Biomarkers Of Injury Research Articles

Traumatic Brain Injury as a Public Health Issue: Epidemiology, Prognostic Factors and Useful Data from Forensic Practice

Traumatic brain injury (TBI) represents a major public health problem, being a leading cause of disability and mortality among young people in developed countries. Head trauma occurs across all age groups, each experiencing consistently high rates of mortality and disability. This review aims to present an overview of TBI epidemiology and its socioeconomic impact, alongside data valuable for prevention, clinical management, and research efforts. Methods: A narrative review of TBI was performed with a particular focus on forensic pathology and public health. In fact, this review highlighted the economic and epidemiological aspects of TBI, as well as autopsy, histology, immunohistochemistry, and miRNA. Results: These data, together with immunohistochemical markers, are crucial for histopathological diagnosis and to determine the timing of injury onset, a fundamental aspect in forensic pathology practice. There is compelling evidence that brain injury biomarkers may enhance predictive models for clinical and prognostic outcomes. By clarifying the cause of death and providing details on survival time after trauma, forensic tools offer valuable information to improve the clinical management of TBI and guide preventive interventions. Conclusions: TBI is one of the most common causes of death today, with high costs for health care spending. Knowing the different mechanisms of TBI, reduces health care costs and helps improve prognosis.

Abstract 4143225: Carotid Artery Ultrasound Grayscale and Incident Dementia: The Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: Vascular contributions to cognitive impairment and dementia are potentially modifiable. Early detection of reversible arterial injury may improve dementia risk stratification and provide an opportunity for treatment monitoring. We hypothesized that carotid ultrasound grayscale-median (GSM), a novel imaging biomarker of early arterial injury, would predict incident all-cause dementia in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: The MESA enrolled adults aged 45-84 years old who were free of atherosclerotic cardiovascular disease at baseline. Common carotid artery GSM (grayscale units) was measured at baseline. Incident all-cause dementia events were identified by hospital and death records. Adjusted Cox proportional hazards models with natural cubic splines allowing for non-linear effects investigated the associations of baseline GSM and incident all-cause dementia. Results: The 1,788 participants were a mean (standard deviation) 63.1 (10.3) years old (53% female). Over a median of 13.7 years, 157 all-cause dementia events occurred. Lower (worse) carotid GSM independently predicted incident all-cause dementia (Hazard Ratio [HR] 1st to 3rd tertile, 1.39 [95% Confidence Intervals, 1.08-1.80], p =0.04). In models adjusting additionally for carotid IMT there was no attenuation of the association of GSM and incident all-cause dementia (HR 1.63 [95% CI 1.13-2.35], p=0.033) (Figure 1). Conclusions: Lower GSM predicts incident all-cause dementia independent of carotid intima-media thickness, suggesting it may serve as an early marker of dementia risk.

Asymptomatic Cerebrospinal Fluid HIV-1 Escape: Incidence and Consequences.

The incidence and clinical relevance of asymptomatic cerebrospinal fluid escape (CSF-E) during antiretroviral therapy (ART) is uncertain. We examined the impact and incidence of asymptomatic CSF-E in a Swedish HIV cohort. Neuroasymptomatic people living with HIV (PLWH) who have been on ART for at least six months with suppressed plasma viral load were followed longitudinally. CSF-E was defined as either increased CSF HIV-1 RNA with concurrent plasma suppression or as CSF HIV-1 RNA exceeding that in plasma when both were quantifiable. Paired CSF and plasma were analyzed for HIV-1 RNA, neopterin, neurofilament light protein (NfL), white blood cell (WBC) count, and albumin ratio. Asymptomatic CSF-E (cut-off 50 copies/mL) was found in 4/173 PLWH (2%) and 5/449 samples (1%). The corresponding proportions were 8% of PLWH and 4% for samples using a 20 copies/mL cut-off for CSF HIV-1 RNA. CSF-E samples (cut-off 20 copies/mL) had a 25% higher geometric mean of CSF neopterin (P = .01) and 8% higher albumin ratio (P = .04) compared to samples without CSF-E. No differences were observed in CSF NfL levels (P = .8). The odds ratio for increased CSF WBC (≥ 3 cells/μL) in samples with CSF-E was 3.9 (P = .004), compared to samples without elevated CSF viral load. Asymptomatic CSF-E was identified in only four (2%) PLWH, with no cases of continuous CSF-E observed. Increased CSF HIV-1 RNA was associated with biomarkers of CNS immune activation and blood-brain-barrier impairment, but not with biomarkers of neuronal injury.

Neutrophil-albumin ratio serves as a superior prognostic biomarker for traumatic brain injury.

Traumatic brain injury (TBI) represents a common and severe medical condition necessitating prompt risk stratification to enhance patient outcomes. Although substantial research has been conducted on the prognostic utility of various biomarkers for TBI, no single biomarker has been definitively recognized as the most precise predictor of disease outcomes. In comparison to other markers, the neutrophil-albumin ratio (NAR) has emerged as a cost-effective and reproducible inflammatory biomarker, demonstrating potential in evaluating the severity of inflammation and prognosticating outcomes in infections and cerebrovascular diseases. This study evaluated the prognostic significance of the NAR in comparison to two other readily accessible and cost-effective composite indices: the Neutrophil-Lymphocyte Ratio (NLR) and the Platelet-Lymphocyte Ratio (PLR) in individuals with TBI. We conducted a retrospective cohort analysis involving 297 hospitalized TBI patients, gathering comprehensive demographic, anthropometric, medical, clinical, laboratory, and imaging data to assess the expression changes of these biomarkers. Our findings suggest that both the NAR and the NLR possess predictive value regarding prognosis following TBI. However, receiver operating characteristic (ROC) curve analysis revealed that NAR outperformed NLR as a prognostic predictor. In conclusion, our examination of blood biochemistry composite indicators indicates that, while both NAR and NLR serve as significant prognostic markers, NAR is a more effective predictor of outcomes in patients with TBI.

Predictive value of systemic immune-inflammatory biomarkers for drug-induced liver injury in hepatitis B virus surface antigen positive tuberculosis patients: A retrospective observational study.

Drug-induced liver injury (DILI) is a major concern in tuberculosis (TB) treatment. For early detection of DILI, immune-inflammatory biomarkers are needed for better management. To explore the predictive effect of systemic immune-inflammation index (SII) combined with neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), eosinophil (EOS%), and CD4/CD8 on DILI occurrence in TB patients with HBsAg positive. This is a retrospective study enrolling patients who were treated with anti-tuberculosis drugs and infected with hepatitis B virus (HBV) in the Guangzhou Chest Hospital from 2018 to 2023. Population demographics and clinical data of 2643 patients were collected by reviewing electronic medical records. Using a propensity score matching model, the study ultimately included 516 patients (258 patients with DILI and 258 patients without DILI). Logistic regression analysis was conducted to investigate the predictive role of systemic immune-inflammatory biomarkers (SII, NLR, MLR, EOS%, and CD4/CD8) in DILI in hepatitis B virus surface antigen-positive TB patients (HBV-TB-DILI). As compared to patients without DILI, patients with DILI have elevated levels of systemic immune-inflammatory biomarkers (SII, NLR, MLR, EOS%, and CD4/CD8), (all P < .05). The SII, NLR, MLR, PLR, EOS%, and CD4/CD8 are risk factors of HBV-TB-DILI. The NLR, MLR, SII, and EOS% were positively correlated with liver function (P < .001). The combination of SII, NLR, MLR, EOS%, and CD4/CD8 demonstrated good predictive performance for DILI occurrence in HBV-TB patients. The combination of SII, NLR, MLR, EOS%, and CD4/CD8 demonstrated good predictive performance for DILI occurrence in HBV-TB patients.

Diagnostic value of TRIM22 in diabetic kidney disease and its mechanism.

Diabetic kidney disease (DKD) is the primary reason of chronic kidney disease. Our objective was to discover potential autophagy-related biomarkers of tubulointerstitial injury in DKD and assess their clinical value. We retrieved four datasets (GSE104954, GSE30122, GSE30529, and GSE99340) of renal tubule samples from Gene Expression Omnibus (GEO) and used two algorithms (LASSO and SVM-RFE) to screen for autophagy-related differentially expressed genes (ARDEGs) in DKD. Tripartite motif containing 22 (TRIM22) was identified for subsequent validation. Validation of TRIM22 and autophagic indicators expression in clinical samples and HK-2 cells stimulated by high glucose using immunohistochemistry, immunofluorescence, and western blot. We identified four ARDEGs (TRIM22, PLK2, HTR2B, and FAS) using a diagnostic gene model. ROC curves further confirmed that TRIM22 had the best diagnostic efficacy for DKD. Both clinical samples and HK-2 cells stimulated by high glucose showed high protein expression of TRIM22. The correlation analysis revealed that TRIM22 correlates with SQSTM1, NGAL, and some clinical and pathological indicators in patients with DKD. We identified TRIM22 as a potential diagnostic biomarker for DKD, revealing its high diagnostic value in patients with DKD with moderate-to-severe interstitial fibrosis and tubular atrophy (IFTA). TRIM22 is involved in tubulointerstitial injury and autophagy dysregulation in DKD.

Serum Glutamate dehydrogenase activity enables sensitive and specific diagnosis of hepatocellular injury in humans.

Serum activities of alanine- and aspartate- aminotransferases (ALT and AST) are considered the "gold standard" biomarkers of hepatocyte injury in clinical practice and drug development. However, due to expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced muscle injury, is severely limited. Thus, we proposed glutamate dehydrogenase (GLDH) as a liver-specific alternative to serum ALT and AST. In fact, our exploratory studies showed that GLDH has comparable performance to ALT for detecting hepatocyte injury without interference from concomitant muscle injury. Here, we report the results of studies confirming the reference intervals in a healthy human population and sensitivity and specificity of GLDH for detection of hepatocyte injury in human subjects. In human subjects, we could not perform liver biopsies due to ethical reasons, we also confirmed the relationship of GLDH and histopathologic lesions using 32 model toxicants in rats. Furthermore, we have shown that injury to tissues that are known to express appreciable levels of GLDH does not affect serum GLDH measurements, indicating excellent liver specificity of serum GLDH. Finally, we observed faster elimination of GLDH than ALT in humans, indicating that decreasing GLDH values could be considered an early sign of recovery. This study provides comprehensive evidence of excellent sensitivity and liver specificity of GLDH for diagnosis of hepatocellular injury, including evaluation of reference intervals that is essential for interpretation of serum GLDH in human subjects.

Cerebrospinal fluid neurofilament light chain levels in children with acquired demyelinating syndrome

ObjectiveTo study the cerebrospinal fluid (CSF) neurofilament light chain (NfL) in pediatric acquired demyelinating syndrome (ADS) and its association with factors of laboratory and imaging results.MethodsWe analyzed clinical data from children with ADS collected from May 2020 to January 2021 at the Department of Neurology of Guangzhou Women and Children's Medical Center. Enzyme-linked immunosorbent assays were used to detect the CSF NfL of patients.ResultsThirty pediatric ADS patients (17 male, 13 female) were included in the study. The most frequent diagnosis was uncategorized ADS (36.7%, 11/30), followed by acute disseminating encephalomyelitis (ADEM) (23.3%, 7/30), myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) (20.0%, 6/30), NMO (6.7%, 2/30), multiple sclerosis (MS) (6.7%, 2/30), and neuromyelitis optic spectrum disorders (NMOSD) (6.7%, 2/30). The median CSF NfL for the first time was 7,425.28 pg/ml (interquartile range, 1,273.51, &amp;gt;10,000 pg/ml). CSF NfL increase over normal value (&amp;lt;290.00 pg/ml for people younger than 30 years old) was seen in 98.7% of patients. Patients were divided into uncategorized ADS, ADEM, MOGAD, and MS/NMO/NMOSD groups, with no significant difference in CSF NfL between each group. The CSF NfL positively correlated with the immunoglobulin (Ig) G (ρ = 0.473) and IgE (ρ = 0.366). However, the CSF NfL did not correlate with CSF white blood count and CSF protein. Furthermore, there was no significant difference between patients with oligoclonal bands positive and without. The CSF NfL negatively correlated with interferon γ (ρ = −0.501), CD45 + CD3+ T (ρ = −0.466), CD45 + CD3 + CD4+ T (ρ = −0.466), and CD45 + CD3 + CD8+ T cells (ρ = −0.521). However, it did not correlate with CD45 + CD19+ B cells. CSF NfL in patients with cerebral white matter lesions in MRI was higher than in patients without. Moreover, the CSF NfL positively correlated with the number of brain MRI locations (ρ = 0.362). Nine patients underwent multiple detections of CSF NfL, and their CSF NfL for the last detection was not significantly different from the first.ConclusionsThe CSF NfL increases significantly in pediatric ADS, and it can be a biomarker of neuro-axonal injury and a good indication of the extent of lesions.

Discovery of biophysical rate laws from the electronic health record enables real-time liver injury estimation from transaminase dynamics.

Alanine (ALT) and aspartate (AST) aminotransferases are standard-of-care biomarkers for liver injury though their temporal dynamics during injury and resolution remain incompletely characterized. Here, we analyze aminotransferase kinetics to determine whether rate laws can be ascertained during acute liver injury agnostic to etiology. From 6.5 million AST and ALT measurements in 91,086 patients, we identify a single rate-limiting step in transaminase decline enabling the discovery of plasma clearance rates of AST (1.13days-1) and ALT (0.47days-1). These rates highlight that transaminases lag real-time liver injury on timescales relevant to clinical decision-making. To resolve this delay, we introduce a correction for AST and ALT, the hepatocyte injury index (HIX, hix.massgeneral.org), which yields a real-time estimate of liver injury. For both liver biopsies and choledocholithiasis, the HIX better distinguishes persistent versus resolved liver injury than transaminase values alone. The HIX can enable more timely clinical decisions for patients with acute liver injury.

Association of gut microbiota with allograft injury in kidney transplant recipients: a comparative profiling through 16S metagenomics and quantitative PCR.

Introduction. The existence of a mutual relationship between gut microbiota and immune homeostasis highlights its importance in the context of kidney transplantation.Gap statement. The translational utility of gut microbiota as a biomarker for allograft injury has not been assessed before.Aim. In this study, we aimed to characterize the gut microbial diversity in kidney transplant recipients and investigate the alterations in the gut microbial composition in association with allograft injury such as histopathological graft rejection and calcineurin inhibitor toxicity. In addition, we compared the gut microbial quantitation using 16S metagenomics and quantitative PCR (qPCR) to assess its translational utility.Methodology. In this prospective longitudinal cohort study, we enrolled 38 kidney transplant recipients and collected serial faecal specimens (n=114), once before the induction therapy, and twice after transplant, during the first and third month. We characterized the gut microbial composition through 16S rRNA sequencing and qPCR from the DNA isolates of the samples. The recipients were clinically followed up for a median of 600 days post-transplant. Histopathological evidence of allograft rejection and calcineurin inhibitor toxicity were used for the correlational analysis with gut microbial diversity.Results. Significant differences in the gut microbial diversity were observed between the pre- and post-transplant samples. Pre-transplant gut microbiota revealed a higher relative abundance of phylum Bacteroidetes in the allograft rejection group, and a higher relative abundance of phylum Firmicutes was observed in the histopathological features of calcineurin inhibitor toxicity (hCNI toxicity) group. We found a high concordance between 16S metagenomics and qPCR outputs for assessing the gut microbial diversity. Furthermore, the receiver operating characteristic curve analysis has also proven that the pre-transplant levels of gut microbial dysbiosis, as a potential predictive biomarker for allograft injury.Conclusion. Our pilot study found a strong statistical association of gut microbial dysbiosis with kidney allograft injury, highlighting the potential of gut microbiota as a predictive biomarker and that qPCR serves as a more reliable and economic tool for assessing dysbiosis paving the way for its translational utility.

Cumulative Socioeconomic Status Risk is Associated with Greater Increase in Serum Neurofilament Light Chain Levels Among Middle-Aged Black Adults.

This study examined the longitudinal relationship between cumulative socioeconomic status (SES) risk and serum neurofilament light chain (NfL) levels to better understand the association between social factors and a biomarker of neurodegeneration. We used data from the Family and Community Health Study (FACHS), collecting psychosocial and blood data at two waves (2008) and (2019) from 254 Black Americans (43 males and 211 females). Blood samples were analyzed at each wave for serum NfL concentrations. Regression analysis and mixed-effect modeling examined relationships between cumulative SES risk and serum NfL, controlling for covariates and assessing time effects. Utilizing 11-year longitudinal data, serum NfL levels increased with age. Higher cumulative SES risk at baseline correlated with elevated serum NfL at the 11-year follow-up and predicted a greater increase in NfL levels. Clinically, NfL is a sensitive biomarker for axonal injury and neurodegeneration, commonly used to detect early and preclinical stages of conditions such as Alzheimer's disease (AD), multiple sclerosis, and other neurodegenerative disorders. Our results suggest that exposure to cumulative SES risk among Black adults may contribute to elevated levels of NfL, indicating potential early neurodegeneration. Given the established role of NfL in detecting neurodegenerative processes, these findings underscore the importance of interventions that bolster social safety nets and social connectedness to enhance brain health and mitigate neurodegenerative risks.

Serum neurofilament light chain: a novel biomarker for cardiovascular diseases in individuals without hypertension

Serum neurofilament light chain (sNFL) is a biomarker for axonal injury. Previous studies have linked sNFL levels to cardiovascular risk factors such as diabetes and hypertension, but its association with cardiovascular diseases (CVD) remains unclear. This study aims to explore the association between sNFL and CVD and evaluates its predictive value. Utilizing NHANES 2013–2014 data, this study included 2,035 participants aged ≥ 20 years with measured sNFL quantified using a Siemens immunoassay. CVD was self-reported and included myocardial infarction, stroke, heart failure, coronary heart disease, or angina. Logistic regression models assessed the association between sNFL levels and CVD. The predictive value of sNFL for CVD was evaluated using area under the curve (AUC) and DeLong test. Participants with higher sNFL levels were typically older, male, non-Hispanic white, smokers, and had lower socioeconomic status, higher CVD, hypertension, and diabetes prevalence. Higher sNFL levels were significantly associated with increased odds of CVD (adjusted OR = 1.41, 95% CI: 1.05–1.88). The association was significant in non-hypertensive individuals (OR = 2.72, 95% CI: 1.61–4.62) but not in hypertensive individuals (OR = 1.13, 95% CI: 0.81–1.56). sNFL addition to traditional risk models improved predictive accuracy, especially in non-hypertensive individuals (AUC from 0.827 to 0.856). sNFL levels are significantly associated with CVD in the general population, with a strong predictive value in non-hypertensive individuals. Future longitudinal studies should validate sNFL’s efficacy in various populations and explore the underlying mechanisms of its relationship with hypertension and CVD.

Prognostic value of alveolar surfactant type-B in acute heart failure: a long-term comparative analysis vs NT-proBNP

Abstract Background In heart failure (HF) biomarkers are an integral component of prognostic assessment. Natriuretic peptides are the gold standard, but they do not directly reflect lung vascular injury. Surfactant type B (Surf-B) is released by type 2 alveolar cells under pressure induced trauma, with few reports just addressing its plasmatic levels in stable chronic HF (CHF). Information on acute HF (AHF) is lacking. Purpose To clarify the prognostic value of Surf-B changes vs NT-proBNP levels after decongestion therapy and to compare their prognostic ability at 1-year follow-up. Methods Patients with acute pulmonary edema (APE) underwent a combined evaluation of Surf-B and NT-proBNP serum levels with quantification of B-lines at hospital admission (time 0), discharge (time 1) and at 1 year (time 2). Results 54 patients (mean age 72.1 ± 11 years; mean LVEF 36% ± 13%; 65% men) were enrolled. At time 1, the average Surf-B, NT-proBNP and B-lines were significantly reduced compared to time 0 (p&amp;lt;0.0001). No correlation between Surf-B and NT-proBNP was observed either at time 0 (r=-0.21; p=0.12) or at time 1 (r=0.05; p=0.71). Despite the significant decrease in Surf-B levels from time 0 to time 1, 18.5% of patients behaved as non-responders exhibiting no changes in Surf-B; conversely, only 5.5% did not show significant reduction in NT-proBNP, despite significant decongestion. 38 patients were followed up to time 2: of these, 13 (34%) reached the composite endpoint of death or hospitalization for HF. Surf-B measured at time 1 was a strong predictor of adverse outcome. Patients with Surf-B above median at discharge displayed a worse survival-free from HF hospitalization compared to the remainders (Log rank p=0.012) (Figure). Also, patients with Surf-B above median at discharge had a more than 4-fold increased risk of the composite endpoint (HR 4.5, 95%CI 1.4-20.2, p=0.023). Conversely, NT-proBNP at discharge was not significantly associated with HF-free survival (Log rank p=0.26) (Figure) and was not a significant predictor of the composite outcome (HR 1.9, 95%CI 0.6-9.3, p=0.25). At ROC analysis, discharge Surf-B levels showed a higher area under the curve (AUC=0.763, p=0.011) than NT-proBNP values (AUC=0.69, p=0.063). Conclusions These data suggest that Surf-B, an organ specific biomarker of lung injury, is highly sensitive to the effectiveness of decongestion therapy, outperforming NT-proBNP. Given the high rate of patients who do not improve their Surf-B levels over time, the reparative processes of alveolar break damage may dissociate from mere decongestion and cardiac healing in AHF.Figure:1yr Kaplan-Meier survival curves

Residual post-infarct myocardial inflammation detected by 68Ga-DOTATATE PET/MRI predicts long-term adverse cardiac remodelling

Abstract Background Maladaptive inflammatory responses are associated with adverse cardiac remodelling after myocardial infarction (MI), but clinical methods for detecting residual myocardial inflammation post-MI are lacking. Purpose To investigate somatostatin receptor subtype 2 (SST2) positron emission tomography (PET)/magnetic resonance imaging (MRI) using 68Ga-DOTATATE after MI. Methods In a prospective observational cohort study, infarct-related myocardial inflammation detected by 68Ga-DOTATATE PET at 2wk and 3mo post-MI was compared with MRI characteristics including left ventricular (LV) volumetric changes at 1yr, as well circulating immune cell phenotyping and serum proteomic markers. Patients with a prior history of MI or heart failure were excluded. Histological SST2 expression was assessed in myocardial biopsies. Results 38 participants (mean age 60 [SD 9] years; 84% male) with recent MI were enrolled, of whom 58% had an ST-segment elevation MI. Mean peak Troponin I was 16,665 (range 408 to &amp;gt;25,000) ng/L and mean post-infarct LV ejection fraction was 51 (SD 9) %. 68Ga-DOTATATE maximum standardized uptake values (SUVmax) at 10 (SD 4) days accurately localised infarcted myocardial segments defined by late-gadolinium enhancement MRI (LGE; Fig. 1); were 14.2% higher in akinetic/hypokinetic vs. normo-kinetic segments (p&amp;lt;0.0001); and were correlated both with peak segmental strain (r=0.47, p=0.003) and segmental T1 values (r=0.51, p=0.02). Mean infarct SUVmax was 19.7% lower on repeat PET/MRI after a mean 102 (SD 22) days (p&amp;lt;0.0001), and this change was in keeping with parallel reductions in T2-weighted oedema signal on MRI and serum biomarkers of cardiac injury and systemic inflammation. Residual inflammation assessed by mean infarct SUVmax at 3mo was correlated with ΔLV indexed end-diastolic volume at 369 (SD 14) days, after adjustment for baseline infarct size and other clinical variables (p=0.038). The 3mo:2wk ratio of mean infarct SUVmax was an even stronger predictor of adverse myocardial remodelling (p=0.0025). Circulating SST2+ classical monocytes were correlated with infarct 68Ga-DOTATATE signal (r=0.47, p=0.02), and SST2 was co-expressed with CD68+ macrophages in inflamed myocardial specimens of patients with recent MI and ischaemic heart failure. After statistical feature selection and multiple comparisons adjustments, among the blood markers associated with 3mo:2wk infarct SUVmax was CCL25, a chemokine involved in macrophage recruitment which has been implicated in adverse cardiac remodelling. Conclusions Here, in the first prospective clinical study of serial SST2 PET/MRI after MI, we show that 68Ga-DOTATATE can identify and track resolving infarct-related myocardial inflammation. Moreover, residual inflammation detected by 68Ga-DOTATATE is associated with long-term adverse myocardial remodelling and could provide a potential future imaging biomarker to help stratify high-risk patients for emerging immunomodulatory therapies.Figure 1.68Ga-DOTATATE PET-MRI after MI

Cardiac myosin-binding protein-C: assessing fragmentation patterns to differentiate between forms of myocardial injury

Abstract Background Cardiac myosin-binding protein-C (cMyC) is a novel biomarker of myocardial injury. We hypothesize that fragmentation of cMyC differs according to aetiology of myocardial injury. Assessing the fragmentation pattern of the protein may aid diagnosis of these conditions. Purpose This work represents an examination of cMyC fragmentation in human serum, and studies its utility in differentiating between forms of myocardial injury. Methods Patients who were admitted to a hospital during October-November 2023 with acute myocardial injury were recruited. Acute myocardial injury was defined as a dynamic troponin rise above the 99th centile (Abbott Alinity: cTnI&amp;gt;34ng/L male, cTnI &amp;gt;16ng/L female). Following collection, samples were left at room temperature for 30 minutes and then centrifuged. Serum was separated for cMyC measurement, frozen in liquid nitrogen and stored at -80 °C. Recruited patients were followed up during their inpatient journey. Their final diagnosis was defined using the 4th universal definition of MI by two cardiologists, with a third cardiologist acting as adjudicator, if required. The serum samples were analysed using two separate electrochemiluminescence sandwich ELISA assays detecting different portions of cMyC. One assay formulated for total concentration of cMyC using high affinity mouse N-terminal monoclonal antibodies (mAb) targeting epitopes in close proximity (Limit of Detection (LoD) = 9.0ng/L). The other assay uses a N-terminal and a C-terminal mouse mAb which straddle the major proteolytic cleavage site of cMyC. This assay detects the intact (fuller-length) cMyC (LoD= 14.2ng/L). Both assays perform with good sensitivity, low variability and are capable of detecting cMyC at concentrations well below the 99th centile. Results 11 patient samples were collected with final diagnoses of; type 1 MI (STEMI n=3, NSTEMI n=4), type 4 MI (alcohol septal ablation n=1), acute myocardial injury (myocarditis n=2) and type 2 MI (chest sepsis with known coronary disease n=2). Figure one details the percentage of intact cMyC relative to total cMyC measured in serum for each patient, and is split into their adjudicated diagnosis. The bars display the median and interquartile range (IQR). Our findings suggest that the fragmentation pattern of cMyC could help differentiate between forms of myocardial injury. The ratio of intact: total cMyC was higher in the type 2 MI than any other condition. The results did not reach statistical significance (p = 0.06) due to the small sample size. Conclusions The fragmentation pattern of cMyC is dependent on the type of myocardial injury and could aid in the differentiation between type 2 MI and other forms of myocardial injury.Figure One

Myocardial injury and heart failure biomarkers in acute intermittent porphyria

Abstract Background Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by the defect in the hydroxymethylbilane synthase gene, encoding the third enzyme in heme biosynthesis pathway. The main symptoms include abdominal pain, vomiting, paralysis, confusion. Exacerbation of AIP may manifest with elevation of blood pressure and tachycardia due to hyperactivity of sympathetic nervous system. Data regarding cardiac function in AIP are scarce. Purpose The aim of this study was to assess the myocardial injury and heart failure biomarkers during AIP exacerbations and remission. Methods This cohort prospective study encompassed patients at the age 18-65 years who had at least one exacerbation of AIP in their lifetime. Patients examined during the AIP exacerbations were reassessed in the remission phase. The concentrations of sodium, troponin T, CK-MB mass, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and metoxycatecholamines in blood were assessed. Blood pressure was measured with 24-hour ABPM. Echocardiography was performed according to the current recommendations. Results The total number of 70 patients with AIP were enrolled to the study (April 2019 - March 2023). We assessed 36 patients in both phases of disease, mean age 37 years (21-63), 75% females. The median of prior AIP exacerbations was 8. During the exacerbations a significant increase in the concentrations of NT-proBNP (250 [97 ; 501] vs. 89 [48 ; 140] pg/mL, p&amp;lt;0.001), metanephrine (49.0 [37.8 ; 61.2] vs. 41.4 [36.8 ; 53.3] pg/mL, p=0.009) and normetanephrine (169.8 [118.2 ; 327.2] vs. 93.2 [78.1 ; 120.9] pg/mL, p&amp;lt;0.001) was observed. Conversely, sodium concentrations decreased (136 [133 ; 140] vs. 140 [139 ; 142] mmol/L, p&amp;lt;0.001). There were no significant differences in the values of troponin (5.4 [4.0 ; 11.3] vs. 5.6 [3.7 ; 9.5] ng/L, p=0.445), CK-MB mass (1.88 [0.84 ; 2.64] vs. 1.21 [0.83 ; 2.80] ng/mL, p=0.80). In the acute phases of AIP the levels of NT-proBNP were correlated negatively with the values of sodium concentrations (r=-0.36, p=0.032) and positively with average systolic blood pressure (r=0.32, p=0.06). Echocardiography showed an increase in left ventricular (LV) mass indices in some patients hospitalized due to AIP symptoms. Sodium concentrations correlated negatively with these changes (r=-0.36, p=0.032). LV ejection fraction was slightly higher during AIP exacerbations. There were no significant differences in other parameters of LV systolic and diastolic function. Conclusions During acute intermittent porphyria (AIP) exacerbations there is an increase in the concentrations of NT-proBNP and catecholamines in blood. In most patients the levels of markers of myocardial injury, such as troponin and CK-MB mass, do not differ significantly between phases of disease. During AIP exacerbations some patients experience an increase in LV mass which may be associated with hyponatremia. In most cases cardiac function do not change significantly.Frequency of abnormal laboratory resultsResults of echocardiography

Impact of chronic kidney disease on patients with Myocardial Infarction with Non Obstructive Coronary Arteries (MINOCA)

Abstract Background Chronic kidney disease (CKD) in patients with myocardial infarction (MI) is associated with more advanced disease, a higher risk of complications and poorer prognosis, as well as increased mortality. The aim of this study is to assess the impact of CKD in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) and its influence on the prognosis of these patients. Methods it was an observational, prospective and analytic study. We analyzed all consecutive patients with MI who underwent coronary angiography admitted to our Hospital between 2016 and 2023; MINOCA patients were classified following the 2023 ESC Guidelines definition. The patients were divided into two groups depending on whether they had CKD or not. Median follow-up was 43 months [20-71]. Results we included 136 patients with MINOCA, of whom 11 (8.1%) had CKD. Patients with impaired kidney function were older and mostly male. They also exhibited a higher prevalence of classic cardiovascular risk factors such as hypertension, diabetes, or dyslipidemia. However, there were fewer smokers in this group. We did not find significant differences in coronary artery anatomy (smooth or small plaques) between both groups. Additionally, the majority of patients in both groups had preserved left ventricular function. Despite that, patients with CKD typically had ST segment elevation in the ECG and higher myocardial injury biomarkers’ levels as well as NT-proBNP. During hospitalization, patients without renal dysfunction had more complications (11.2% vs 0%, p=0.062) such as inotropic requirements, stroke or cardiogenic shock, but overall there were very few. In terms of treatment, it was fairly similar in both groups, although patients with kidney disease received diuretics significantly more often. Throughout the follow up, there were no significant differences in MACE (major adverse cardiovascular events) between death (27.3% vs 7.4%, p=0.06), readmission (10% vs 10.8%, p=1) or MI (0% vs 3.4%, p=1), but patients with CKD suffered more frequently from stroke (40% vs 4.2%, p&amp;lt;0.01). Conclusions 1) Patients with MINOCA and CKD are typically older and predominantly male with a high prevalence of cardiovascular comorbidities (hypertension, diabetes, dyslipidaemia). 2) The severity of MI appears to be slightly higher in this group, as evidenced by more ST-segment elevation upon admission and higher hs Troponine T levels. However, they experience fewer cardiovascular complications and maintain normal left ventricular function. 3) Although we found no significant differences in major adverse cardiovascular events (MACE), patients with CKD were more likely to suffer from stroke.Table 1Table 1

Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1)phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

Comparative analysis of compartment-specific immunothrombotic biomarker profiles in bronchoalveolar lavage fluid and serum of patients with pneumonia-related acute respiratory distress syndrome: A preliminary cross-sectional study.

Immunothrombosis has emerged as a potential mechanistic link underlying the development and progression of acute respiratory distress syndrome (ARDS), but understanding its specific profile in patients, both locally and systemically, is limited. The objective of this study was to characterize and compare the immunothrombotic signatures in patients diagnosed with pneumonia-related ARDS (p-ARDS) at both the pulmonary and systemic levels and to evaluate their clinical relevance. The study included 23 consecutive patients diagnosed with p-ARDS admitted to the intensive care unit at a tertiary university hospital from July 2022 to May 2023, alongside 40 concurrently hospitalized patients with common pneumonia as controls. Paired bronchoalveolar lavage fluid (BALF) and serum samples were collected from the participants for the analysis of 15 biomarkers to assess and quantify the pulmonary and systemic immunothrombotic signatures. The study results revealed significant pulmonary inflammation and systemic endothelial injury in p-ARDS patients compared to pneumonia controls. These observations were maintained after adjustment for severity of illness (Acute Physiology and Chronic Health Evaluation II scores). In terms of clinical relevance, inflammatory biomarkers (interleukin [IL]-6, IL-8) in BALF were found to correlate with PaO2/FiO2 ratio, while serum levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS-13) and thrombomodulin showed associations with Sequential Organ Failure Assessment and Disseminated Intravascular Coagulation scores. In conclusion, this preliminary investigation identified compartment-specific variations in the immunothrombotic signature between patients with p-ARDS and those with pneumonia alone, with inflammatory responses predominantly localized in the alveolar compartments and coagulation/endothelial injury biomarkers more pronounced in peripheral blood.

ASSOCIATION OF SERUM ADENOSINE DEAMINASE LEVELS WITH ACUTE KIDNEY INJURY IN DIABETIC PATIENTS

Diabetes mellitus is a significant global health issue, and complications such as acute kidney injury (AKI) are prevalent in patients with type 2 diabetes. Serum adenosine deaminase (ADA) has been suggested as a potential biomarker for various metabolic conditions, including inflammation and kidney injury, but its association with diabetic kidney health remains understudied. Objective: To assess the association of serum adenosine deaminase (ADA) levels with acute kidney injury (AKI) in patients with type 2 diabetes. Methods: This observational comparative study was conducted at DHQ Teaching Hospital KDA, Kohat, from February 7, 2023, to August 7, 2023, following ethical approval. A total of 120 participants were enrolled, including 60 patients with type 2 diabetes and 60 non-diabetic controls. Laboratory investigations for both groups included serum ADA (U/L), HbA1c (%), and estimated glomerular filtration rate (eGFR) (mL/min/1.73 m²). Statistical comparisons between groups were made using appropriate tests, and correlations between serum ADA and other parameters were assessed. Results: The mean age of diabetic patients was 55.40 ± 8.29 years, and that of controls was 54.58 ± 21.64 years. The mean serum ADA level in diabetic patients was significantly higher at 43 ± 4.29 U/L compared to 16.32 ± 1.20 U/L in controls (p = 0.0001). Diabetic patients had a mean HbA1c of 8.30 ± 0.59%, significantly higher than that of controls (5.28 ± 0.59%) (p = 0.0001). The mean eGFR in diabetic patients was 82.61 ± 17.22 mL/min/1.73 m², lower than in controls (105.97 ± 12.07 mL/min/1.73 m²) (p = 0.0001). In diabetic patients, serum ADA levels were positively correlated with HbA1c (indicating poorer glycemic control) and negatively correlated with eGFR (suggesting declining kidney function). Conclusion: Elevated serum adenosine deaminase levels in type 2 diabetic patients are significantly associated with poor glycemic control and decreased kidney function. These findings indicate that serum ADA could serve as a potential biomarker for monitoring glycemic status and kidney health in diabetic patients at risk for acute kidney injury.