Optical coherence tomography of retinal and choroidal layers in patients with familial hypercholesterolaemia treated with lipoprotein apheresis

Detect and quantify morpho-functional alterations of the retina and choroid in patients affected by familial hypercholesterolemia (FH) treated with lipoprotein apheresis (LA) using optic coherence tomography (OCT) and optic coherence tomography-angriography (OCTA).Observational study.To be diagnosed: A group of 20 patients (40 eyes) being clinically and genetically diagnosed as FH and under treatment (FH-Group)", for at least 2 years, was compared to a control group of 20 healthy subjects (40 eyes), with a normal lipid profile and no ocular disease (CT-Group).Participants were studied with the slit lamp, binocular indirect fundoscopy, OCT and OCTA.Best corrected visual acuity (BVCA), spherical equivalent (SE), intraocular pressure (IOP), central macular thickness (CMT), choroidal thickness (CHT), retinal nerve fiber layer in four quadrants (RNFL (Superior = Sup; Inferior = Inf; Nasal = Nas Temporal = Temp), and the mean value across the four quadrants (RNFL G), foveal avascular zone (FAZ) and vascular density (VD).FH subjects had smaller RNFL superiorly (108 ± 19,38 μm OD/111 ± 16,56 μm OS FH-Group vs 127 ± 7,42 μm OD/129 ± 14,64 μm OS CT-Group; P  0,001 for both OD and OS) and inferiorly (108 ± 23,58 μm OD/115 ± 17,33 μm OS FH-Group vs 128 ± 18,15 μm OD/133 ± 17,38 μm OS CT-Group; P = 0,002 OD; P = 0,001 OS). G RNFL was consequently smaller (93 ± 12,94 μm OD/94 ± 10,49 μm OS FH-Group vs 101 ± 9,01 μm OD/101 ± 10,20 μm OS CT-Group; P = 0,03 OD; P = 0,02 OS). FH subjects had a larger FAZ (0,31 ± 0,08 mmEarly signs of retinal vessel damage in FH patients can be detected and quantified with OCT and OCTA

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis

Background: Hyperlipidemic pancreatitis (HP) is caused by severe hypertriglyceridemia (SHTG). Evidence of SHTG refractoriness to standard medical treatment but not to therapeutic apheresis has increased in the last years. Methods: Described is the timing of clinical events and the sequence of therapeutic plasma-exchange (TPE) procedures to treat pancreatitis due to SHTG in a male patient, Caucasian, aged 49. years, referred to emergency for severe epigastric pain. There was no history of alcohol consumption, a pre-existing mild hyperlipidemia was treated with diet alone, and biliary imaging was normal. Physical examination revealed epigastric tenderness. Laboratory investigation revealed marked hypertriglyceridemia (11,355. mg/dL; range: 30-150), and hypercholesterolemia (941. mg/dL; range: 80-200). Serum amylase (Amy) and lipase (Lip) were increased: 160. UI/L (range: 20-100) and 175. UI/L (range: 13-60), respectively. A computerized tomography (CT) scan of the abdomen revealed a picture compatible with acute pancreatic phlogosis. It was diagnosed as " acute secondary pancreatitis (AP) and SHTG" Results: The patient was successfully submitted to three sessions of TPE in emergency. He was released from hospital after 13. days of hospitalization. The levels of lipids and lipoproteins in his plasma were as follows: triglycerides (TG) 185. mg/dL; total cholesterol (TC) 179. mg/dL; HDL-cholesterol (HDLC) 22. mg/dL; LDL-cholesterol (LDLC) 120. mg/dL. Conclusions: The decision to submit the patient with clinical evidence of HP caused by SHTG to apheresis was correct. The improvement in the clinical picture was fast and the recovery was complete. © 2011 Elsevier Ltd

Lipid apheresis in secondary cardiovascular risk prevention in HyperLp(a)lipidemia. Why not?.

http://www.scitopics.com/Lipid_apheresis_in_secondary_cardiovascular_risk_prevention_in_HyperLp_a_lipidemia_Why_not.htm

LDL aferesi: stato dell’arte

Nella rassegna si riportano elementi inerenti la Lipidoaferesi e la LDL aferesi (LA, LDL_a). Sono descrittein breve le tecniche, nella loro evoluzione nelle ultime tre decadi, del resto già ampiamente elucidatein letteratura. Le indicazioni consolidate, il trattamento e le nuove possibili indicazioni emergenti,sono illustrate più ampiamente. In particolare, si riportano le evidenze di letteratura sull’uso della LAe della LDL_a nella Ipercolesterolemia Familiare (IF), nella Restenosi, nella Glomerulosclerosi Focale,nell’Arteriosclerosi Obliterante, nella Sudden Hearing Loss, nella Maculopatia Degenerativa Senile,nella Sepsi, nel post Trapianto Cardiaco e nello Stroke. Si descrivono in sintesi il progetto ed i risultatidello Studio Multicentrico Italiano per la LDL_a, che ha condotto nel 2009 alla II Consensus ConferenceItaliana sulla LDL_a. Uno spazio più ampio è dedicato agli effetti delle tecniche di LA ed LDL_a sugliendpoints cardiovascolari e sulla progressione e regressione dell’arteriosclerosi. La LDL_a pediatricaviene illustrata nelle sue più recenti evidenze. Infine, si conferisce una trattazione ampia e dettagliatasugli effetti lipid-unrelated della LDL_a, cioè quelli cd. pleiotropici e pleiotropici-equivalenti, con particolareriguardo per gli effetti sulla protezione vascolare e sui peptidi mediatori dell’infiammazione.Su questi ultimi sono riportate le evidenze più recenti della letteratura. Infine, vengono brevementeesposti i farmaci ipolipemizzanti di più recente introduzione, con un particolare interesse verso future,promettenti nuove molecole ancora in fase di sperimentazione

New clinical perspectives of hypolipidemic drug therapy in severe hypercholesterolemia

Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated LDL-Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or even nonresponsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to HMGCoA-reductase inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (NCEP ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL (prior CAD or CAD equivalent) or ≥ 250 mg/dL (no prior CAD or CAD risk-equivalent). The only current therapy option for these patients is Low Density Lipoproteins-apheresis (LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the LDL receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HozFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C and triglycerides. Lomitapide is currently being developed for patients with HozFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe, genetically determined dyslipidemias, are reviewed

[LDL apheresis: an update and overview. LDL apheresis in Sardinia, Italy (SMILDLa)]. [LDL-aferesi: aggiornamenti e stato dell'arte. Studio Multicentrico Italiano LDL-Aferesi (SMILDLa).]

LDL apheresis (LDLa) is an invasive therapeutic tool to control qualitative and quantitative disorders of lipid metabolism. It is aimed at achieving a metabolic balance in association with lipid-lowering drugs in patients with severe, genetically determined or acquired dyslipidemia who do not reach clinically adequate LDL-cholesterol (LDL-C) levels (<70 mg/dL) despite appropriate lipid-lowering drug treatment. A poorly known dyslipidemia is constituted by elevation of lipoprotein (a) [Lp(a)], which appears to be genetically determined and not influenced by diet or lipid-lowering medication. An Lp(a) level exceeding 30 mg/dL is an independent risk factor for premature cardiovascular disease and cerebrovascular disease. Numerous data support the notion that cardiovascular risk reduction is related to the degree of reduction of LDL-C, and the progression of atherosclerosis can be delayed or reversed by intensive and continuous cholesterol-lowering treatment. After the introduction of HMG-CoA reductase inhibitors (statins), the clinical benefit of cholesterol-lowering treatment has received significant confirmation. However, this treatment has shown poor results in the most severe, genetically determined forms. LDLa is an intensive extracorporeal cholesterol-lowering treatment approach with well documented efficacy and safety. It has also shown effects not directly correlated with its lipid-lowering activity, such as antioxidant effects on oxidized LDL and antiinflammatory effects on the cytokine network, the endothelium and the coagulation system. Finally, data acquired by the Italian Multicenter Study on LDLa Working Group were highlighted and the new evidence in the literature discussed

Cyclophosphamide and immunoadsorption apheresis treatment of lupus nephritis nonresponsive to drug therapy alone

In this report we present a 28-year-old male patient with systemic lupus erythematosus (SLE) that was treated with immunoadsorption apheresis (IA) and cyclophosphamide for lupus nephritis (proliferative glomerulonephritis, class IV-B) after proving nonresponsive to drug therapy alone. Before starting the therapeutic cycle with IA, the patient was administered prednisone 25 mg/d, hydroxychloroquine 200mg twice/d, ACE inhibitors 5 mg/d, aspirin 100 mg/d, furosemide 50 mg/d, and intravenous (IV) albumin (20%) 50 mL. Deteriorating clinical conditions necessitated a renal biopsy, and thereafter an increase in medication. The patient was given a bolus of IV cyclophosphamide 1 g/d for 1 day and IV methylprednisone 500 mg/d for 3 days. This was not followed by any improvement and the renal functions worsened. Thus, 3 weeks after the more aggressive pharmacologic treatment with cyclophosphamide, which had been prescribed to improve renal function, and given the young age of the patient, the decision was made to administer IA (Selesorb). IA selectively removes IgG and IgM immune complexes from the plasma, thereby reducing the complications induced by the pathogenic autoimmune reaction. The treatment was administrated twice a week for the first 15 days, once a week for a further 5 weeks, and biweekly in the last month with a bolus of cyclophosphamide (average 250-100 mg) after each session. After twelve sessions of IA over 3 months, renal function was completely restored and the patient discharged. Although it is not proven, the concomitant use of cyclophosphamide could presumably improve the final clinical outcome