain barrier permeability and recruit immune mediators leading to neuroinflammation and neurodegeneration. Continued biomedical advances in understanding the microbiota-gut-brain axis will extend the frontier of neurodegenerative disorders and enable the utilization of novel diagnostic and therapeutic strategies to mitigate the pathological burden of these diseases.