Differential Role of Factor XIII in Acute Myocardial Infarction and Ischemic Stroke.

Factor XIII is a transglutaminase enzyme that plays a crucial role in hemostasis and wound healing. It crosslinks fibrin strands, stabilizing clots and promoting clot resistance to fibrinolysis. Additionally, Factor XIII has been found to have multiple other functions that extend beyond coagulation, including the regulation of inflammation and tissue repair processes. Emerging evidence suggests that Factor XIII may also have differential roles in acute myocardial infarction and ischemic stroke, two common cardiovascular events with significant morbidity and mortality. In acute myocardial infarction, Factor XIII has been implicated in promoting clot stability and reducing the risk of re-occlusion. In ischemic stroke, Factor XIII may also contribute to the pathogenesis of cerebral ischemia by promoting clot formation and exacerbating neuronal damage. Several studies have investigated the association between Factor XIII and these cardiovascular events, using various approaches such as genetic polymorphism analysis, animal models, and clinical data analysis. These studies have provided important insights into the role of Factor XIII in acute myocardial infarction and ischemic stroke, highlighting its potential as a therapeutic target for interventions aimed at improving outcomes in these conditions. In this review, we will summarize the current understanding of Factor XIII's role in acute myocardial infarction and ischemic stroke.

Impact of Radiotherapy on Malfunctions and Battery Life of Cardiac Implantable Electronic Devices in Cancer Patients.

PURPOSE: This study analyses a large number of cancer patients with CIEDs for device malfunction and premature battery depletion by device interrogation after each radiotherapy fraction and compares different guidelines in regard to patient safety. METHODS: From 2007 to 2022, a cohort of 255 patients was analyzed for CIED malfunctions via immediate device interrogation after every RT fraction. RESULTS: Out of 324 series of radiotherapy treatments, with a total number of 5742 CIED interrogations, nine device malfunctions (2.8%) occurred. Switching into back-up/safety mode and software errors occurred four times each. Once, automatic read-out could not be performed. The median prescribed cumulative dose at planning target volume (PTV) associated with CIED malfunction was 45.0 Gy (IQR 36.0-64.0 Gy), with a median dose per fraction of 2.31 Gy (IQR 2.0-3.0 Gy). The median maximum dose at the CIED at time of malfunction was 0.3 Gy (IQR 0.0-1.3 Gy). No correlation between CIED malfunction and maximum photon energy (p = 0.07), maximum dose at the CIED (p = 0.59) nor treatment localization (p = 0.41) could be detected. After excluding the nine malfunctions, premature battery depletion was only observed three times (1.2%). Depending on the national guidelines, 1-9 CIED malfunctions in this study would have been detected on the day of occurrence and in none of the cases would patient safety have been compromised. CONCLUSION: Radiation-induced malfunctions of CIEDs and premature battery depletion are rare. If recommendations of national safety guidelines are followed, only a portion of the malfunctions would be detected directly after occurrence. Nevertheless, patient safety would not be compromised.

Internal carotid artery blood flow and pulsatility index in cognitively impaired people with chronic heart failure.

AIMS: Mild cognitive impairment and dementia are common and serious co-morbidities in people with chronic heart failure (HF) as they increase hospitalization rates, mortality and health care costs. Upon other factors, dysregulated cerebral perfusion might contribute to brain pathology. We aimed to evaluate the association of non-invasively measured blood flow (BF) and pulsatility index (PI) of the internal carotid artery (ICA) with (i) chronic HF parameters, (ii) brain morphologic measures and (iii) cognitive impairment. METHODS AND RESULTS: This post-hoc analysis of the observational, prospective Cognition.Matters-HF study included 107 chronic HF patients without atrial fibrillation or carotid artery stenosis (aged 63 ± 10 years; 19% women). Using extracranial sonography, we measured ICA-BF and ICA-PI 1.5 cm distal of the carotid bifurcation. Brain magnetic resonance imaging was performed on a 3-Tesla scanner to quantify cerebral atrophy, hippocampal atrophy and white matter hyperintensities. Extensive neuropsychological testing tested the cognitive domains intensity of attention, visual/verbal memory and executive function (including its subdomains selectivity of attention, visual/verbal fluency and working memory) using a comprehensive test battery. (i) Neither ICA-BF (median 630 (quartiles 570, 700) mL/min) nor ICA-PI (1.05 (0.96. 1.23)) related to left ventricular ejection fraction, left atrial volume index or NT-proBNP. (ii) Higher ICA-PI (r = 0.25; P = 0.011), but not ICA-BF (r = 0.08; P = 0.409), associated with increased volume of white matter hyperintensities beyond ageing, while neither ICA-PI nor ICA-BF related to cerebral or hippocampal atrophy indices. (iii) ICA-BF, but not ICA-PI, positively correlated with age-adjusted T-scores of executive function (r = 0.38; P < 0.001) and its subdomains working memory (r = 0.32; P < 0.001) and visual/verbal fluency (r = 0.32; P < 0.001). In a multivariate linear model of executive function, only ICA-BF (T = 3.79; P < 0.001), but not HF or magnetic resonance imaging parameters, remained a significant correlate of executive function. CONCLUSIONS: ICA-BF and ICA-PI, measured in broadly available extracranial sonography, independently related to measures of functional and structural brain changes in people with chronic HF, respectively. Due to limitations of this cross-sectional approach without a healthy control group, larger controlled longitudinal studies are needed to further elucidate the role of ICA-BF dysregulation and its implication for clinical care in this vulnerable cohort.

Profiles of cognitive impairment in chronic heart failure-A cluster analytic approach.

Background: Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods: The prospective cohort study "Cognition.Matters-HF" recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results: Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the "global deficits" cluster and the "no deficits" group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion: Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.

Chronic Neuroinflammation and Cognitive Decline in Patients with Cardiac Disease: Evidence, Relevance, and Therapeutic Implications.

Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target.

Features of metabolic syndrome and inflammation independently affect left ventricular function early after first myocardial infarction.

BACKGROUND: A high body mass index (BMI) is often associated with metabolic syndrome, which is accompanied by systemic low-grade chronic inflammation. Here, we analyzed whether BMI, other components of metabolic syndrome, and/or inflammatory markers correlate with left ventricular geometry, function, and infarct size as assessed by serial cardiac magnetic resonance imaging (MRI) after a first (clinically evident) ST-elevation MI (STEMI). METHODS: Within the Etiology, Titre-Course, and effect on Survival (ETiCS) study, cardiac MRI conducted 7-9 days and 12 months after MI enabled longitudinal characterization of patients with a first STEMI along with serial routine blood counts and multiplex cytokine measurements. RESULTS: Of 91 locally included STEMI patients, 47% were overweight (25 kg/m2 < BMI < 30 kg/m2) and 24% were obese (BMI ≥ 30 kg/m2). No patient died during 12 months of follow-up. Left ventricular ejection fraction (LVEF), measured 7-9 days after STEMI, was significantly lower in overweight (49.5 ± 7.1%) and obese (45.8 ± 12.0%) patients than in the normal weight group (56.2 ± 7.7%). Along with BMI (T = -3.8; p < 0.001), hemoglobin A1c (HbA1c; T = -3.1; p = 0.004) and peak C-reactive protein (T = -2.6; p = 0.013) emerged as independent predictors of worse LVEF 7-9 days post MI (R2 = 0.45). Only peak C-reactive protein (T = -4.4; p < 0.001), but not parameters of the metabolic syndrome, predicted worse LVEF 12 months after STEMI (R2 = 0.20). CONCLUSION: Both BMI and HbA1c correlated negatively with LVEF only early, but not late after STEMI. Peak CRP evolved as strongest predictor of cardiac function at all time points independent of the metabolic syndrome.

Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients.

BACKGROUND: Chronic heart failure (HF) is known to increase the risk of developing Alzheimer's dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. METHODS: Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). RESULTS: Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = - 0.21; p = 0.013) and pTau (ρ = - 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = - 2.4 for pTau; T = - 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = - 3.1). CONCLUSIONS: pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.

Sustained Increase in Serum Glial Fibrillary Acidic Protein after First ST-Elevation Myocardial Infarction.

Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.

Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure.

AIMS: Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. METHODS AND RESULTS: Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = -4.7; P < 0.001), alanine aminotransferase (T = -2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = -3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). CONCLUSIONS: Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF.

B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders.

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

Differential Effects of MS Therapeutics on B Cells-Implications for Their Use and Failure in AQP4-Positive NMOSD Patients.

B cells are considered major contributors to multiple sclerosis (MS) pathophysiology. While lately approved disease-modifying drugs like ocrelizumab deplete B cells directly, most MS medications were not primarily designed to target B cells. Here, we review the current understanding how approved MS medications affect peripheral B lymphocytes in humans. These highly contrasting effects are of substantial importance when considering these drugs as therapy for neuromyelitis optica spectrum disorders (NMOSD), a frequent differential diagnosis to MS, which is considered being a primarily B cell- and antibody-driven diseases. Data indicates that MS medications, which deplete B cells or induce an anti-inflammatory phenotype of the remaining ones, were effective and safe in aquaporin-4 antibody positive NMOSD. In contrast, drugs such as natalizumab and interferon-ß, which lead to activation and accumulation of B cells in the peripheral blood, lack efficacy or even induce catastrophic disease activity in NMOSD. Hence, we conclude that the differential effect of MS drugs on B cells is one potential parameter determining the therapeutic efficacy or failure in antibody-dependent diseases like seropositive NMOSD.

Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS.

OBJECTIVE: We examined the effect of glatiramer acetate (GA) on B-cell maturation, differentiation, and antigen presentation in MS and experimental autoimmune encephalomyelitis (EAE). METHODS: A cross-sectional study of blood samples from 20 GA-treated and 18 untreated patients with MS was performed by flow cytometry; 6 GA-treated patients with MS were analyzed longitudinally. GA-mediated effects on B-cell antigen-presenting function were investigated in EAE, or, alternatively, B cells were treated with GA in vitro using vehicle as a control. RESULTS: In MS, GA diminished transitional B-cell and plasmablast frequency, downregulated CD69, CD25, and CD95 expression, and decreased TNF-α production, whereas IL-10 secretion and MHC Class II expression were increased. In EAE, we observed an equivalent dampening of proinflammatory B-cell properties and an enhanced expression of MHC Class II. When used as antigen-presenting cells for activation of naive T cells, GA-treated B cells promoted development of regulatory T cells, whereas proinflammatory T-cell differentiation was diminished. CONCLUSIONS: GA immune modulates B-cell function in EAE and MS and efficiently interferes with pathogenic B cell-T cell interaction.

Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients.

BACKGROUND: In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. METHODS: Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. RESULTS: While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. CONCLUSION: Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. TRIAL REGISTRATION: Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).

Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis.

In multiple sclerosis (MS), the effect of dimethyl fumarate (DMF) treatment is primarily attributed to its capacity to dampen pathogenic T cells. Here, we tested whether DMF also modulates B cells, which are newly recognized key players in MS, and to which extent DMF restricts ongoing loss of oligodendrocytes and axons in the central nervous system (CNS). Therefore, blood samples and brain tissue from DMF-treated MS patients were analyzed by flow cytometry or histopathological examination, respectively. Complementary mechanistic studies were conducted in inflammatory as well as non-inflammatory CNS demyelinating mouse models. In this study, DMF reduced the frequency of antigen-experienced and memory B cells and rendered remaining B cells less prone to activation and production of pro-inflammatory cytokines. Dissecting the functional consequences of these alterations, we found that DMF ameliorated a B cell-accentuated experimental autoimmune encephalomyelitis model by diminishing the capacity of B cells to act as antigen-presenting cells for T cells. In a non-inflammatory model of toxic demyelination, DMF limited oligodendrocyte apoptosis, promoted maturation of oligodendrocyte precursors and reduced axonal damage. In a CNS biopsy of a DMF-treated MS patient, we equivalently observed higher numbers of mature oligodendrocytes as well as a reduced extent of axonal damage when compared to a cohort of treatment-naïve patients. In conclusion, we showed that besides suppressing T cells, DMF dampens pathogenic B cell functions, which probably contributes to its clinical effectiveness in relapsing MS. DMF treatment may furthermore limit chronically ongoing CNS tissue damage, which may reduce long-term disability in MS apart from its relapse-reducing capacity.