High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

Protein kinase C iota mediates lipid-induced apoptosis of human coronary artery endothelial cells.

Apoptosis is involved in the development and progression of atherosclerotic lesions. Protein kinase C (PKC) signalling is of importance in atherosclerosis as well as apoptosis. Therefore, we tested the involvement of PKC in lipid-induced apoptosis of human coronary artery endothelial cells (HCAEC). Protein expression of PKC isoforms alpha, beta I, delta, epsilon, and iota was detected, whereas no relevant protein amounts of PKC isoforms beta II, gamma, eta, theta, and zeta were found. Inhibition of classical and novel PKC isoforms by treatment with bisindolylmaleimide or PKC down-regulation by long-term treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA) could not prevent apoptosis induced by palmitate or stearate. In contrast, a specific myristoylated, cell-permeable PKC zeta/iota pseudosubstrate prevented lipid-induced apoptosis in HCAEC. Furthermore, saturated fatty acids activated PKC iota as evidenced by PKC iota down-regulation upon long-term treatment with stearate. Our data provide evidence that PKC iota is activated by saturated fatty acids and mediates lipid-induced apoptosis of HCAEC.

Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors.

Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations.

Lipoprotein(a)-an interdisciplinary challenge.

Lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor which is inherited and not changed by nutrition or physical activity. At present, only proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may modestly decrease its concentration (but not in all patients)-leading to a certain decrease in cardiovascular events (CVE) in controlled studies. However, at present an elevation of Lp(a) is not a generally accepted indication for their use. More effective is lipoprotein apheresis (LA) therapy with respect to both lowering Lp(a) levels and reduction of CVE. In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available. Atherosclerosis in patients with an elevation of Lp(a) may affect several vessel regions (carotids, aorta, coronaries, leg arteries). Thus, Lp(a) should be measured in high-risk patients. These patients are usually cared for by their family doctors and by other specialists who should closely cooperate. Lipidologists should decide whether costly therapies like PCSK9 inhibitors or LA should be started. The main aim of current therapy is to optimize all other risk factors (LDL cholesterol, hypertension, diabetes mellitus, body weight, renal insufficiency). Patients should be regularly monitored (lab data, heart, arteries). This paper describes the duties of physicians of different specialties when caring for patients with high Lp(a) concentrations.

Kinetics of Lipoprotein(a) in patients undergoing weekly lipoprotein apheresis for Lp(a) hyperlipoproteinemia.

INTRODUCTION: Lipoprotein apheresis (LA) represents the only effective therapeutic option for patients with elevated Lipoprotein(a) (Lp(a)) levels. We aimed at analyzing the Lp(a) reduction, rebound rates as well as mean interval values between two weekly apheresis sessions, since this might be important for the prediction of the residual cardiovascular risk and development of individualized approaches for this special therapeutic strategy. MATERIALS AND METHODS: 20 patients under weekly and 2 patients under twice weekly apheresis were included. We measured serum concentrations of Lp(a), total, LDL-, HDL - cholesterol and triglycerides daily over 7 days after single LA sessions. RESULTS: Mean Lp(a) levels was 158.1 ± 69.82 nmol/l before the LA session, decreased acutely by 76 ± 7% and increased to 97 ± 13% of the baseline value within 7 days in patients under weekly treatment. By mathematical modeling, the acute Lp(a) reduction can be calculated from the function: y (nmol/l) = 3.415 + 0.738 * x (R2 = 0.970), where x is the baseline Lp(a) value. The recovery rate can be predicted from the equation: y (%) = 22.49 + 18.64 * x - 1.14 * x2 (R2 = 0.874), where x is the day after apheresis. The empirical formula for the mean interval value is: y (nmol/l) = x - 12, where x is the absolute reduction in nmol/l. CONCLUSION: We modeled - for the first time - equations to predict the course of Lp(a) serum levels under weekly LA which are simple, reliable and enable the development of optimal individualized protocols of this costly lipid lowering therapy.

Most significant reduction of cardiovascular events in patients undergoing lipoproteinapheresis due to raised Lp(a) levels - A multicenter observational study.

OBJECTIVES: Lipoprotein(a) (Lp(a)) is an independent cardiovascular (CV) risk factor, predisposing to premature and progressive CV events. Lipoproteinapheresis (LA) is the only efficacious therapy for reducing Lp(a). Data comparing the clinical efficacy of LA with respect to reduction of CV events in subjects with elevated Lp(a) versus LDL-C versus both disorders is scarce. We aimed to perform this comparison in a multicenter observational study. METHODS: 113 LA patients from 8 apheresis centers were included (mean age 56.3 years). They were divided into 3 groups: Group I: Lp(a) < 600 mg/l, LDL-C > 2.6 mmol/l, Group II: Lp(a) > 600 mg/l, LDL-C < 2.6 mmol/l, and Group III: Lp(a) > 600 mg/l, LDL-C > 2.6 mmol/l. CV events were documented 2 years before versus 2 years after LA start. RESULTS: Before start of LA Group II showed the highest CV event rate (p 0.001). Group III had a higher CV event rate than Group I (p 0.03). During LA there was a significant reduction of CV events/patient in all vessel beds (1.22 ± 1.16 versus 0.33 ± 0.75, p < 0.001). The highest CV event rate during LA was seen in coronaries followed by peripheral arteries, cerebrovascular events were least common. Greater CV event reduction rates were achieved in patients with isolated Lp(a) elevation (-77%, p < 0.001) and in patients with Lp(a) and LDL-C elevation (-74%, p < 0.001) than in subjects with isolated hypercholesterolemia (-53%, p 0.06). CONCLUSION: This study demonstrates that patients with Lp(a) elevation benefit most from LA treatment. Prospective trials to confirm these data are warranted.

Lipoprotein apheresis influences monocyte subpopulations.

BACKGROUND: Monocytes can be differentiated into subpopulations depending on their expression profile of CD14 and CD16. CD16-positive monocytes are associated with coronary artery disease. Up to now, no data exist about the effect of lipoprotein apheresis (LA) on the distribution of monocyte subpopulations. METHODS: 80 patients who underwent LA at the University Hospital Dresden were included in the study. 8 out of the 80 LA patients received LA for the first time at the time point of blood analysis. Six different methods of LA were used (H.E.L.P. n = 8; Liposorber D n = 10; LF n = 14; DALI n = 17; MONET n = 11; Therasorb® LDL n = 12). Blood samples were taken immediately before and after LA and analyzed for CD14 and CD16 expression on monocytes. A total of 42 patients with cardiovascular risk factors but no indication for LA served as control group. RESULTS: The composition of monocyte-population was analyzed in regard to the 3 subpopulations. After LA, an increase in classical monocytes (CD14++CD16-) (93.3% vs. 93.9%, p < 0.01) and a decrease in non-classical monocytes (CD14+CD16+) (1.5% vs 1.0%; p < 0.001) were observed. LA did not change the amount of intermediate monocytes (CD14++CD16+) (5.3% vs. 5.1%). Two methods (MONET and Therasorb® LDL) did not influence the distribution of monocyte subpopulations. Interestingly, patients with LDL-C above 2.5 mmol/l prior LA showed increased amounts of intermediate monocytes. CONCLUSION: The distribution of monocyte populations is influenced by LA but depends on the distinct method of LA. Influences of LA were mainly observed in the content of classical and non-classical monocytes, whereas the intermediate monocyte population remained unaltered by LA.

Practical recommendations for the management of hyperlipidemia.

Hyperlipidemia is a risk factor for atherosclerosis. Raised low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) levels are severe risk factors for atherosclerosis. The role of high-density lipoprotein cholesterol (HDL-C) is controversial. Total cholesterol, LDL-C, HDL-C, triglycerides and lipoprotein(a) levels should be determined in a fasting state. The basis of treating hyperlipidemia remains diet, physical exercise and weight reduction. Olive oil and nuts have been shown to be beneficial. Statins remain first line drug treatment. Further treatment options are ezetimibe, bile acid sequestrants, fibrates and fish oil. Side effects of statins include myopathies and, as shown during the last years, also an increased risk of diabetes mellitus. In patients with statin-related myopathies first results of a gene analysis have been published showing a means of predicting which statin can be administered at which dose for the individual patient with least risk of side effects. Most convincing data have been shown for simvastatin. Patients with renal insufficiency have been shown to have a raised cardiovascular risk. In the SHARP Study the combination of simvastatin plus ezetimibe was effective in reducing cardiovascular events in patients with severe renal insufficiency (especially before dialysis but also in dialysis dependent patients). Important aspects of treating patients with chylomicronemia syndrome are illustrated. Treating young patients with hyperlipidemia as primary prevention remains problematic.

Adverse events of lipoprotein apheresis and immunoadsorption at the Apheresis Center at the University Hospital Dresden.

BACKGROUND: Lipoprotein apheresis and immunoadsorption methods have a firm place among therapeutic approaches in order to treat disorders of lipoprotein metabolism or anti-body induced diseases. The extracorporeal treatment is associated with adverse effects, we wanted to report the Dresden experience. METHODS: In this study we retrospectively analyzed the adverse events of several lipoprotein apheresis and immunoadsorption methods at the Apheresis Center in Dresden (Germany). We carefully looked into all available documents. The first extracorporeal lipoprotein apheresis was performed in 1990 and the first extracorporeal immunoadsorption was executed in 1995. Throughout the 23 years study period, 10 different methods were employed in treating 268 patients for a total of 25,293 treatments. RESULTS: Adverse events of varying severity occurred in 1948 of the treatments (7.7%). We subdivided them into mild (61.3% no treatment was necessary), moderate (37.0% oral medication or infusion was given) and severe (1.7% emergency hospitalization was necessary). Therapy had to be stopped prematurely in 1.5% of the treatments. We compared adverse events profiles among the different methods and evaluated for differences by gender. Females were found to have a significantly higher risk of adverse events than male patients. In males, the rate of adverse events ranged from 3.3% (Liposorber(®) D) to 11% (Therasorb™ Ig); in females the minimum rate was 7.8% (DALI) and the maximum 30% (rheopheresis). Adverse events were evenly distributed between the ages of 30-69, the age range at which most of the therapies were performed. We also found that all methods had a higher rate of adverse events during the first year of treatment. Puncture problems and hypotension were the most common adverse events. CONCLUSION: It can be stressed that in general the extracorporeal methods used can be regarded as safe.

Effects of different lipoprotein apheresis methods on serum protein levels.

BACKGROUND: A total plasma exchange was the first extracorporeal method to treat patients with severe hypercholesterolemia. But in the long run it has several disadvantages. The newer lipoprotein apheresis (LA) methods claim to be more selective with respect to the removal of atherogenic lipoproteins and thus are supposed to avoid an additional protein loss. METHODS: We wanted to compare the effect of these methods on serum protein concentrations (total serum protein, albumin, proteins measured with electrophoresis, immunoglobulins, fibrinogen, transferrin, and ferritin) which were checked before and after a single LA session in 75 patients. All patients underwent active LA treatment using 6 different LA methods (HELP, TheraSorb(®) LDL, DALI, Lipidfiltration, Liposorber D, MONET). Post-apheresis concentrations were corrected for changes in hematocrit. RESULTS: The slightest impact on total serum protein was observed with the whole-blood methods. Liposorber D showed the least reduction of albumin levels. All LA methods had a small effect on alpha1-globulins and beta-globulins, but alpha2-and gamma-globulins were reduced to a different extent. A major effect was seen on the immunoglobulins when filtration methods were applied. In the patients treated with MONET, both pre- and post-apheresis Immunoglobulin M concentrations were below the normal range. HELP and the filtration methods significantly reduced the fibrinogen concentrations. The filtration methods also decreased ferritin levels but the post-apheresis ferritin levels were still in the normal range. CONCLUSION: All LA methods had an influence on protein concentrations. At present, these findings will not yield an individualized treatment approach for any selective LA method due to the lack of prospective comparative studies. At minimum, special attention should be paid to protein concentrations in patients suffering from protein deficit.

TIDILAP: Treatment of iron deficiency in lipoprotein apheresis patients --A prospective observational multi-center cohort study comparing efficacy, safety and tolerability of ferric gluconate with ferric carboxymaltose.

OBJECTIVES: Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM). METHODS: Inclusion criteria were a) serum ferritin <100 µg/L or b) serum ferritin <300 µg/L and transferrin saturation <20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients. RESULTS: 80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p < 0.0001) and by 13% (p < 0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p < 0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred. CONCLUSIONS: Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines.

Validity and boundary conditions of automatic response activation in the Simon task.

Three experiments were conducted to determine whether spatial stimulus-response compatibility effects are caused by automatic response activation by stimulus properties or by interference between codes during translation of stimulus into response coordinates. The main evidence against activation has been that in a Simon task with hands crossed, responses are faster at the response location ipsilateral to the stimulus though manipulated by the hand contralateral to the stimulus. The experiments were conducted with hands in standard and in crossed positions and electroencephalogram measures showed coactivation of the motor cortex induced by stimulus position primarily during standard hand positions with visual stimuli. Only in this condition did the Simon effect decay with longer response times. The visual Simon effect appeared to be due to specific mechanisms of visuomotor information transmission that are not responsible for the effects obtained with crossed hands or auditory stimuli.

Current standards in diagnosis and therapy of hyperlipoproteinemia.

Raised lipid parameters, especially increased LDL-cholesterol and lipoprotein(a) (Lp(a)) levels, are severe risk factors for atherosclerosis. Targets in the therapy of hyperlipoproteinemia are dependent on other risk factors including diabetes mellitus and manifest cardiovascular disease. Fasting levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides are measured for diagnosis of this disease. Lp(a) should be evaluated in instances of positive family history for cardiovascular disease and/or severe progress of cardiovascular disease or premature cardiovascular events. The basis of therapy includes diet measures as well as weight reduction and lifestyle modifications (raised physical activity after excluding contraindications). Numerous patients require lipid-lowering drug therapy, including most importantly statins but also bile acid sequestrants, ezetimibe, fibrates, nicotinic acid or omega-3-fatty acids. Special forms of hyperlipoproteinemia such as chylomicronemia syndrome and raised Lp(a) are described herein.

Iron deficiency and its management in patients undergoing lipoprotein apheresis. Comparison of two parenteral iron formulations.

OBJECTIVES: There is evidence of iron deficiency (ID) in patients treated with lipoprotein apheresis. Aim of this study was to assess ID in apheresis patients and to study its management comparing safety and efficacy of two approved intravenous (i.v.) iron formulations. METHODS: Inclusion criteria were defined as a) serum ferritin < 300 µg/l and transferrin saturation < 20%, b) ferritin < 100 µg/l. Both iron deficient alone and ID anemic (IDA) patients were included. Other causes for anemia were ruled out by thorough history-taking and examination/blood tests. Patients were treated with six different lipoprotein apheresis methods: DALI, Liposorber D, TheraSorb LDL, HELP, MONET and Lipidfiltration. 50 patients were randomized to either ferric carboxymaltose (FCM, 500-1000 mg as single shot infusion over 20 min) or ferric gluconate (FG, 62.5 mg once weekly). RESULTS: 50 of 67 patients of our Lipoprotein Apheresis Center showed iron deficiency. Both i.v. iron formulations studied were equally safe (no serious adverse events (SAEs), 6 patients/group showed adverse events (AEs)) and both effective (clinically and with respect to laboratory data) in lipoprotein apheresis patients, however FCM led to a more rapid and steeper rise of iron parameters. CONCLUSIONS: ID and IDA are common findings in lipoprotein apheresis patients. The pathogenesis remains yet poorly understood and is probably multifactorial. Differential diagnosis of ID/IDA is as essential as differential therapy. Handled with care, older i.v. iron preparations like FG appear to be safe and effective in lipoprotein apheresis patients. However, novel formulations like FCM can be administered rapidly at higher doses due to high complex stability, allowing faster filling of iron stores. Newer laboratory parameters (Reticulocyte-He, low/medium/high fluorescence reticulocytes (LFR/MFR/HFR)) assessing iron status may be helpful in early detection of ID and in monitoring iron replacement therapy.