Low HDL-C and the Risk of Hospitalisation in Children with COVID-19.

OBJECTIVE: To investigate high-density lipoprotein cholesterol (HDL-C) levels in children with COVID-19. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Goztepe Professor Suleyman Yalcin City Hospital, Istanbul, Turkiye, between 2020 and 2022. METHODOLOGY: The hospital data were examined to find children (<18 years) who presented with COVID-19. The associations between HDL-C, inflammatory biomarkers, hospital admission requirements, and prolonged hospital stays in children with COVID-19 were analysed. RESULTS: During the study period, 1,056 children were diagnosed with COVID-19. Lipid levels were measured in 193 patients during outpatient clinic visits from the same hospital records. One hundred and twenty-seven (65.5%) patients displayed low HDL-C levels. One hundred and nine (86.5%) of the patients with low HDL-C and 33 (50.0%) of the patients with normal HDL-C were hospitalised (p=0.012). Patients with lower HDL-C exhibited higher triglyceride (median 124 vs. 81 mg/dl, p<0.001), glucose (median 116 vs. 101 mg/dl, p=0.001), lactate dehydrogenase (LDH) (median 343 vs. 251 mg/dl, p<0.001), C-reactive protein (CRP) (median 0.6 vs. 0.5 mg/L, p=0.009), D-dimer (median 1.3 vs. 0.3 mcg/mL, p<0.001), ferritin (median 127 vs. 40 µg/L, p<0.001), and uric acid (median 5.5 vs. 4.5 mg/dL, p=0.002) levels compared to children with normal HDL-C. Logistic regression (LR) analysis showed that age (OR = 0.87, CI for OR 0.80-0.94, p < 0.001), ferritin (OR = 1.004, CI for OR 1.001-1.006, p = 0.003), and D-dimer (OR = 2.171, CI for OR 1.183-3.984, p = 0.012) were associated with lower HDL-C level in children with COVID-19. CONCLUSION: Low HDL-C levels were common in children with COVID-19. Children with COVID-19 and low HDL-C were more frequently hospitalised and had higher inflammatory biomarkers of COVID-19 than children with COVID-19 and normal HDL-C levels. KEY WORDS: HDL-C, HDL-C levels in children, COVID-19, Children with COVID-19.

A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.

An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized, double-blind, placebo-controlled trial was conducted in Japanese COVID-19 patients with mild to moderate pneumonia. The number of study participants was set to be 50 in each arm. Even after extension of the enrollment period, the number of study participants did not reach the initially intended sample size, and 75 patients were enrolled in the study. The total oxygenation scale from Day 1 to Day 14 as the primary endpoint was 1.5 in the TM5614 group vs 4.0 in the placebo group (p = 0.22), and the number of days of oxygen administration required as the secondary endpoint was 2.0 days in the TM5614 group vs 3.5 days in the placebo group (p = 0.34). Further studies will be necessary to verify the efficacy of PAI-1 inhibition for the treatment of COVID-19 pneumonia.Clinical trial registration: Two studies were conducted: a prospective, multicenter, open-label phase II study at https://jrct.niph.go.jp (jRCT2021200018) (First registration date 18/08/2020) and a prospective, multicenter, randomized, double-blind, placebo-controlled, phase II study at https://jrct.niph.go.jp (jRCT2021210006) (First registration date 28/05/2021).

Association of Low Levels of Soluble Low-Density Lipoprotein Receptor-Related Protein-1 and COVID-19 Outcomes During the First Wave of Pandemic.

Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytosis receptor that clears inflammatory proteins from circulation. LRP1 has anti-inflammatory effects that bind pro-inflammatory cytokines or ligands. LRP1 has a soluble form (sLRP1) which can be measured in serum. We report sLRP1 levels in hospitalized patients with COVID-19. The first objective of this study is to compare the sLRP1 levels between COVID-19 patients and healthy controls. The second objective is to examine the association between sLRP1 and the clinical outcome of COVID-19. All patients (20-80 years of age) were evaluated in a hospital using a positive PCR test for SARS­CoV­2 between April 1, 2020, and June 1, 2020. Controls (n=59) were selected from healthy subjects. sLRP1 levels were measured in patients from the emergency department (ED), inpatient service (IS), and the intensive care unit (ICU). The study included 180 cases. COVID-19 patients showed significantly lower sLRP1 levels compared to controls (1.43 (1.86) versus 2.27 (1.68) µg/mL, respectively, p<0.001). sLRP1 levels were 1.26 (1.81), 1.37 (1.65), and 1.74 (1.98) µg/mL in patients from ED, IS, and ICU, respectively (p=0.022). Patients who were admitted from ED displayed lower sLRP1 levels compared to those who were discharged (median sLRP1 levels were 0.86 versus 1.7 µg/mL, p=0.045). COVID-19 patients display significantly lower sLRP1 levels compared to the healthy controls. sLRP1 levels do not show any association with the clinical outcome of COVID-19. This study demonstrates that LRP1 displays a bidirectional course in COVID-19. A low sLRP1 level is a potential risk factor for susceptibility and hospital admission due to COVID-19. Further studies with larger sample sizes and longer follow-ups are needed to understand the long-term effects of novel biomarkers such as sLRP1 on the outcome of COVID-19.

Predictors of Long-Term Mortality in Patients with Stable Angina Pectoris and Coronary Slow Flow.

Background and Objectives: Coronary slow flow (CSF) is an angiographic phenomenon characterized by the slow progression of an injected contrast agent during diagnostic coronary angiography in the absence of significant stenosis. Although CSF is a common angiographic finding, the long-term outcomes and mortality rates are still unknown. This study aimed to investigate the underlying causes of mortality over a 10-year period in patients diagnosed with stable angina pectoris (SAP) and CSF. Materials and Methods: This study included patients with SAP who underwent coronary angiography from 1 January 2012 to 31 December 2012. All patients displayed CSF despite having angiographically normal coronary arteries. Hypertension (HT), diabetes mellitus (DM), hyperlipidaemia, medication compliance, comorbidities, and laboratory data were recorded at the time of angiography. Thrombolysis in myocardial infarction (TIMI) frame count (TFC) was calculated for each patient. The cardiovascular (CV) and non-CV causes of long-term mortality were assessed. Results: A total of 137 patients with CSF (93 males; mean age: 52.2 ± 9.36 years) were included in this study. Twenty-one patients (15.3%) died within 10 years of follow-up. Nine (7.2%) and 12 (9.4%) patients died of non-CV and CV causes, respectively. Total mortality in patients with CSF was associated with age, HT, discontinuation of medications, and high-density lipoprotein cholesterol (HDL-C) levels. The mean TFC was associated with CV mortality. Conclusion: Patients with CSF exhibited a notable increase in cardiovascular-related and overall mortality rates after 10 years of follow-up. HT, discontinuation of medications, HDL-C levels, and mean TFC were associated with mortality in patients with CSF.

Soluble LRP-1 in Parkinson's disease: clues for paradoxical effects.

Background: Low density lipoprotein receptor-related protein-1 (LRP-1) is highly expressed in the central nervous system and plays a role in neurodegenerative disorders. The available data on this subject-matter seem to support the presence of a correlation between LRP-1 levels and abnormal aggregation of a plurality of proteins, including tau, amyloid, and α­synuclein. Understanding the molecular mechanisms underlying Parkinson's disease (PD) is critical for development of new therapies.Aim: To investigate serum soluble LRP-1 (sLRP-1) concentrations in patients with PD and explored their potential role as a biomarker in diagnosis and prognosis of disease.Methods: Based on well-defined inclusion and exclusion criteria, we have included 133 PD patients and 45 healthy controls. The clinical severity was assessed using Hoehn Yahr and Unified PD Rating Scale (UPDRS). Following a fasting period, venous blood samples were taken, and centrifuged. Serum samples were stored until analysis. sLRP-1 was measured by ELISA assay.Results: The median of serum sLRP-1 levels was higher in PD patients compared to that in healthy controls, but without reaching a statistical significance. There was a positive, but statistically insignificant, correlation between sLRP-1 levels and duration of disease. sLRP-1 levels had a significant correlation with UPDRS Parts I and IV. Patients with hypertension showed lower levels of sLRP-1.Conclusion: The present study suggests that serum sLRP-1 concentrations are associated with the factors influencing prognosis of PD and disease severity. Further studies are needed to definitively determine whether or not sLRP-1 can be utilized as a diagnostic and prognostic biomarker for PD.

Clinical Presentation, Electrocardiographic Findings, and Factors Related to the Hospitalization In Mad-Honey Intoxication.

Objectives: Mad-honey intoxication (MHI) often presents with all kinds of bradyarrhythmias. Despite numerous publications focused on clinical findings, we aim to evaluate poor prognostic implications, ischemia likely electrocardiography (ECG) changes, and detailed ECG findings of MHI in the largest series. Methods: This is a retrospective single-center study of 117 MHI patients admitted to emergency service. Results: The study had 26 (22.2%) females (median 52.5 years) and 91 (77.8%) males (median 51.0 years). Fifty-six (47.9%) patients had ischemia likely changes on ECG. Multivariate model demonstrated that beta-blocker usage (odds ratio (OR): 52.871; 95% confidence interval (CI): 3.618-772.554 (p=0.004)), atrioventricular junctional rhythm (AVJR) (OR: 5.319; 95%CI: 1.090-25.949 (p=0.039)), and quantity of mad-honey consumption (OR: 1.035; 95% CI: 1.008-1.063 (p=0.011)) are predictors of hospitalization. ROC curve analysis showed cutoff value of mad-honey consumption quantity 24.79 g had 57% sensitivity and 68% specificity for predicting hospitalization (AUC: 0.7, 95% CI: 0.55-0.816, p=0.027). In addition, all hospitalized cases were male. Conclusion: Our study has shown that male gender, AVJR, the quantity of mad-honey consumption, and beta-blocker usage are high-risk criteria for hospitalization in MHI patients. Furthermore, ischemia likely ECG changes is often observed with MHI even independently from hypotension or bradycardia.

Coronary flow velocity reserve is reduced in patients with an exaggerated blood pressure response to exercise.

Coronary artery disease and cardiovascular mortality are increased in patients with an exaggerated blood pressure response to exercise. The exact cause of this increase remains unknown, but previous studies have indicated the presence of endothelial dysfunction in peripheral arteries and subclinical atherosclerosis in these patients. The present study aimed to clarify whether coronary microvascular dysfunction is also present in patients with exaggerated blood pressure response to exercise. A total of 95 patients undergoing exercise testing were consecutively enrolled. Flow-mediated vasodilatation and carotid intima-media thickness were measured using standardized methods. A transthoracic echocardiography examination was performed to measure coronary flow velocity reserve. Patients with an exaggerated blood pressure response to exercise had significantly lower coronary flow velocity reserve than the controls (2.06 (1.91-2.36) vs. 2.27 (2.08-2.72), p = 0.004), and this difference was caused by a reduction in hyperemic flow velocity (57.5 (51.3-61.5) vs. 62.0 (56.0-73.0), p = 0.004) rather than a difference in basal flow (26.5 (22.3-29.8) vs. 26.0 (24.0-28.8), p = 0.95). Patients with an exaggerated blood pressure response to exercise also had a significantly greater carotid intima-media thickness and significantly lower flow-mediated vasodilatation than controls. However, an exaggerated blood pressure response to exercise remained a significant predictor of coronary microvascular dysfunction after adjusting for confounders (OR: 3.60, 95% CI: 1.23-10.54, p = 0.02). Patients with an exaggerated blood pressure response to exercise show signs of coronary microvascular dysfunction, in addition to endothelial dysfunction and subclinical atherosclerosis. This finding might explain the increased risk of coronary artery disease and cardiovascular mortality in these patients.

Prognostic significance of HDL-C on long-term mortality in patients with COVID-19 pneumonia in the Turkish population: A potential mechanism for population differences.

Coronavirus disease 2019 (COVID-19) is diagnosed by the evidence of the presence of multiple phenotypes, including thrombosis, inflammation, and alveolar and myocardial damage, which can cause severe illness and mortality. High-density lipoprotein cholesterol (HDL-C) has pleiotropic properties, including anti-inflammatory, anti-infectious, antithrombotic, and endothelial cell protective effects. The aim of this study was to investigate the HDL-C levels and one-year mortality after the first wave of patients with COVID-19 were hospitalized. Data from 101 patients with COVID-19 were collected for this single-center retrospective study. Lipid parameters were collected on the admission. The relationship between lipid parameters and long-term mortality was investigated. The mean age of the non-survivor group (n = 38) was 68.8 ± 14.1 years, and 55% were male. The HDL-C levels were significantly lower in the non-survivors group compared with the survivors (26.9 ± 9.5 vs 36.8 ± 12.8 mg/dl, respectively p < 0.001). Multivariate regression analysis determined that age, C-reactive protein, D-dimer, hypertension, and HDL-C as independent predictors for the development of COVID-19 mortality. HDL-C levels <30.5 mg/dl had 71% sensitivity and 68% specificity to predict one-year mortality after COVID-19. The findings of this study showed that HDL-C is a predictor of one-year mortality in Turkish patients with COVID-19. COVID-19 is associated with decreased lipid levels, and it is an indicator of the inflammatory burden and increased mortality rate. The consequences of long-term metabolic dysregulations in patients that have recovered from COVID-19 still need to be understood.

Soluble low density lipoprotein receptor-related protein-1 levels in the differential diagnosis of myopericarditis versus acute coronary syndrome.

INTRODUCTION: Differential diagnosis of myopericarditis (MPC) versus acute coronary syndromes (ACS) can be difficult in the emergency room (ER). Low density lipoprotein receptor-related protein-1 (LRP-1) is a transmembrane receptor with diverse biological functions. LRP-1 is increased after viral infections as a defense mechanism. sLRP-1 (soluble form) can be measured in the serum. We study the diagnostic sLRP-1 levels in patients with MPC, ACS and healthy controls. METHODS: The study included consecutive patients who were admitted between the dates of 1.1.2018 and 1.1.2019 with the diagnosis of MPC or ACS. All patients reported to the ER with chest pain (CP) and elevated cardiac troponin levels. Control group (n = 61) was selected from healthy subjects. In addition to routine laboratory work up, serum sLRP-1 concentrations were measured on admission. RESULTS: sLRP-1 levels were significantly higher in MPC, compared to controls (p = 0.005) and ACS (p = 0.001). Median (IQR) sLRP-1 levels in MPC, controls and ACS were 7.39 (22.42), 2.27 (1.74), 2.41 (0.98) µg/ml, respectively (p = 0.004). Among the covariates: sLRP-1, age, gender, HDL-C and LDL-C; only sLRP-1 differentiated a diagnosis of MPC versus ACS (OR = 1684, p = 0,046, CI for OR (1008-2812). The area under the curve (AUC) was measured as 0.79 [CI 0.62-0.95] in ROC analysis, p = 0.001; sLRP-1 had 69% sensitivity and 85% specificity for diagnosis of MPC with a cut-off value of 4.3 µg/ml. CONCLUSION: sLRP-1 is a potential biomarker in the differential diagnosis of MPC versus ACS in ER. Future studies are needed to evaluate and develop the utility of sLRP-1 as a diagnostic and prognostic biomarker in MPC.

Discrepancy between biomarkers of lung injury and 1-year mortality in COVID-19.

BACKGROUND: COVID-19 global pandemic started in late 2019 with the first wave. In this cross-sectional and observational study, we evaluated the associations between the biomarkers, COVID-19 pneumonia severity and 1-year mortality. METHODS: A sample of 276 polymerase chain reaction (PCR)-positive patients for SARS-CoV-2 was included. Computerized tomography severity score (CT-SS) was used to assess the severity of COVID-19 pneumonia in 222 cases. Multivariate analyses were performed to find the predictors of CT-SS, severe CT-SS (≥20) and 1-year mortality. Biomarkers of ferritin, high-sensitive C-reactive protein (CRP), lactate dehydrogenase (LDH), cardiac troponin (cTn), neutrophil-to-lymphocyte ratio (NLR), uric acid (UA) and d-dimer were routinely measured. RESULTS: Severe CT-SS (>20) was observed in 86 (31.2%) cases. Mortality was observed in 75 (27.2%) patients at 1 year. LDH displayed the highest predictive accuracy for severe CT-SS (AUC 0.741, sensitivity = 81% and specificity = 68%, cut-off value: 360 mg/dl). Linear regression analysis displayed that LDH predicted CT-SS [B = 11 (95% CI for B = 5-17, p < .001)]. Age was the most significant parameter that was associated with severe CT-SS (OR 0.96, 95% CI 0.92-0.99, p = .015). d-dimer was the only biomarker that predicted with 1-year mortality (OR 1.62, 95% CI 1.08-2.42, p = .020). CONCLUSION: LDH is a sensitive and specific biomarker to determine patients with severe lung injury in COVID-19. d-dimer is the only biomarker that predicts 1-year mortality. Neither LDH nor CT-SS is associated with 1-year mortality.

Three-dimensional echocardiographic assessment of Chiari's network relationship with the left ventricular false tendon.

BACKGROUND: Left ventricular false tendon (LVFT) is a fibromuscular band crossing the left ventricular cavity. And Chiari's network (CN) is a highly mobile, mesh-like, echogenic structure in right atrium. In this study, we aimed to evaluate the coexistence of LVFT in patients with CN. CN patients were examined with live/real-time three-dimensional transthoracic echocardiography (TTE) for visualization of LVFT. RESULTS: This is a single-center prospective study of 49 patients with CN. In literature studies, the average ratios of LVFT were 22% in the normal population. In our study, an increased ratio of LVFT (n = 31, 63.3%) was found in CN patients evaluated with a three-dimensional TTE (63.3% versus 22%) (p = 0.01). The interatrial septal aneurysm was found in 31 (63.3%) patients with CN. And, the positive contrast echocardiography examination was determined in 22 (61.1%) patients with CN. CONCLUSIONS: Our study reveals that CN is associated with LVFT and is also associated with cardiac anomalies like an interatrial septal aneurysm, and atrial septal defect. And LVFT can be evaluated better with three-dimensional TTE than with traditional two-dimensional TTE. Patients with CN should be evaluated more carefully by three-dimensional echocardiography as they can be in synergy in terms of the cardiac pathologies they accompany.

Coronary microvascular dysfunction is common in patients hospitalized with COVID-19 infection.

BACKGROUND AND AIMS: Microvascular disease is considered as one of the main drivers of morbidity and mortality in severe COVID-19, and microvascular dysfunction has been demonstrated in the subcutaneous and sublingual tissues in COVID-19 patients. The presence of coronary microvascular dysfunction (CMD) has also been hypothesized, but direct evidence demonstrating CMD in COVID-19 patients is missing. In the present study, we aimed to investigate CMD in patients hospitalized with COVID-19, and to understand whether there is a relationship between biomarkers of myocardial injury, myocardial strain and inflammation and CMD. METHODS: 39 patients that were hospitalized with COVID-19 and 40 control subjects were included to the present study. Biomarkers for myocardial injury, myocardial strain, inflammation, and fibrin turnover were obtained at admission. A comprehensive echocardiographic examination, including measurement of coronary flow velocity reserve (CFVR), was done after the patient was stabilized. RESULTS: Patients with COVID-19 infection had a significantly lower hyperemic coronary flow velocity, resulting in a significantly lower CFVR (2.0 ± 0.3 vs. 2.4 ± 0.5, p < .001). Patients with severe COVID-19 had a lower CFVR compared to those with moderate COVID-19 (1.8 ± 0.2 vs. 2.2 ± 0.2, p < .001) driven by a trend toward higher basal flow velocity. CFVR correlated with troponin (p = .003, r: -.470), B-type natriuretic peptide (p < .001, r: -.580), C-reactive protein (p < .001, r: -.369), interleukin-6 (p < .001, r: -.597), and d-dimer (p < .001, r: -.561), with the three latter biomarkers having the highest areas-under-curve for predicting CMD. CONCLUSIONS: Coronary microvascular dysfunction is common in patients with COVID-19 and is related to the severity of the infection. CMD may also explain the "cryptic" myocardial injury seen in patients with severe COVID-19 infection.

Leukocyte telomere length as a compensatory mechanism in vitamin D metabolism.

Vitamin D deficiency is common among postmenopausal women. Telomere length can be a potential protective mechanism for age-related diseases. The objective of our study is to examine the association of vitamin D supplementation on leukocyte telomere length (LTL) in healthy postmenopausal women with vitamin D deficiency. The study was designed as a placebo-controlled study to investigate the short-term effects of vitamin D supplementation and seasonal changes on vitamin D related parameters, including 25(OH)D, 1,25(OH)2D parathormone (PTH), Vitamin D binding protein (VDBP), vitamin D receptor (VDR), and telomere length in a cohort of postmenopausal women (n = 102). The group was divided as supplementation (n = 52) and placebo groups (n = 50). All parameters were measured before and after treatment. Serum VDBP levels were measured by ELISA method and VDR, GC (VDBP) gene expressions and relative telomere lengths were measured in peripheral blood mononuclear cells (PBMC) using a quantitative real-time PCR method. The results demonstrate that baseline levels were similar between the groups. After vitamin D supplementation 25(OH)D, 1,25(OH)2D, PTH and VDBP levels were changed significantly compared to the placebo group. At the end of the study period, LTL levels were significantly increased in both groups and this change was more prominent in placebo group. The change in GC expression was significant between treatment and placebo groups but VDR expression remained unchanged. Even though the study was designed to solely assess the effects of vitamin D supplementation, LTL was significantly increased in the whole study group in summer months suggesting that LTL levels are affected by sun exposure and seasonal changes rather than supplementation. The study displayed the short-term effect of Vitamin D supplementation on vitamin D, PTH levels, LTL and vitamin D associated gene expressions. The relation between Vitamin D and LTL is not linear and could be confounded by several factors such as the population differences, regional and seasonal changes in sun exposure.

Low levels of soluble low-density lipoprotein receptor-related protein 1 in patients with type 2 diabetes mellitus and diabetic retinopathy.

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a large transmembrane receptor. LRP-1 plays a role in diverse cellular processes, including lipid metabolism, cell growth, migration, and regeneration. Soluble form of LRP-1 (sLRP-1) can be detected in serum. sLRP-1 can serve as a biomarker of atherosclerosis and cardiometabolic diseases. This study investigated the concentrations of the circulating serum sLRP-1 in patients with retinopathy and type 2 diabetes mellitus. Fifty-two patients with diabetic retinopathy and 71 controls were enrolled based on well-defined eligibility criteria. Venous blood samples were collected after 12 h of fasting. sLRP-1 concentrations were measured using the commercially available ELISA in an accredited laboratory. The mean age of patients and control groups were 63.6 and 48.5 years, respectively. The median disease duration was 8.1 years. The median serum sLRP-1 levels were lower in patients with diabetic retinopathy compared to the controls (2.11 µg/mL versus 2.44 µg/mL, p = 0.034). No significant correlation was observed between the sLRP-1 and serum lipid levels. The sLRP-1 levels are low in patients with diabetic retinopathy compared to healthy controls, and future studies are needed to assess sLRP-1 as a potential biomarker in diabetic retinopathy.