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Session Webcast
Acute coronary syndrome patients
Webcast
Chronic kidney disease patients
Webcast
Association between Apolipoprotein B and cardiovascular risk: a meta-analysis of randomized controlled trials
Abstract
Background and Aims
Recent evidence from Mendelian randomization studies suggests that the clinical benefit of any lipid-lowering therapy should be proportional to the absolute change in apolipoprotein B (apoB) containing lipoproteins. We sought to compare and to estimate the magnitude of the expected clinical benefit per unit reduction in apoB for several classes of lipid-lowering therapies.
Methods
We conducted a study-level meta-analysis of randomized trials evaluating statins, ezetimibe, PCSK9-inhibitors, CETP-inhibitors, niacin, and fibrates. We included all studies reporting apoB levels and cardiovascular (CV) outcomes, with at least 1000 participants and 1-year follow-up. The primary outcome was major CV events (MACEs). We estimated the relative risk (RR) of MACEs, adjusted for study duration, for each class and in a combined analysis.
Results
Twenty-five trials that enrolled 285,241 participants (mean age: 63.3 years; female sex: 24.7%) who experienced 40,244 first MACEs were included. The mean absolute difference in apoB between the treatment and comparison groups at 1 year was 24.1 mg/dL. The pooled RR per 30 mg/dL reduction in apoB levels was 0.79 (95% confidence intervals (CI) 0.77-0.81) for MACEs, consisting of significant risk reduction in non-fatal myocardial infarction (RR 0.76; 95%CI 0.73-0.79), coronary revascularisation (0.78; 0.73-0.82), stroke (0.79; 0.76-0.81), and CV death (0.87; 0.82-0.92).
Conclusions
All the lipid-lowering therapies are associated with very similar reductions in the risk of major CV events per unit change in apoB, suggesting that the clinical benefit may be proportional to the achieved absolute reduction in apoB, regardless of the observed changes in other lipids.
Webcast
Specification of ACMG/AMP guidelines for standardized variant interpretation in familial hypercholesterolemia: On behalf of the ClinGen FH Variant Curation Expert Panel
Abstract
Background and Aims
Familial hypercholesterolemia (FH) is a heritable disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. Increasingly, patients with a clinical suspicion of FH are being offered genetic testing as part of diagnosis. However, determining pathogenicity of identified DNA variants remains a major challenge; this process is often rudimentary and differs among laboratories. To improve accuracy, concordance and standardization, the ClinGen FH Variant Curation Expert Panel (VCEP) has been tasked with developing FH-specific variant interpretation guidelines, derived from American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) recommendations (2015).
Methods
Following review of ACMG/AMP recommendations, the FH VCEP met through frequent emails and conference calls to propose FH-specific modifications. After multiple preliminary iterations, pilot testing, debate and further commentary, consensus among experts was reached.
Results
Here, we present a consensus set of FH-ACMG/AMP guidelines, which focus first on the LDL receptor gene (LDLR), and include: 1) indications for loss-of-function variant types; 2) functional study criteria specifications; 3) alteration of population data frequency thresholds; 4) specific use and thresholds for in silico prediction tools; and 5) co-segregation criteria specifications.
Conclusions
Establishment of these guidelines will help to achieve a more evidence-based, standardized method for the classification of variants detected in FH patients worldwide. Ultimately, all ~3000 FH-associated variants currently deposited in the ClinVar database will be re-classified using the FH-ACMG/AMP criteria, while promoting these guidelines as the new “gold standard” for variant classification among the FH community will ensure novel variants identified in real-time are appropriately evaluated.
Webcast
Hypercholesterolemia disrupts the metabolic regulation of hematopoietic stem cell behavior, favoring the production of pro-inflammatory monocytes in patients with familial hypercholesterolemia
Abstract
Background and Aims
We hypothesize that hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), results in enhanced production of pro-inflammatory monocytes in patients with familial hypercholesterolemia (FH).
Methods
10 FH patients with an indication for lipid lowering treatment (LLT) (statin, PCSK9-antibody or both) as primary prevention were included. Transcriptomic and functional analyses of BM HSPCs and peripheral monocytes were performed at baseline and after 12 weeks of LLT. Results were compared to healthy controls matched for age, sex and BMI.
Results
Untreated FH patients have more CD34+ HSPCs with decreased expression of homing marker CXCR4, and more CCR2+ monocytes in the bone marrow compared to healthy controls. Transcriptomic analyses of untreated FH patients versus controls showed increased expression of genes involved in the migration and proliferation of HSPCs. Expression of genes involved in these pathways were partly reduced after LLT, with concomitant functional reduction in myeloid progenitor capacity. This reduction coincided with increased oxidative phosphorylation in CD34+ HSPCs measured on gene expression level, as well as with functional Seahorse analyses. Interestingly, these changes on bone marrow level did not result in a reduction of CCR2 expression measured by flow cytometry in circulating monocytes.
Conclusions
Hypercholesterolemia in untreated FH patients results in functional alterations of HSPC behavior, favoring the production of pro-inflammatory monocytes. This effect was only partly reduced after 12 weeks of lipid lowering treatment. Altered metabolic regulation of stem cell behavior could explain this persistent effect post-treatment.
Webcast
Colchicine inhibits neutrophil extracellular trap formation in acute coronary syndrome patients post percutaneous coronary intervention
Abstract
Background and Aims
Release of neutrophil extracellular traps (NETs) after PCI in ACS patients is associated with peri-procedural myocardial infarction, as a result of microvascular obstruction via pro-inflammatory and pro-thrombotic pathways. Colchicine is a potent, well-established anti-inflammatory agent with growing evidence to support its use in patients with coronary disease. However, its effects on post-PCI NET formation in ACS patients is unknown.
Methods
60 patients (40 ACS; 20 stable angina pectoris [SAP]) were prospectively recruited and allocated to colchicine (1.5 mg) or no treatment. Within 24 h of treatment, serial coronary sinus blood samples were collected during PCI for quantification of NETosis. Isolated neutrophils from 10 ACS patients post-PCI and 4 healthy controls were treated with colchicine (25 nM) and stimulated with either ionomycin (5 mM) or PMA (50 nM) in vitro. Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst and anti-alpha tubulin.
Results
Untreated ACS patients had higher NET release post-PCI, versus untreated SAP patients (p<0.001). In ACS patients, colchicine treatment resulted in suppression of NETosis versus control (AUC 0.58 vs. 4.29; p<0.001); a phenomenon that was not observed in SAP patients. In vitro, colchicine suppressed spontaneous (p=0.004), PMA-induced (p=0.05) and ionomycin-induced (p=0.02) NETosis in neutrophils from ACS patients, but not healthy controls. Colchicine caused alteration to the neutrophil microtubule complex, inhibiting release of DNA.
Conclusions
Colchicine suppresses NET formation in ACS patients post-PCI and is independent of classic NET signalling pathways. These findings warrant further investigation in randomised trials powered for clinical endpoints.