S. Tselmin

Beyond lowering circulating LDL: Apheresis-induced changes of systemic oxidative stress markers by four different techniques

OBJECTIVE AND METHODS Dyslipidemia and oxidative stress are causally related to atherogenesis and cardiovascular disease. We assessed acute changes of systemic oxidative stress biomarkers in thirty-two patients undergoing regular apheresis using four different techniques: heparin-induced extracorporeal LDL precipitation (HELP), direct adsorption of lipoproteins (DALI), lipidfiltration (LF), and immunoadsorption of lipoproteins (IA). RESULTS All apheresis procedures were similarly effective in lowering LDL cholesterol (-2.5+/-0.2 mmoL/L), oxidized LDL (-52.4+/-4.4 U/L), and levels of antioxLDL antibodies (-59.5+/-15.1 U/L). Among the LDL-apheresis methods investigated, only the DALI technique without prior separation of blood plasma led to a decline in leukocyte count (p=0.01 vs. LF post apheresis) and to decreased phagocyte oxidant-generating activity as evaluated by chemiluminescence. Moreover, DALI was followed by a smaller decrease of blood total antioxidant capacity than the other techniques (p<0.01 vs. HELP post apheresis). CONCLUSION Together, our data suggest that compared with other common techniques, the DALI apheresis system is accompanied by the lowest systemic oxidative burden evoked by a single apheresis treatment.

Acute effects of lipid apheresis on human serum lipidome

Lipid apheresis is an efficient method for reducing cholesterol and triglyceride serum levels, but its effect on other lipid species has not been investigated. This study explored the effect of LDL apheresis on the serum lipidome in hyperlipidemic patients with cardiovascular complications. Lipid analysis was performed before and immediately after a single apheresis procedure in serum samples of six patients treated with different apheresis methods. Conventional lipid parameters (TC, LDL-C, HDL-C, TG) were determined by standard enzymatic methods. Phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), PE-based plasmalogens (PE_pl), lysophosphatidylcholines (LPC), ceramides (Cer), free cholesterol (FC) and cholesterol ester (CE) were detected with electrospray ionization tandem mass spectrometry. LDL apheresis induced a mean reduction of LDL-C by 68% and of HDL-C by 14%, respectively. CE, FC, SM, and Cer revealed an apheresis-induced decrease of about 47%, which was not statistically different from LDL-C reduction. In contrast, the decline of PC (31%), LPC (26%), PE (2%), and PE_pl (37%) after apheresis was significantly lower in comparison to LDL-C reduction, but not statistically different from HDL-C decrease. While the group of PC-species declined uniformly during apheresis, changes in particular LPC-, Cer-, and SM-species revealed significant differences, reflecting their differential distribution in lipoprotein particles and blood cells. We conclude that the acute effect of lipid apheresis on serum lipidome could be predominantly attributed to lipoprotein changes, while blood cell damages during this procedure caused additional, less pronounced changes. The importance of specific changes in particular lipid species remains to be established.

LDL apheresis improves deranged cardiovagal modulation in hypercholesterolemic patients

OBJECTIVE Hypotensive episodes are relatively frequent adverse effects during LDL apheresis. To evaluate the impact of LDL apheresis on autonomic cardiovascular control we investigated hypercholesterolemic patients before and after a single LDL apheresis in comparison to an age-matched control group. METHODS We continuously recorded systemic arterial blood pressure, electrocardiogram and respiration in 21 hypercholesterolemic patients (57 ± 15 years) on regular LDL apheresis treatment and 22 healthy control subjects (56 ± 4 years) during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt). Baroreflex sensitivity and frequency spectra of R-R intervals and systolic blood pressure were evaluated by trigonometric regressive spectral analysis. RESULTS Hypercholesterolemic patients had reduced resting baroreflex sensitivity and high-frequency power of heart rate variability compared to controls. Consequently, there was a sympathetic predominance of heart rate modulation reflected by increased ratio of low-to-high frequency power of R-R intervals. Cardiovascular stimulation failed to adequately activate baroreflex mechanisms before LDL apheresis. After LDL apheresis, the parasympathetic response to cardiovascular stimulation improved and sympathetic outflow to peripheral vasculature was reduced. Baroreflex sensitivity remained low. CONCLUSION Hypercholesterolemic patients on regular LDL apheresis treatment have significant autonomic dysfunction. A single LDL apheresis does not evoke sympathetic overactivation but improved deranged cardiovagal heart rate modulation in hypercholesterolemia.

An elevated lipoprotein(a) plasma level as a cardiovascular risk factor

INTRODUCTION The causal association of elevated lipoprotein(a) (Lp(a)) plasma levels with the increased cardiovascular risk is still controversial and presently there are no standard recommendations on managing of hyperLp(a)emia. Our retrospective analysis is aimed to explore the Lp(a) thresholds, the magnitude of various cardiovascular risk factors and their combinations. METHODS The files of 544 outpatients from our Outpatient Department of Lipid Disorders were divided into quintiles with respect to Lp(a) levels and reviewed regarding age, gender, Body Mass Index, dyslipidemias, arterial hypertension, diabetes mellitus, smoking and incidence of vascular events in coronaries, carotids and lower extremities. Furthermore we built 15 small quantiles to identify the Lp(a) threshold more precisely. RESULTS The incidence odds ratio for cardiovascular events rose from 2.65 in the 2nd quintile with Lp(a) 483-821 mg/L to 6.36 in the 5th quintile (Lp(a) ≥ 1495 mg/L). The relative risk of cardiovascular events was 0.08 in subjects with a Lp(a) level under 232 mg/l and 3.6 at Lp(a) ≥ 315 mg/L. The magnitude of the combination of elevated Lp (a) with arterial hypertension factor exceeded that of gender, age and combination of arterial hypertension with smoking. CONCLUSIONS A Lp(a) plasma level of higher than about 300 mg/L seems to be a threshold for occurring of cardiovascular events. The combination of raised Lp(a) with arterial hypertension was found to be the most important cardiovascular risk factor. Lp(a) levels under 232 mg/L appeared to be a marker for good prognosis.

Immunoadsorption Followed by Rituximab as a Definitive Treatment for Insulin Autoimmune Syndrome (Hirata Syndrome): A Case Report

A 59-year-old Caucasian man (170 cm, 78 kg, BMI 27 kg/m2) was referred for evaluation of recurrent episodes of severe hypoglycemia, which had commenced a week earlier. Computed tomography and MRI scans excluding abnormalities of the pancreas had already been performed. The patient had previously suffered from arterial hypertension, hyperlipoproteinemia, and an acute myocardial infarction the year before. Pharmacological therapy consisted of a β-receptor antagonist, a statin, low dose aspirin, clopidogrel, and vitamin D. Importantly, there was no history of alcohol abuse or diabetes and no previous exposure to antidiabetes medication (Fig. 1). Upon admission, the patient showed a sustained need for intravenous glucose supplementation with repetitive symptomatic declines of blood glucose to levels of relevant hypoglycemia (<2.5 mmol/L) immediately after discontinuation of parenteral glucose. Figure 1 Serum parameters in relation to the course of treatment. Results of IAB, protein, and IgG are depicted in the graph during the …

Successful and well-tolerated bi-weekly immunoadsorption regimen in pemphigus vulgaris

BACKGROUND Pemphigus vulgaris is a chronic autoimmune disease characterized by blisters and erosions forming in the mucous membranes and the skin. Many patients are severely impaired by pain, weight loss and increased risk of infections. The disease is mediated by specific autoantibodies directed against desmogleins that contribute to connect keratinocytes in the epidermis. Autoantibody deposition in the skin causes inflammation and intraepidermal akantholysis. The concentration of autoantibodies in serum correlates with disease activity. Therefore, the removal of autoantibodies by immunoadsorption is a targeted therapeutic intervention for patients with pemphigus vulgaris. PATIENTS AND METHODS A total of 9 patients with pemphigus vulgaris resistant to the standard treatment regimen were treated by immunoadsorption using the TheraSorb™-Ig adsorber system and analyzed retrospectively. Patients received immunoadsorption on two or four consecutive days. Cycles were repeated every two or four weeks, respectively. Treatment was performed for a mean period of 17.5 months (range 6-26). Outcome was measured as improvement in clinical disease analyzed by the investigators global assessment and the reduction of autoantibodies in serum measured by indirect immunofluorescence and ELISA. Tolerability of treatment by patients was evaluated using a visual analog scale. RESULTS Retrospective analysis of 9 patients consecutively treated by immunoadsorption revealed an 80% reduction of the autoantibody concentration in serum after 6 months of treatment, led to a clinical improvement of disease in combination with classical immunosuppression. Steroid consumption could be reduced by 50% after 30 and 75% after 90 days. Therapy resulted in a total response rate of 89%, with 56% of patients reaching partial and 33% complete remission. The bi-weekly treatment regimen resulted in effective improvement of disease and was in favor to the 4-weekly regimen by the subjective judgment of tolerability by the patients. CONCLUSION Immunoadsorption for the treatment of pemphigus vulgaris is safe and effective. The good tolerability of a bi-weekly treatment regimen shown here might be a valuable therapeutic option in further studies defining the optimal frequency of immunoadsorption required in treatment of pemphigus.

Hypertriglyceridemia in an outpatient department – Significance as an atherosclerotic risk factor

BACKGROUND Although a relationship between elevated triglycerides (TG) and cardiovascular diseases is generally accepted, its extent is still discussed. This retrospective study analyzed the incidence of cardiovascular events (CVE) and pancreatitis as well as the therapeutic regimen in patients being treated for hypertriglyceridemia (HTG) at an outpatient department. METHODS The cohort included 183 patients with mild and 49 patients with severe HTG; subgroups were formed and compared according to gender, presence of metabolic vascular syndrome (MVS) and lipid values. RESULTS Patients in this study seem to have had CVE at younger age than reported event rates in the general population. TG levels, rates of CVE and pancreatitis were reduced in all groups during therapy, which could be linked to use of omega-3 fatty acids and fibrates. Patients with persisting severe HTG as a result of incompliance showed massive risk for pancreatitis. CONCLUSION Although no significant association between TG levels and CVE could be established, the combination of HTG and other cardiovascular risk factors such as MVS seems to be especially dangerous. The lipid-lowering drug therapy appeared to be effective with respect to CVE and pancreatitis incidence.

LIPOPROTEIN APHERESIS: YESTERDAY, TODAY, TOMORROW. REVIEW

The first attempts to treat patients with homozygous familial hypercholesterolemia (HCH) were performed in the 60ies and 70ies using a total plasma exchange. Later on, more specific lipoprotein apheresis (LA) methods have been developed – the replacement with foreign proteins was no longer necessary. It could be demonstrated that LA is life-saving in these patients, lipid-lowering drugs were shown to be much less effective than in other HCH patients. A severe HCH became an accepted indication for LA when cardiovascular events appeared. An elevation of Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Thus, an increasing number of patients with high Lp(a) concentrations suffering from life-threatening cardiovascular events like a myocardial infarction or a stroke started to be treated extracorporeally. Russian specific Pocard R anti-Lp(a) columns are produced, their position within the LA methods is discussed. In the future, an antisense oligonucleotide against apolipoprotein(a) will represent another therapeutic option.

How effectively will PCSK9 inhibitors allow retrieval of freedom from apheresis in cardiovascular high risk patients? – Estimates form a large single center

Lipoprotein apheresis (LA) has been the last-resort therapeutic option in patients suffering from limited pharmaceutical options to lower highly elevated low density lipoprotein cholesterol (LDL-C) levels. Facing the introduction of the proprotein convertase subtilisin/kexine type 9 (PCSK-9) inhibitors, it has been speculated that they might replace LA to a large extend. Given an efficacy of approx. 55-65% to lower LDL-C it is important to analyze whether this might be realistic i) for potential candidates in apheresis sites and ii) for the future structures of the sites themselves. We performed a review of our own single center, one of the largest apheresis centers in Germany to answer these questions. Therefore we analyzed all actively treated apheresis patients and identified those with the primary indication of LDL-C elevation. In a next step we used pre-apheresis LDL-C values to calculate expected LDL-C under three given models of PCSK9 inhibitor efficacy. Including other aspects such as the accompanying presence of elevated lipoprotein(a), we identified 11-17 patients among 29 patients undergoing treatment for insufficiently treated LDL-C (38-58%). In the total cohort of 112 patients this reflects 10-15% of all patients that might potentially stop apheresis therapy due to the availability of PCSK9 inhibitor therapy, which is in clear contrast to speculations on the future perspective of apheresis therapy.