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Europace : European Pacing,... Dec 2023Pulsed field ablation (PFA) has been proposed as a novel alternative to radiofrequency (RF) and cryoablation in the treatment of atrial fibrillation (AF). Following the...
AIMS
Pulsed field ablation (PFA) has been proposed as a novel alternative to radiofrequency (RF) and cryoablation in the treatment of atrial fibrillation (AF). Following the occurrence of two cases of acute kidney injury (AKI) secondary to haemolysis after a PFA procedure, we evaluated haemolysis in a cohort of consecutive patients.
METHODS AND RESULTS
Two cases of AKI occurred in last May and June 2023. AKI was secondary to acute and severe haemolysis after a PFA procedure. From June 2023, a total of 68 consecutive patients (64.3 ± 10.5 years) undergoing AF ablation with PFA were enrolled in the study. All patients had a blood sample the day after the procedure for the assessment of haemolysis indicators. The pentaspline PFA catheter was used with a total number of median applications of 64 (54; 76). Nineteen patients (28%) showed significantly depleted haptoglobin levels (<0.04 g/L). A significant inverse correlation was found between the plasma level of haptoglobin and the total number of applications. Two groups were compared: the haemolysis+ group (haptoglobin < 0.04 g/L) vs. the haemolysis- group. The total number of applications was significantly higher in the haemolysis+ group vs the haemolysis - group respectively 75 (62; 127) vs 62 (54; 71) P = 0.011. More than 70 applications seem to have better sensitivity and specificity to predict haemolysis.
CONCLUSION
Intravascular haemolysis can occur after certain procedures of PFA. Acute kidney injury is a phenomenon that appears to be very rare after a PFA procedure. However, caution must be exercised in the number of applications to avoid severe haemolysis.
Topics: Humans; Atrial Fibrillation; Hemolysis; Haptoglobins; Acute Kidney Injury; Catheter Ablation; Pulmonary Veins; Treatment Outcome
PubMed: 38175788
DOI: 10.1093/europace/euad371 -
Clinical Chemistry and Laboratory... Jul 2023Detection of hemoglobin (Hb) and red blood cells in urine (hematuria) is characterized by a large number of pitfalls. Clinicians and laboratory specialists must be... (Review)
Review
Detection of hemoglobin (Hb) and red blood cells in urine (hematuria) is characterized by a large number of pitfalls. Clinicians and laboratory specialists must be aware of these pitfalls since they often lead to medical overconsumption or incorrect diagnosis. Pre-analytical issues (use of vacuum tubes or urine tubes containing preservatives) can affect test results. In routine clinical laboratories, hematuria can be assayed using either chemical (test strips) or particle-counting techniques. In cases of doubtful results, Munchausen syndrome or adulteration of the urine specimen should be excluded. Pigmenturia (caused by the presence of dyes, urinary metabolites such as porphyrins and homogentisic acid, and certain drugs in the urine) can be easily confused with hematuria. The peroxidase activity (test strip) can be positively affected by the presence of non-Hb peroxidases (e.g. myoglobin, semen peroxidases, bacterial, and vegetable peroxidases). Urinary pH, haptoglobin concentration, and urine osmolality may affect specific peroxidase activity. The implementation of expert systems may be helpful in detecting preanalytical and analytical errors in the assessment of hematuria. Correcting for dilution using osmolality, density, or conductivity may be useful for heavily concentrated or diluted urine samples.
Topics: Humans; Hematuria; Peroxidase; Hemoglobins; Erythrocytes; Osmolar Concentration
PubMed: 37079906
DOI: 10.1515/cclm-2023-0260 -
Stroke Jul 2023Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This... (Review)
Review
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.
Topics: Adult; Middle Aged; Humans; Animals; Mice; Sheep; Subarachnoid Hemorrhage; Haptoglobins; Consensus; Nitric Oxide; Inflammation; Hemoglobins
PubMed: 37232189
DOI: 10.1161/STROKEAHA.123.040205 -
Annual Review of Biomedical Engineering Jun 2023Hemolysis (i.e., red blood cell lysis) can increase circulatory levels of cell-free hemoglobin (Hb) and its degradation by-products, namely heme (h) and iron (Fe). Under... (Review)
Review
Hemolysis (i.e., red blood cell lysis) can increase circulatory levels of cell-free hemoglobin (Hb) and its degradation by-products, namely heme (h) and iron (Fe). Under homeostasis, minor increases in these three hemolytic by-products (Hb/h/Fe) are rapidly scavenged and cleared by natural plasma proteins. Under certain pathophysiological conditions, scavenging systems become overwhelmed, leading to the accumulation of Hb/h/Fe in the circulation. Unfortunately, these species cause various side effects such as vasoconstriction, hypertension, and oxidative organ damage. Therefore, various therapeutics strategies are in development, ranging from supplementation with depleted plasma scavenger proteins to engineered biomimetic protein constructs capable of scavenging multiple hemolytic species. In this review, we briefly describe hemolysis and the characteristics of the major plasma-derived protein scavengers of Hb/h/Fe. Finally, we present novel engineering approaches designed to address the toxicity of these hemolytic by-products.
Topics: Humans; Heme; Hemolysis; Iron; Haptoglobins; Hemoglobins
PubMed: 37289555
DOI: 10.1146/annurev-bioeng-081622-031203 -
International Journal of Molecular... Nov 2023Haptoglobin is the body's first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated...
Haptoglobin is the body's first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated the haptoglobin response after SAH in cerebrospinal fluid (CSF) and serum. Paired CSF and serum samples from 19 controls and 92 SAH patients were assayed as follows: ultra-performance liquid chromatography for CSF haemoglobin and haptoglobin, immunoassay for serum haptoglobin and multiplexed CSF cytokines, and colorimetry for albumin. There was marked CSF haptoglobin deficiency: 99% of extracellular haemoglobin was unbound. The quotients for both CSF/serum albumin (qAlb) and haptoglobin (qHp) were used to compute the CSF haptoglobin index (qHp/qAlb). CSF from SAH patients had a significantly lower haptoglobin index compared to controls, especially in Haptoglobin-1 allele carriers. Serum haptoglobin levels increased after SAH and were correlated with CSF cytokine levels. Haptoglobin variables were not associated with long-term clinical outcomes post-SAH. We conclude that: (1) intrathecal haptoglobin consumption occurs after SAH, more so in haptoglobin-1 allele carriers; (2) serum haptoglobin is upregulated after SAH, in keeping with the liver acute phase response to central inflammation; (3) haptoglobin in the CSF is so low that any variation is too small for this to affect long-term outcomes, emphasising the potential for therapeutic haptoglobin supplementation.
Topics: Humans; Subarachnoid Hemorrhage; Haptoglobins; Cytokines; Hemoglobins
PubMed: 38069244
DOI: 10.3390/ijms242316922 -
Acta Neuropathologica Nov 2023In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These...
In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.
Topics: Humans; Multiple Sclerosis; Iron; Haptoglobins; Biomarkers; Hemoglobins; Myeloid Cells; Magnetic Resonance Imaging
PubMed: 37715818
DOI: 10.1007/s00401-023-02627-4 -
Critical Care Explorations Feb 2024Cell-free hemoglobin (CFH) is a potent mediator of endothelial dysfunction, organ injury, coagulopathy, and immunomodulation in hemolysis. These mechanisms have been... (Review)
Review
OBJECTIVES
Cell-free hemoglobin (CFH) is a potent mediator of endothelial dysfunction, organ injury, coagulopathy, and immunomodulation in hemolysis. These mechanisms have been demonstrated in patients with sepsis, hemoglobinopathies, and those receiving transfusions. However, less is known about the role of CFH in the pathophysiology of trauma, despite the release of equivalent levels of free hemoglobin.
DATA SOURCES
Ovid MEDLINE, Embase, Web of Science Core Collection, and BIOSIS Previews were searched up to January 21, 2023, using key terms related to free hemoglobin and trauma.
DATA EXTRACTION
Two independent reviewers selected studies focused on hemolysis in trauma patients, hemoglobin breakdown products, hemoglobin-mediated injury in trauma, transfusion, sepsis, or therapeutics.
DATA SYNTHESIS
Data from the selected studies and their references were synthesized into a narrative review.
CONCLUSIONS
Free hemoglobin likely plays a role in endothelial dysfunction, organ injury, coagulopathy, and immune dysfunction in polytrauma. This is a compelling area of investigation as multiple existing therapeutics effectively block these pathways.
PubMed: 38352942
DOI: 10.1097/CCE.0000000000001052 -
Critical Care (London, England) Jul 2023There is a clear relationship between quantitative measures of fitness (e.g., VO max) and outcomes after surgical procedures. Whether or not fitness is a modifiable risk...
BACKGROUND
There is a clear relationship between quantitative measures of fitness (e.g., VO max) and outcomes after surgical procedures. Whether or not fitness is a modifiable risk factor and what underlying biological processes drive these changes are not known. The purpose of this study was to evaluate the moderate exercise training effect on sepsis outcomes (survival) as well as the hepatic biological response. We chose to study the liver because it plays a central role in the regulation of immune defense during systemic infection and receives blood flow directly from the origin of infection (gut) in the cecal ligation and puncture (CLP) model.
METHODS
We randomized 50 male (♂) and female (♀) Sprague-Dawley rats (10 weeks, 340 g) to 3 weeks of treadmill exercise training, performed CLP to induce polymicrobial "sepsis," and monitored survival for five days (Part I). In parallel (Part II), we randomized 60 rats to control/sedentary (G1), exercise (G2), exercise + sham surgery (G3), CLP/sepsis (G4), exercise + CLP [12 h (G5) and 24 h (G6)], euthanized at 12 or 24 h, and explored molecular pathways related to exercise and sepsis survival in hepatic tissue and serum.
RESULTS
Three weeks of exercise training significantly increased rat survival following CLP (polymicrobial sepsis). CLP increased inflammatory markers (e.g., TNF-a, IL-6), which were attenuated by exercise. Sepsis suppressed the SOD and Nrf2 expression, and exercise before sepsis restored SOD and Nrf2 levels near the baseline. CLP led to increased HIF1a expression and oxidative and nitrosative stress, the latter of which were attenuated by exercise. Haptoglobin expression levels were increased in CLP animals, which was significantly amplified in exercise + CLP (24 h) rats.
CONCLUSIONS
Moderate exercise training (3 weeks) increased the survival in rats exposed to CLP, which was associated with less inflammation, less oxidative and nitrosative stress, and activation of antioxidant defense pathways.
Topics: Rats; Male; Female; Animals; Rats, Sprague-Dawley; NF-E2-Related Factor 2; Liver; Sepsis; Signal Transduction; Superoxide Dismutase; Disease Models, Animal
PubMed: 37407986
DOI: 10.1186/s13054-023-04551-1 -
Alternative Therapies in Health and... Jul 2023Sepsis is one of the leading causes of mortality for patients with severe infections who had been admitted to intensive care units (ICUs). Early diagnosis, accurate...
CONTEXT
Sepsis is one of the leading causes of mortality for patients with severe infections who had been admitted to intensive care units (ICUs). Early diagnosis, accurate treatment, and management of sepsis remain extremely difficult in clinical settings, due to a lack of early biomarkers and diverse clinical manifestations.
OBJECTIVE
The study intended to identify the key genes and pathways associated with inflammation in sepsis-using microarray technology combined with bioinformatics and key inflammation-related genes (IRGs)-to perform an enrichment analysis and evaluate the value of those genes for the diagnosis and evaluation of prognosis for patients with sepsis.
DESIGN
The research team performed a genetic analysis.
SETTING
The study took place at the Center for Emergency and Critical Medicine at Jinshan Hospital of Fudan University in Jinshan District, Shanghai, China.
GROUPS
The research team created two groups, the sepsis group, individuals with sepsis, and the control group, individuals without sepsis, using data for those groups from five microarray datasets obtained from the Gene Expression Omnibus (GEO) database.
OUTCOME MEASURES
The research team: (1) downloaded the GSE57065, GSE28750, GSE9692, GSE13904, and GSE54514 datasets from the Gene Expression Omnibus (GEO) database for analysis; (2) analyzed the GSE57065, GSE28750, and GSE9692 datasets to detect the differentially expressed genes (DEGs) in the sepsis and control groups; (3) used Venn diagrams to obtain the intersection of DEGs and inflammation-related genes (IRGs); (4) mapped the protein-protein interaction (PPI) network using the Search Tool for Retrieval of Interacting Genes (STRING) database; (5) detected the hub genes using Cytoscape and cytoHubba; (6) performed an enrichment analysis of hub IRGs using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG); (7) validated the expression of hub IRGs in sepsis using the GSE13904 dataset; and (8) performed a survival analysis in sepsis using the GSE54514 dataset to explore the prognostic value of the hub IRGs.
RESULTS
The research team: (1) identified 104 upregulated DEGs and 4 downregulated DEGs; (2) after defining the intersection of DEGs and IRGs, detected nine differentially expressed IRGs (DEIRGs); and (3) identified five IRGs- haptoglobin (HP), high affinity immunoglobulin gamma Fc receptor I (FCGR1A), cluster of differentiation 163 (CD163), complement C3a receptor 1 human (C3AR1), C-type lectin domain containing 5A (CLEC5A)-that overlapped DEIRGs. The GO and KEGG pathway analyses showed that the hub IRGs became enriched during acute-phase response, acute inflammatory response, specific granule, specific granule membrane, endocytic vesicle membrane, tertiary granule, immunoglobulin G (IgG) binding, complement receptor activity, Ig binding, scavenger receptor activity, and scaffold protein binding. The DEGs also played a significant role in Staphylococcus aureus (S. aureus) infection. The ROC curves showed that HP (AUC: 0.956, 95% CI: 0.924-0.988); FCGR1A (AUC: 0.895,95% CI: 0.827-0.963); CD163 (AUC: 0.838, 95% CI: 0.774-0.901); C3AR1 (AUC: 0.953, 95% CI: 0.913-0.993); and CLEC5A (AUC: 0.951, 95% CI: 0 920-0 981) had meaningful diagnostic value for sepsis. Survival analysis showed that the sepsis and control groups had significant differences in HP (P = .043) and CLEC5A (P < .001).
CONCLUSIONS
HP, FCGR1A, CD163, C3AR1, and CLEC5A have value for clinical application. Clinicians can use them as diagnostic biomarkers, and they provide research direction for treatment targets for sepsis.
Topics: Humans; Gene Expression Profiling; Gene Regulatory Networks; Staphylococcus aureus; China; Biomarkers; Sepsis; Receptors, Cell Surface; Lectins, C-Type
PubMed: 37235492
DOI: No ID Found -
Cardiovascular Diabetology Jun 2023The occurrence and development of coronary heart disease (CHD) are closely linked to fluctuations in blood glucose levels. While the efficacy of intensified treatment... (Review)
Review
The occurrence and development of coronary heart disease (CHD) are closely linked to fluctuations in blood glucose levels. While the efficacy of intensified treatment guided by HbA1c levels remains uncertain for individuals with diabetes and CHD, this review summarizes the findings and conclusions regarding HbA1c in the context of CHD. Our review showed a curvilinear correlation between regulated level of HbA1c and therapeutic effectiveness of intensified glycemic control among patients with type 2 diabetes and coronary heart disease. It is necessary to optimize the dynamic monitoring indicators of HbA1c, combine genetic profiles, haptoglobin phenotypes for example and select more suitable hypoglycemic drugs to establish more appropriate glucose-controlling guideline for patients with CHD at different stage of diabetes.
Topics: Humans; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Blood Glucose; Glycemic Control; Hypoglycemic Agents; Coronary Disease
PubMed: 37349787
DOI: 10.1186/s12933-023-01875-8