[Primary disorders of lipid metabolism: their place in current dyslipidemia guidelines and treatment innovations]. / Primäre Fettstoffwechselstörungen ­ Stellenwert in aktuellen Dyslipidämieleitlinien und therapeutische Innovationen.

According to current guidelines, the selection and intensity of lipid-effective therapies are based on the risk to be treated. The sole clinical categories of primary and secondary prevention of cardiovascular diseases result in over- and under-treatment, which may be a contributory cause of incomplete implementation of current guidelines in everyday practice. For the extent of benefit in cardiovascular outcome studies with lipid-lowering drugs, the importance of dyslipdemia for the pathogenesis of atherosclerosis-related diseases is crucial. Primary lipid metabolism disorders are characterized by life-long increased exposure to atherogenic lipoproteins. This article describes the relevance of new data for low density lipoprotein-effective therapy: inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), adenosine triphosphate (ATP) citrate lyase with bempedoic acid, and ANGPTL3 with special consideration of primary lipid metabolism disorders, which are insufficiently taken into account, or not taken into account at all, in current guidelines. This is due to their apparently low prevalence rate and thus the lack of large outcome studies. The authors also discuss the consequences of increased lipoprotein (a), which cannot be sufficiently reduced until the ongoing intervention studies examining antisense oligonucleotides and small interfering RNA (siRNA) against apolipoprotein (a) are completed. Another challenge in practice is the treatment of rare, massive hypertriglyceridemia, especially with the aim of preventing pancreatitis. For this purpose, the apolipoprotein C3 (ApoC3) antisense oligonucleotide volenasorsen is available, which binds to the mRNA for ApoC3 and lowers triglycerides by around three quarters.

[Lipid-lowering therapy in the elderly : Who profits from which target values?] / Lipidsenkende Therapie im Alter : Wer profitiert von welchem Zielwert?

Lowering low-density lipoprotein (LDL) cholesterol levels has been proven to reduce the incidence of cardiovascular and cerebrovascular events and mortality. So far recommendations have not provided information as to a meaningful duration of cholesterol-lowering therapy and were largely guided by economic constraints and limited therapeutic options. In light of the decline in the price of statins, the essential therapeutic agent and the increased efficacy of therapeutic options, treatment can nowadays be geared to target values that can be expected to have an optimal effect even in old age. The most favorable level of LDL-cholesterol for primary prevention is around and below 100 mg/dl, provided continuous adherence to these low levels from adolescence onwards. With later onset of cholesterol reduction the existence of initial atheromatous deposits must be expected. Therefore, with age and the manifestation of other risk factors the optimal treatment targets increasingly converge to those for which experience has been gained from secondary prevention. Both measurements of the effect of cholesterol lowering on the volume of atheromatous plaques and of the incidence of vascular events indicate a target for LDL-cholesterol well below 70 mg/dl and in the range 50-60 mg/dl. At the onset of cholesterol lowering in advanced age, a smaller effect has to be expected but due to the increasing incidence rate of vascular events a higher number of events may be avoided; thus, the efficiency does not necessarily decrease; however, long-term studies indicate that earlier cholesterol lowering provides an advantage for more than a decade, in terms of preventing vascular disease, which tends to increase. Therefore, optimal cardiovascular prevention involves moderate measures to maintain the LDL-cholesterol below 100 mg/dl lifelong from childhood on.

[Introduction of PCSK9 inhibitors : New perspectives in treatment and practical implementation]. / Einführung der PCSK9-Inhibitoren : Neue Perspektiven in der Behandlung und praktische Umsetzung.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is of critical importance in the regulation of the low-density lipoprotein (LDL) receptor-mediated metabolism of cholesterol. The discovery of mutations in the gene encoding PCSK9 in families with an autosomal dominant form of familial hypercholesterolemia (FH), which were later shown to be "gain-of-function" mutations, led to the development of antibodies against PCSK9. The efficacy in markedly reducing levels of LDL-cholesterol and preliminary evidence for benefits in the prevention of cardiovascular diseases indicated that special groups of patients can be more effectively treated. This includes forms of hypercholesterolemia refractory to conventional treatment as well as patients with FH and/or statin intolerance. Further information on long-term efficacy, tolerability and cost-effectiveness of PCSK9 inhibition and possibilities of implementation in the healthcare system are awaited from ongoing clinical outcome trials, such as FOURIER, ODYSSEY OUTCOMES, SPIRE 1 and 2 involving more than 70,000 high-risk patients.

[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

FTIR spectroscopy study of the pressure-dependent behaviour of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1-palmitoyl-2-oleolyl-sn-glycero-3-phosphocholine (POPC) at low degrees of hydration.

High-pressure investigations of phospholipids at low degrees of hydration are highly important due to the continuous interest in hydration related phenomena. This is for instance the case when discussing differences between the molecular behaviour under hydrostatic or hydration pressure, e.g. to characterise the structural and thermodynamic conditions that hold for the different theoretical approaches proposed in the literature. The stability of phospholipid aggregates in aqueous solutions is determined by a balance of attractive end repulsive forces as well as entropic and energetic interactions. The pressure-dependent variation of the frequency of molecular vibrations determined by FTIR spectroscopy might be an appropriate tool to study the nature of these interactions as well as of conformational changes for various degrees of hydrations. The paper reports preliminary results for the stretching and bending vibration of the CH2 groups that are mainly situated in the hydrocarbon chains. In a hydration range of about 2 water molecules per lipid in the case of DOPC and 6 water molecules for POPC, the pressure-dependent vibrations in the liquid crystalline phase change between red shift and blue shift. A further interesting parameter is the onset pressure for the correlation field splitting. It increases with dehydration, and it is assumed that the correlation field splitting does not only depend on the disorder related to the gauche conformer population in the hydrocarbon chains but also on the chain tilt in the gel phase.

Hydration behaviour of POPC/C(12)-Bet mixtures investigated by sorption gravimetry, (31)P NMR spectroscopy and X-ray diffraction.

The hydration behaviour of mixtures of the zwitterionic phospholipid 1-palmitoyl-2-oleolyl-sn-glycero-3-phosphocholine (POPC) and the zwitterionic surfactant N,N-dimethyl-N-dodecyl-betain (C(12)-Bet) was investigated by sorption gravimetry, solid-state (31)P NMR-spectroscopy and small angle X-ray diffraction (SAXD). Negative excess hydration (dehydration) was found for almost all hydration degrees investigated. This behaviour is explained by the formation of an inner salt between the dipoles of phospholipid and surfactant headgroups that show a reverse sequence of partial charges with respect to the hydrocarbon backbone. The formation of an inner-salt most probably reduces potential water binding sites. Moreover, NMR data suggest that the incorporation of the zwitterionic surfactant into the phospholipid membrane is correlated with reorientation of the phosphate axis towards the membrane director as well as with reduced lateral and wobbling diffusion.

[Optimal lipid treatment: possibilities and current limitations]. / Möglichkeiten und Grenzen der modernen Lipidtherapie.

Prevention is a major contributor to the decline in cardiovascular morbidity and mortality. Cardiovascular diseases still are the leading cause of death (42%) in Germany and indicate unmet preventive needs. Limitations of healthy lifestyle, the basis of many recommendations, include insufficient compliance and efficacy in individual cases. In their latest metaanalysis the Cholesterol Treatment Trialists' Collaborators showed updated estimates of treatment effects of statins including more or less intensive regimens.The average reduction in major vascular events was 21% per 1.0 mmol/l reduction in LDL cholesterol. Appropriateness of receiving lipid modulating treatment in the population will be discussed in the light of controversial recommendations in treatment strategies. Residual risk in statin treated patients may be ameliorated by options beyond LDL-lowering. Suggestions for clinical practice are provided on the background of clinical relevant characteristics of current lipid lowering drugs and future developments are outlined.

Thermodynamic and structural behaviour of equimolar POPC/CnE4 (n=8, 12, 16) mixtures by sorption gravimetry, 2H NMR spectroscopy and X-ray diffraction.

The hydration behaviour of equimolar mixtures of phospholipids and nonionic surfactants with different chain length was investigated by gravimetric sorption, NMR spectroscopy and X-ray diffraction. At the most hydration degrees investigated, the incorporation of nonionic surfactants in a phospholipid bilayer leads to an increase of the hydrophilicity, which can be shown by the presence of excess hydration. The increased hydrophilicity could be explained by the excavation of additional water binding sites due to the "dilution" of the dipole field of the phospholipid bilayer. Another related contribution arises from the increase of the accessible surface area due to the increase of gauche conformers that result from the steric mismatch when surfactants are incorporated into the phospholipid matrix. (2)H NMR spectroscopy was used to determine the quadrupolar splitting representing a measure of the order state of water. The swelling behaviour could be assessed by small-angle X-ray diffraction. (31)P NMR spectroscopy was applied for the assignment of phase structures to the respective hydration range.

Thermotropic phase behaviour of the pseudobinary mixtures of DPPC/C12E5 and DMPC/C12E5 determined by differential scanning calorimetry and ultrasonic velocimetry.

The present paper reports on the phase behaviour of the pseudobinary aqueous mixtures of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/pentaethylene glycol monododecyl ether (C12E5) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine monohydrate (DMPC)/C12E5. Both systems exhibit a variety of mesophases, such as lamellar gel, liquid crystalline and micellar phases. The phase diagrams show peritectic and eutectic behaviours. The existence of a compound complex is established. From the phase diagrams, the temperature dependence of the solubilisation parameters is obtained. The phase diagrams, especially with respect to the solubilisation process were qualitatively explained assuming that the packing of the constituents plays a dominating role. Finally, differential scanning calorimetry and ultrasonic velocimetry are compared concerning their potentials to determine characteristics of phase transitions in pseudobinary phospholipid/surfactant mixtures.