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Session Webcast
Monogenic versus polygenic familial hypercholesterolemia: genetic risk score and response to treatment.
Abstract
Background and Aims
Background: A polygenic background can be recognized in part of patients with clinically diagnosed familial hypercholesterolemia (FH). The phenotypical distinction between monogenic (due to causative mutations in major LDLR, APOB or PCSK9 genes) and polygenic FH is not completely clarified.
Aims: We aimed to compare the clinical phenotype and response to treatment in monogenic vs. polygenic FH
Methods
Methods: Five hundred patients with clinical FH diagnosed based upon DLCNC> 3 were genotyped. Causative monogenic variants were identified by NGS and the polygenic score (GRS) was estimated by the 6-LDL-rising SNPs panel. Patients’ clinical characteristic and LDL-C changes during cholesterol-lowering treatments were retrospectively obtained.
Results
Results: 323 (64.6%) patients were FH-mutation positive (monogenic FH) and 177 (35.4%) patients were classified as FH-mutation negative (FH/M-). In comparison with normocholesterolemic subjects, FH/M- patients had higher mean GRS (0.71± 0.19 and 0.61±0.20, p<0.001). Based on a GRS value above 0.69 (the best cut-off discriminating FH/M– and normocholesterolemic individuals), 21% of clinically diagnosed FH were classified as polygenic. Polygenic FH were older and showed lower untreated total and LDL-C as compared to monogenic FH. During about 33 months of follow-up, monogenic FH showed higher on-treatment, last visit and best LDL-C as compared with FH/M- patients (P<0.005). These differences persisted even after adjustment for intensity of cholesterol-lowering therapies.
Conclusions
Conclusions: Our results highlight that a polygenic GRS might explain the elevation of LDL-C observed in FH/M- patients. In these patients, the burden of LDL-C is lower than that in monogenic FH patients.
Webcast
Over 30 years of elaborate experience in LDL apheresis: an effective and well-tolerated treatment option for specific patient subgroups
Abstract
Background and Aims
Low-density lipoprotein cholesterol (LDL-c) and lipoprotein(a) (Lp(a)) are independant cardiovascular risk factors. Although modern drugs allow to reach treatment targets in most patients, for a subgroup of patients (patients with homozygous familial hypercholesterolaemia, patients with persistent dislipidaemia due to either drug resistance or intolerance, and patients with severely elevated Lp(a)) regular lipoprotein apheresis is the only option to improve cardiovascular outcome.
Methods
Between 1987 and 2018 our apheresis center at the University of Munich has conducted a total of 44,236 lipoprotein apheresis sessions, corresponding to a mean of 1,340 sessions per year in a total of 140 patients.
Results
On average each apheresis treatment decreases LDL-c and Lp(a) levels by 60-67% in a representative sample. The procedure is generally well-tolerated, with hypotension due to volume depletion being the most common side effect. Out of 140 patients, 21 patients (15%) died, whereas 70 patients (50%) stopped treatment due to a variety of other reasons, i.e. change of place of residence (25.7%), introduction of more potent drugs (newer statins, PCSK9-inhibitors) and thus rendering apheresis redundant (12.9%), senescence (2.1%) and other causes (7.9%). Only 2 patients (1.4%) stopped apheresis because of intolerance. 56 patients are currently treated in our center, 4 of them have been treated for more than 30 years.
Conclusions
In our experience, treatment success is associated with a number of factors such as experience (high quantity of procedures) and the engagement of a consistent medical staff, resulting in an elaborate expert knowledge of both, applied techniques and individual patient characteristics.
Webcast
Antibodies against the c-terminus of apolipoprotein A-1 as predictors of death in the general population but not as therapeutic targets actionable through cognate peptides immunomodulation.
Abstract
Background and Aims
Autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgGs) have emerged as an independent biomarker for cardiovascular disease and mortality in humans, promote death in ApoE -/- mice, and seem to be preferentially oriented against the c-terminal part of apoA-1 (cterA1). Corresponding specific mimetic peptides were shown to reverse anti-apoA-1 IgG pro-inflammatory effects in vitro. We evaluated the association of IgG against c-terminus apoA-1 (anti-cterA1 IgGs) with all-cause mortality in the community and tested the ability of two cterA1 mimetic peptides to reverse the anti-apoA-1 IgG-induced inflammation in vitro and mortality in ApoE -/- mice.
Methods
Anti-cterA1 IgGs were measured on serum samples of 5220 consecutive participants included in the CoLaus study with median follow-up duration of 5.6 years. The primary study outcome was all-cause mortality. Two chemically engineered optimized cterA1 mimetic peptides were tested i) on HEK cells to modulate interleukin-8 (IL-8) and tumor necrosis-alpha (TNF-α) production, and ii) in apoE -/- mice exposed to 16 weeks of anti-apoA-1 IgG passive immunisation.
Results
Anti-cterA1 IgG independently predicted all-cause mortality, each standard deviation of anti-cterA1 IgG being associated with a 18% increase in mortality risk (Hazard Ratio:1.18, 95%confidence intervals:1.04-1.33;p=0.009). Both cterA1 mimetic peptides reduced the anti-apoA-1 IgG-induced inflammation in a dose-dependent manner in vitro, but did not rescue the anti-apoA-1 IgG-associated mortality in mice.
Conclusions
Anti-cterA1 IgG independently predict all-cause mortality in the general population. By failing to reverse the anti-apoA-1 IgG-induced mortality in mice, our data do not support the hypothesis that these autoantibodies could be actionable through cognate peptides immunomodulation.
Webcast
High plasma lipoprotein(a) levels are associated with increased prevalence of cardiovascular disease and poorer metabolic control in patients with type 1 diabetes mellitus
Abstract
Background and Aims
To investigate the association between Lipoprotein(a) [Lp (a)] plasma levels, vascular complications and metabolic control in patients with type 1 diabetes mellitus.
Methods
Patients with type 1 diabetes mellitus receiving regular care were recruited in this observational cross-sectional study. Patients were grouped by Lp(a) levels (nmol/L) into very Low <10; Low 10-30; Intermediate 30-120; High>120, and prevalence of vascular complications were compared between the groups. Lp(a) plasma levels in patients with good (HbA1c <52 mmol/mol) or poor (HbA1c >52 mmol/mol) metabolic control were studied.
Results
The patients (n=1860) had a median age 48 years, diabetes duration 25 years, and HbA1c 61 mmol/mol. The median Lp(a) (interquartile range) was 19 (10-71) nmol/L. No significant differences between males and females were observed, but Lp(a) levels increased with increasing age. Patients in the high Lp(a) group had higher prevalence of complications than patients in the very low Lp(a) group. The age- and smoking-status-adjusted relative risk ratio for any macrovascular disease was 1.51 (CI 1.01-2.28, p=0.048), coronary heart disease 1.70 (CI 0.97-3.00, p=0.063), albuminuria 1.68 (CI 1.12-2.50, p=0.01) and calcified aortic valve disease 2.03 (CI 1.03-4.03; p=0.042). Patients with good metabolic control had significantly lower 80th (p=0.031) and 90th (p<0.001) percentiles Lp(a) levels than patients with poorer metabolic control.
Conclusions
Lp(a) is a significant risk factor for macrovascular disease, albuminuria and calcified aortic valve disease in patients with type 1 diabetes mellitus. Poor metabolic control in these patients is associated with increased Lp(a) levels.