Depletion of Homeostatic Antibodies against Malondialdehyde-Modified Low-Density Lipoprotein Correlates with Adverse Events in Major Vascular Surgery.

We aimed to investigate if major vascular surgery induces LDL oxidation, and whether circulating antibodies against malondialdehyde-modified LDL (MDA-LDL) alter dynamically in this setting. We also questioned relationships between these biomarkers and post-operative cardiovascular events. Major surgery can induce an oxidative stress response. However, the role of the humoral immune system in clearance of oxidized LDL following such an insult is unknown. Plasma samples were obtained from a prospective cohort of 131 patients undergoing major non-cardiac vascular surgery, with samples obtained preoperatively and at 24- and 72 h postoperatively. Enzyme-linked immunoassays were developed to assess MDA-LDL-related antibodies and complexes. Adverse events were myocardial infarction (primary outcome), and a composite of unstable angina, stroke and all-cause mortality (secondary outcome). MDA-LDL significantly increased at 24 h post-operatively (p < 0.0001). Conversely, levels of IgG and IgM anti-MDA-LDL, as well as IgG/IgM-MDA-LDL complexes and total IgG/IgM, were significantly lower at 24 h (each p < 0.0001). A smaller decrease in IgG anti-MDA-LDL related to combined clinical adverse events in a post hoc analysis, withstanding adjustment for age, sex, and total IgG (OR 0.13, 95% CI [0.03-0.5], p < 0.001; p value for trend <0.001). Major vascular surgery resulted in an increase in plasma MDA-LDL, in parallel with a decrease in antibody/complex levels, likely due to antibody binding and subsequent removal from the circulation. Our study provides novel insight into the role of the immune system during the oxidative stress of major surgery, and suggests a homeostatic clearance role for IgG antibodies, with greater reduction relating to downstream adverse events.

High sensitivity troponin and COVID-19 outcomes.

BACKGROUND: Recent reports have demonstrated high troponin levels in patients affected with COVID-19. In the present study, we aimed to determine the association between admission and peak troponin levels and COVID-19 outcomes. METHODS: This was an observational multi-ethnic multi-centre study in a UK cohort of 434 patients admitted and diagnosed COVID-19 positive, across six hospitals in London, UK during the second half of March 2020. RESULTS: Myocardial injury, defined as positive troponin during admission was observed in 288 (66.4%) patients. Age (OR: 1.68 [1.49-1.88], p < .001), hypertension (OR: 1.81 [1.10-2.99], p = .020) and moderate chronic kidney disease (OR: 9.12 [95% CI: 4.24-19.64], p < .001) independently predicted myocardial injury. After adjustment, patients with positive peak troponin were more likely to need non-invasive and mechanical ventilation (OR: 2.40 [95% CI: 1.27-4.56], p = .007, and OR: 6.81 [95% CI: 3.40-13.62], p < .001, respectively) and urgent renal replacement therapy (OR: 4.14 [95% CI: 1.34-12.78], p = .013). With regards to events, and after adjustment, positive peak troponin levels were independently associated with acute kidney injury (OR: 6.76 [95% CI: 3.40-13.47], p < .001), venous thromboembolism (OR: 11.99 [95% CI: 3.20-44.88], p < .001), development of atrial fibrillation (OR: 10.66 [95% CI: 1.33-85.32], p = .026) and death during admission (OR: 2.40 [95% CI: 1.34-4.29], p = .003). Similar associations were observed for admission troponin. In addition, median length of stay in days was shorter for patients with negative troponin levels: 8 (5-13) negative, 14 (7-23) low-positive levels and 16 (10-23) high-positive (p < .001). CONCLUSIONS: Admission and peak troponin appear to be predictors for cardiovascular and non-cardiovascular events and outcomes in COVID-19 patients, and their utilisation may have an impact on patient management.

The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action.

PURPOSE: It is well established that the broad-band muscarinic antagonist, atropine is effective at inhibiting the progression of myopia and does so by preventing the elongation of the vitreous chamber of the eye. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which muscarinic receptor subtype mediates this effect. Previous work, in avian and mammalian models of myopia, implicates the M1 and M4 receptors as potential targets. The current study used physiologically relevant concentrations of highly selective muscarinic antagonists (MT-3 and MT-7) to further characterise the role of the M4 receptor in the control of myopia in the chick model of refractive development. METHODS: Nine groups of week-old chicks underwent 5 days of monocular deprivation, with a translucent occluder, to induce myopia. These animals had either no injection, scleral puncture with a needle, or daily intravitreal injections of MT-3 (M4-selective), MT-7 (M1-selective) or vehicle. Three concentrations of each antagonist were delivered (250 nm, 2.5 µm and 10 µm). After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry. RESULTS: MT-3 treatment produced a significant dose-dependent reduction in relative myopia (treated-control eye) compared to vehicle treatment (vehicle -10.1 ± 1.1 D vs 10 µm MT-3 -4.0 ± 1.5 D, p < 0.01). The majority of this effect was due to reduced relative vitreous chamber elongation in drug treated eyes (vehicle +0.26 ± 0.04 mm, 10 µm MT-3 +0.08 ± 0.07 mm, p < 0.05). In contrast, MT-7 had no significant effect on the development of myopia (MT-7 10 µm: myopia, -12.1 ± 0.8 D and vitreous chamber depth, +0.23 ± 0.07 mm). Calculations indicate that the experimentally achieved concentrations of MT-3 at intraocular receptors necessary to inhibit 50% of myopia development (between 5 and 50 nm) were consistent with published in vitro affinity constants for the M4 receptor and below those for the M1 receptor. Histology demonstrated that MT-3 at the doses used had no gross effects on the retina, indicating a non-toxic mode of action. CONCLUSIONS: In the chick, which lacks a homologue of the mammalian M1 receptor, the above findings represent compelling evidence that muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina.

Ethnicity and COVID-19 cardiovascular complications: a multi-center UK cohort.

BACKGROUND: Recent reports suggest an association between ethnicity and COVID-19 mortality. In the present multi-center study, we aimed to assess the differences underlying this association, and ascertain whether ethnicity also mediates other aspects of COVID-19 like cardiovascular complications. METHODS: Data were collected from a mixed-ethnicity UK cohort of 613 patients admitted and diagnosed COVID-19 positive, across six hospitals in London during the second half of March 2020: 292 were White Caucasian ethnicity, 203 were Asian and 118 were of Afro-Caribbean ethnicity. RESULTS: Caucasian patients were older (P<0.001) and less likely to have hypertension (P=0.038), while Afro-Caribbean patients had higher prevalence of diabetes mellitus (P<0.001). Asian patients were more likely to present with venous thromboembolic disease (adj.OR=4.10, 95% CI 1.49-11.27, P=0.006). On the other hand, Afro-Caribbean had more heart failure (adj.OR=3.64, 95% CI 1.50-8.84, P=0.004) and myocardial injury (adj.OR=2.64, 95% CI 1.10-6.35, P=0.030). Importantly, our adjusted multi-variate Cox regression analysis revealed significantly higher all-cause mortality both for Asian (adj.HR=1.89, 95% CI 1.23-2.91, P=0.004) and Afro-Caribbean ethnicity (adj.HR=2.09, 95% CI 1.30-3.37, P=0.002). CONCLUSIONS: Our data show that COVID-19 may have different presentations and follow different clinical trajectories depending on the ethnicity of the affected subject. Awareness of complications more likely to arise in specific ethnicities will allow a more timely diagnosis and preventive measures for patients at risk. Due to increased mortality, individuals of Afro-Caribbean and Asian ethnicity should be considered as high-risk groups. This may have an impact on health-resource allocation and planning, definition of vulnerable groups, disease management, and the protection of healthcare workers at the frontline.