[State of the art: lipoprotein apheresis]. / State of the Art: Lipoproteinapherese.

Lipoprotein apheresis (LA) is usually a last resort in cardiovascular high-risk patients in the context of secondary prevention after lifestyle measures and maximal pharmacotherapy have failed to prevent the occurrence of new atherosclerotic cardiovascular events (ASCVDE) or to achieve the internationally accepted target values for LDL cholesterol (LDL-C). Patients with homozygous familial hypercholesterolemia (hoFH), in whom myocardial infarctions can occur even in children < 10 years of age without adequate therapy, often owe their survival to LA (used here in primary prevention). Severe hypercholesterolemia (HCH) can often be well controlled with modern potent lipid-lowering agents, including PCSK9 approaches, so that the need for LA has decreased here over the years. In contrast, the number of patients in whom elevation of lipoprotein(a) (Lp(a)) is relevant to atherogenesis is increasing in applications to the apheresis committees of the associations of panel physicians (KV). For this indication, LA is currently the only therapeutic procedure approved by the Federal Joint Committee (G-BA). LA significantly reduces the new occurrence of ASCVDE (comparison with the situation before the start of LA), especially in Lp(a) patients. There are convincing observational studies and a German LA Registry with now 10-year data, but there is no randomized controlled trial. This had been requested by the G-BA in 2008, and a corresponding concept was designed but not accepted by the ethics committee. In addition to the highly effective reduction of atherogenic lipoproteins, many discussed pleiotropic effects of LA itself, the medical rounds and motivating discussions also with the nursing staff, which take place within the weekly LA, certainly contribute to the success of the therapy (steady adjustment of all cardiovascular risk factors, lifestyle measures including smoking cessation, adherence of medication intake). This review article summarizes and discusses the study situation, clinical practical experience as well as the future of LA against the background of the currently rapid development of new pharmacotherapies.

A familial hypercholesterolemia registry as the main tool for adequate management of the disease.

Familial hypercholesterolemia (FH) is the most common, but poorly diagnosed autosomal-dominant genetic disease which increases the cardio-vascular risk. AIM: To evaluate the experience of FH registry conducted in Karelia Republic. METHODS: FH registry in Karelia is existing from 2004, it includes 350 patients with heterozygous FH (110 with definite FH), the mean age is 48 ± 2.3 years. The genetic study was performed in 102 patients (29.1%). RESULT: The creation of the registry has contributed to the active identification of FH, and now the estimated frequency of FH occurrence in Karelia may be 1:300, in patients with cardiovascular disease 1:10. We also analyzed genetic features of FH in our republic and found that the LDL-C level, above which the probability of LDL receptor mutation increases in Karelia, is 6.5 mmol/L. We analyzed risk factors of ischemic heart disease and the prognosis in FH. CONCLUSION: The creation and maintenance of a registry is an effective way of organizing timely diagnosis and adequate treatment of FH patients.

The State of the Problem of Achieving Extremely Low LDL Levels.

Patients who have achieved very low low-density lipoprotein CH (LDL-C) levels in clinical trials have shown the lowest cardio-vascular risk. The current clinical guidelines set such a concentration for LDL-C as < 1.4 mmol/L. However, the question of minimum permissible target values of the lipids remains unresolved. A number of experimental and clinical studies showed some unfavorable consequences of low LDL-C levels At the same time, the modern arsenal of lipid lowering drugs allows reducing LDL-C levels to extremely low values. This review presents an analysis of literature about the safety of low lipid spectrum parameters.

Metabolic and Non-Metabolic Peripheral Neuropathy: Is there a Place for Therapeutic Apheresis?

As the rate of obesity and the incidence of diabetes mellitus have been increasing, diabetic neuropathy has become the most common cause of peripheral neuropathy in developed countries. In addition, a variety of pathogenetically heterogeneous disorders can lead to impairment of the peripheral nervous system including amyloidosis, vitamin deficiencies, uremia and lipid disorders, alcohol abuse, autoimmune and infectious diseases as well as exposure to environmental toxins. We have noted that a combination of these disorders may aggravate the manifestations of peripheral diabetic neuropathy, an effect, which is most pronounced when metabolic and non-metabolic pathologies lead to cumulative damage. Current treatment options are limited and generally have unsatisfactory results in most patients. Therapeutic apheresis (INUSpherese®) allows the removal of metabolic, inflammatory, immunologic and environmental contributors to the disease process and may be an effective treatment option. We reviewed the developments in therapeutic apheresis for metabolic and non-metabolic peripheral neuropathy, including the current literature as well as data from our university diabetes center.

Efficiency and problems of statin therapy in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is associated with a very high risk of cardiovascular complications and the need for an early aggressive lipid-lowering therapy. The achievement of lipid target levels is often an extremely difficult task in these patients. AIMS: to analyze sex and age structure of ischemic heart disease (IHD) in patients with a definite, possible and probable FH. to assess the degree of achievement of low density lipoprotein cholesterol (LDL-C) target levels in FH patients on statin therapy and complications that occur during therapy; to analyze the adherence of FH patients to statin therapy and reveal the factors which have an influence on it. MATERIALS AND METHODS: The analysis of IHD clinical characteristics was performed in 253 FH patients from Karelian register, mean age 52.5 years (confidence interval, CI 22.0; 78.0). Using Dutch Lipid Clinic Network Criteria (DLCN), we established the diagnosis of FH as "definite" if the total number of points was more than eight, "probable" - if the number of points was 6-8, "possible" if the number of points was 3-5. The diagnosis was considered to be excluded if the score was less than three. A definite FH was diagnosed in 96 patients. For the evaluation of target LDL-C levels achievement on statin therapy we analyzed data from 191 FH patients (75 males). For the evaluation of adherence to statin therapy Morisky-Green questionnaire was used in 93 definite FH patients. RESULTS: In the group with a definite FH the incidence of IHD in the age range from 39 to 60 years was higher in women than in men (50% and 39.4%, p > 0.05), in patients older than 60 years IHD was observed in 66.7% of women and 50% of men (p > 0.05). In general, in the group with a definite FH, the frequency of IHD was more than three times higher in the age group over 40 years compared with patients under 40 years. 57% of patients with a definite FH were adherent to lipid-lowering therapy, 16% had partial adherence and no adherence to therapy was documented in 27% of patients. The achievement of LDL-C target levels was 19.2%: 22.6% in definite FH group and 12.5% in possible FH. Smoking and gender were not associated with adherence to statin therapy. Associated factors with increased adherence to statin therapy were age (p = 0.000003), arterial hypertension (OR = 1.90 (1.02; to 3.55), p = 0.044), the history of IHD (OR = 2.99 (1.50; of 5.97) p = 0.002), myocardial infarction (OR = 5.26 (2.03; 13.60), p = 0.0006), myocardial revascularization (OR = 20.3 (2.64; 156.11), p = 0.004) and the fact of target LDL-cholesterol levels achievement (OR = 19.93 (7.03; 56.50), p < 0.0001). The main reason for the non-acceptance of statin therapy for FH patients was the fear of side effects in 87%. The main reasons for stopping current statin intake were myalgia in 12%, an increase in transaminases in 35%, skin rashes in 12%, and high cost in 6%. 29% of patients had made the decision to stop therapy themselves. CONCLUSIONS: the frequency of IHD in FH patients was more than three times higher in the age group over 40 years and was higher in women. In clinical practice statin therapy in FH patients rarely reaches target lipid values, one of the reasons was low adherence to statin therapy.

Cardiovascular risk factors in patients with premature cardiovascular events attending the University of Dresden Lipid Clinic.

OBJECTIVES: Despite improved treatment, premature cardiovascular (CV) events remain a major health problem. Aim of this study was to evaluate the patterns of risk factors in patients with premature CV events. METHODS: CV risk factors (CVRF) were evaluated in 130 patients with a history of CV events (myocardial infarction, stroke, limb ischemia, stent and bypass intervention in any vessel bed) under 50 years of age attending our lipid clinic. Patients were also stratified according to their Lp(a) concentrations: group 1: 0-45 nmol/l (<18 mg/dl); group 2: >45-120 nmol/l (>18-50 mg/dl); group 3: >120 nmol/l (>50 mg/dl). RESULTS: The most common risk factors in our patients were male sex (75%), current (61%) and previous smoking (9%), arterial hypertension (70%), and a positive family history of early CV events (54%) and hyperlipidemia (69%). Only 27% had a BMI >30 kg/m2 and 14% had diabetes mellitus. 69% of patients with premature CV disease (CVD) showed Lp(a) levels > 120 nmol/l (>50 mg/dl). Patients with the highest Lp(a) showed a tendency of more frequent positive family histories of hyperlipidemia. They had experienced their first CV event on average 3 years earlier than those with low Lp(a). CV events predominantly involved coronary arteries. 85% of patients experienced at least one coronary event. CONCLUSION: In patients with premature CV disease male sex, smoking, hypertension, a positive family history and elevated Lp(a) are the most important CV risk factors. Lp(a) should be considered in the management of young patients with CV disease.

Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: The CaReHigh Registry.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is amongst the most common genetic disorders encountered in primary care. Yet, only a minority of affected patients is diagnosed and treated. This interim analysis of the CaRe High Registry aims at examining the state of treatment and attainment of lipid goals in German FH patients. METHODS: The CaRe High registry includes FH patients from lipid clinics and private practices. Data have been collected using questionnaires filled in by the recruiting physicians and by interviewing the participating patients. RESULTS: We examined 512 F H patients diagnosed according to clinical criteria. Median age at the time of the first FH diagnosis was 39 (25th and 75th percentile: 27-50) years, median treatment naïve LDL cholesterol (LDL-C) was 239.4 mg/dl (6.19 mmol/l), 25th to 75th percentile 191.8-342.5 mg/dl (4.96-8.86 mmol/l). 27% of the participants did not receive lipid-lowering drugs. Among the patients treated with lipid-lowering drugs, 19% received a PCSK9 inhibitor (PCSK9i) in combination with a statin, 9% were treated with a PCSK9i alone and 3% were treated with a combination of PCSK9i and a non-statin drug. Patients with pre-existing CVD were more likely to be treated with lipid-lowering drugs and more likely to receive a PCSK9i, but LDL-C targets were only achieved by a minority of patients (<20%). Gap to target LDL-C was lowest and the median achieved LDL-C reduction was 1.4 times higher with PCSK9i treatment than with (oral) lipid-lowering therapy without PCSK9i. CONCLUSIONS: The Care High registry has included patients with the typical clinical features of familial hypercholesterolemia. PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C.

Rationale and design of MultiSELECt: A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by lipoprotein apheresis on Cardiovascular outcomes.

BACKGROUND: Dyslipidemia is a well-known risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). While low density lipoprotein cholesterol (LDL-C) is well-established and taken into consideration for risk management and therapy, lipoprotein(a) is another established CVD risk factor frequently not undergoing screening due to a lack of medical treatment options. For patients suffering from CVD due to massive elevation of Lp(a) in presence of normal LDL-C levels, lipoprotein apheresis is the only available treatment option. While this constellation is an accepted indication for lipoprotein apheresis (LA) in Germany, prospective studies including a control group are still lacking. OBJECTIVE: Primary objective of this trial is to evaluate the clinical benefit of lipoprotein apheresis on myocardial infarction, PCI, CABG and death from cardiovascular disease in subjects with elevated Lp(a). This study evaluates the clinical benefit of weekly LA in subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee (treatment group). Comparator will be well-matched subjects under maximum tolerated lipid lowering therapy without access to LA treatment (control group). METHODS: MultiSELECt, is a prospective, multicenter, multinational, two-arm matched-pair cohort study designed to directly compare subjects with significantly elevated Lp(a) approved for LA subsequently undergoing weekly apheresis treatment versus a continuation of maximal medical therapy. The follow-up period will be 2 years after the baseline visit and until at least 60 events of the primary end-point occurred in the control group. A central trial expert committee will review all subjects with respect to their potential indication for LA according to established German guidelines in a blinded fashion. All control subjects will be contacted monthly via telephone visits to compensate for the more frequent visits during apheresis. Approximately 150 matched pairs will be necessary to detect an event reduction of at least 10% in subjects under LA treatment. CONCLUSION: The MultiSELECt trial provides the unique opportunity to demonstrate the efficiency of LA on CVD in patients with elevated Lp(a) under strongly controlled conditions.

Analysis of lipid metabolism and its impact on the risk of ischemic heart disease in patients with definite familial hypercholesterolemia.

AIM: to analyze the relationship between lipid disturbance, including lipoprotein(a) (Lp(a)) levels, and development of ischemic heart disease (IHD) in patients with familial hypercholesterolemia (FH). MATERIALS AND METHODS: 81 patients (middle age was 39.1 ± 0.4 years, 33 males, 48 females) with a definite FH were examined. The concentration of Lp(a) was determined by immunoturbidimetric method. Lipid profiles were estimated by enzymatic colorimetric method. RESULTS: Lp(a) levels were elevated in 41.9% of FH patients. In FH patients with elevated Lp(a) (>0.3 g/l) IHD occurred 1.7 times more often, myocardial infarction - 2.76 times. The risk of IHD in FH patients was increased in individuals with Lp(a) 1.2 g/l and above. CONCLUSION: Lp(a) elevation plays an additional role in IHD appearance in FH.

CaRe high - Cascade screening and registry for high cholesterol in Germany.

INTRODUCTION: Familial hypercholesterolemia (FH) is an inherited disorder of the LDL metabolism, leading to cardiovascular disease, even at young age. This risk can be significantly lowered by early diagnosis and treatment. About 270,000 patients affected in Germany are not diagnosed correctly and only a small number is treated properly. To improve FH diagnosis in the general population a cascade screening and registry data is warranted, yet missing in Germany. This project aims to fill this gap. METHODS: Study assistants approach physicians and lipid clinics to introduce the cascade screening and registry. The physicians identify potential FH patients and include them in the study. Patient data is acquired via questionnaires about medical history. Patients meeting at least two inclusion criteria (LDL-C >190 mg/dl or total cholesterol >290 mg/dl; tendon xanthomas; family history of hypercholesterolemia or early myocardial infarction) are included in the registry. Family members will be contacted and physicians get feedback about diagnosis and treatment options. Ethical approvals for all German states have been collected. RESULTS: So far physicians, lipid clinics and patients within the Rhein-Neckar region, the Saarland, North-Rhine-Westphalia, Upper Bavaria, Bremen, Saxonia and Berlin have joined the study. We expect to include more than 3000 patients during the next two years. CONCLUSION: After initial patient and data collection the project aims to improve FH-diagnosis and treatment. Utilizing registry data might advance diagnostic criteria and improve detection of FH and thus prevent CVD in this population.

Poly(ADP-ribose)polymerase inhibition counteracts cataract formation and early retinal changes in streptozotocin-diabetic rats.

PURPOSE: This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes. METHODS: Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg(-1) d(-1) intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-1 (GPI-15427, 30 mg kg(-1) d(-1) orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate. RESULTS: PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74% and 275%, respectively, after 4 weeks of diabetes and by approximately 65% early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 microM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells. CONCLUSIONS: PARP activation is implicated in the formation of diabetic cataract and in early retinal changes. These findings provide a rationale for the development of PARP inhibitors for the prevention of diabetic ocular complications.

Comparison of different LDL apheresis methods.

This article presents the generally accepted indications for LDL apheresis treatment. The available LDL apheresis methods differ with respect to acute relative reductions of LDL cholesterol; mean values after the LDL apheresis treatments are not different. Serum triglycerides, HDL-cholesterol, and lipoprotein(a) are also acutely reduced. Available LDL apheresis methods differ with respect to their impact on the coagulation system, on C-reactive protein and on leukocyte count. Cardiovascular events are clearly reduced by the LDL apheresis methods. There is an urgent need to prospectively compare the different LDL apheresis methods taking into account hard end points. The lower target values for LDL cholesterol suggested by international guidelines for high-risk patients will certainly require a more widespread use of LDL apheresis.

[Severe progression of coronary heart disease in a patient with elevated lipoprotein (a) level in spite of optimal LDL-C decrease]. / Schwere Progression einer koronaren Herzkrankheit bei einem Patienten mit erhöhtem Lipoprotein-(a)-Spiegel trotz optimaler LDL-C-Senkung.

The patient introduced in the case history had a myocardial infarction in 2001 and a coronary two-vessel disease (extensive subtotal proximal stenosis of the left anterior descending [LAD] and proximal subtotal stenosis of the right coronary artery) which was diagnosed via coronary angiography at the age of 39 years. Besides smoking and obesity an important coronary risk factor was hyperlipoproteinemia with an especially massive increase in lipoprotein (a) level. The lipoprotein (a) level in January 2002 was massively elevated with 273.7 mg/dl (2 737 mg/l; Table 1). Despite invasive therapy with percutaneous transluminal coronary angioplasty (PTCA) and stent implantation in LAD and immediate therapy with atorvastatin, a restenosis in LAD was detected in April 2002 (Figure 1). Re-PTCA and intracoronary brachytherapy were performed (Figure 2). After presentation of unstable angina pectoris symptoms in November 2003, again a new in-stent restenosis in LAD could be detected via coronary angiography (Figure 3a), so that a single-bypass operation became necessary (Figure 3b). Since December 2001, an intensified treatment in a specialized polyclinic for lipid metabolism has been carried out, in which LDL-C values of 104 mg/dl (2.7 mmol/l) were targeted under aggressive lipid-lowering therapy with atorvastatin 80 mg/d and ezetimibe 10 mg/d (Table 1). Since 1998, the patient has quitted smoking. Blood pressure values are now in the therapeutic range, but the obesity could not be overcome.A distinctly elevated lipoprotein (a) level is an important risk factor for an early-onset and badly progressive arteriosclerosis. Thus, once in lifetime in the scope of risk factor management one should measure the lipoprotein (a) level. In case of elevated values the crucial treatment options include a very good management of all other risk factors, whereas an LDL-C level < 100 mg/dl (< 2.6 mmol/l), optionally < 70 mg/dl (< 1.8 mmol/l), is of vital importance. Nicotinic acid derivatives lower lipoprotein (a) levels by about 20-30%. All other risk factors, e.g., diabetes or hypertension, should be strictly managed as well. Cardiologic and angiologic examinations have to be an integral part of the treatment of these patients.