Targeting LDL Cholesterol: Beyond Absolute Goals Toward Personalized Risk.

PURPOSE OF REVIEW: The aim of this study was to review and assess the evidence for low-density lipoprotein cholesterol (LDL-C) treatment goals as presented in current guidelines for primary and secondary prevention of cardiovascular disease. RECENT FINDINGS: Different sets of guidelines and clinical studies for secondary prevention have centered on lower absolute LDL-C targets [<70 mg/dL (<1.8 mmol/L)], greater percent reductions of LDL-C (≥50%), or more intense treatment to achieve greater reductions in cardiovascular risk. Population-based risk models serve as the basis for statin initiation in primary prevention. Reviews of current population risk models for primary prevention show moderate ability to discriminate [with c-statistics ranging from 0.67 to 0.77 (95% CIs from 0.62 to 0.83) for men and women] with poor calibration and overestimation of risk. Individual clinical trial data are not compelling to support specific LDL-C targets and percent reductions in secondary prevention. Increasing utilization of electronic health records and data analytics will enable the development of individualized treatment goals in both primary and secondary prevention.

Lipoprotein(a)-clinical aspects and future challenges.

Lipoprotein(a) (Lp(a)) was first described by K. Berg and is known for more than 50 years. It is an interesting particle and combines the atherogenic properties of low-density lipoprotein (LDL)-cholesterol as well as the thrombogenic properties of plasminogen inactivation. However, due to technical problems and publication of negative trials the potential role of Lp(a) in atherosclerosis was severely underestimated. In recent years our understanding of the function and importance of Lp(a) improved. Interventional trials with niacin failed to demonstrate any benefit of lowering Lp(a); however, several studies confirmed the residual cardiovascular disease (CVD) risk of elevated Lp(a). LDL/Lp(a) apheresis is able to lower Lp(a) and some new drugs under development should help us to lower Lp(a) in the near future. It will be important to follow this with hard endpoint trials. Until then most clinicians recommend the use of an aggressive LDL-lowering approach in patients with high Lp(a). Since most of these patients with high Lp(a) might have manifested atherosclerosis anyway, we would also consider the use of acetylsalicylic acid.

Impact of the German Lipoprotein Apheresis Registry (DLAR) on therapeutic options to reduce increased Lp(a) levels.

BACKGROUND: The German Lipoprotein Apheresis Registry (DLAR) has been initiated by members of the Nephrology Foundation (WiNe), the German association of kidney centres (DN), the German society of nephrology (DGfN) and additional medical associations taking part in the apheresis working group. Its goal is the introduction of a substantial database, suitable to provide statistical evidence for the assessment of extracorporeal procedures. Data have been added to the DLAR since October 2011. In this article, preliminary results are first reported. METHODS AND RESULTS: Data are stored on a secured Internet platform. The recorded information comprises mean values and rates of change in lipid levels (cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, lipoprotein(a) (Lp(a)) before and after apheresis therapy, blood/plasma volume, frequency and type of adverse effects, medication, vascular events, diagnoses and comorbidity. It is collected by participating apheresis centres from all over Germany. Up until October 2014, a total of 7946 lipoprotein apheresis (LA) treatments of 991 patients (787 with documented LDL-C and 688 with documented Lp(a) levels) via 96 medical accounts were documented and analysed. The current share of Lp(a) patients is 50.6 % (Lp(a) ≥ 60 mg/dl; n = 348/688). For both LDL-C and Lp(a), lowering rates exceeding 60 % have been observed. Likely in conjunction with these reduction rates, the preliminary analysis shows a 90 % decline in major adverse coronary events (MACE) as well as a decrease in major adverse non-coronary events (MANCE) by 69 %. As before, good tolerability and low rates of adverse effects (< 3 %) of LA therapy were found. CONCLUSIONS: The available numbers suggest in parts very good response by the participating centres to the DLAR. Unfortunately, there are also centres that have not documented any patients so far or LA treatments at all. The benchmark values for reduction rates in lipoprotein concentration required by the directives of the German Federal Joint Committee (G-BA) have all been met. The decrease in MACE and MANCE rates currently observed is very promising. However, the comparably short runtime of the registry does not allow for high confidence in the current results. Certainly, reliable data will be extractable in the coming years. Given the high interest expressed by European neighbours, the extension of the registry to the European level should be a future goal for the DLAR as well.

Indications for apheresis as an ultima ratio treatment of refractory hyperlipidemias.

Lipid apheresis is at present well established in routine treatment of diverse hyperlipoproteinemias refractory to conventional dietary and medical regimens, especially in countries with high medical and socioeconomic standards. Severe familial hypercholesterolemia with atherosclerotic vessel disease involving the coronary arteries is the most frequent indication for lipid apheresis as well as homozygous familial hypercholesterolemia before the development of cardiovascular complications.In hyperlipoproteinemia (a) with progressive vessel disease, lipid apheresis is regularly accepted in Germany. The indication of apheresis in Refsum's disease and the chylomicronemia syndrome is described.

Changes in low-density lipoprotein cholesterol levels after discharge for acute myocardial infarction in a real-world patient population.

Aggressively managing low-density lipoprotein cholesterol (LDL-C) after myocardial infarction (MI) is a cornerstone of secondary prevention. The changes in LDL-C after MI and the factors associated with LDL-C levels are unknown. Therefore, we directly measured fasting LDL-C levels in 797 MI patients from 24 US hospitals from 2005 to 2008. Mean LDL-C levels at discharge, 1 month, and 6 months were 95.1, 81.9, and 87.1 mg/dL, respectively. In a hierarchical, multivariable, repeated measures model, older age, male sex, and hypertension were associated with lower LDL-C levels, whereas self-reported avoidance of health care because of cost was associated with higher LDL-C. Both the presence and intensity of statin therapy at discharge were strongly associated with LDL-C levels, with adjusted mean 6-month changes of -3.4 mg/dL (95% confidence interval (CI): -12.1, 5.3) for no statins; 1.7 mg/dL (95% CI: -4.7, 8.1) for low statins; -10.2 mg/dL (95% CI: -14.5, -6.0) for moderate statins; and -13.9 mg/dL (95% CI: -19.7, -8.0) for intensive statins (P < 0.001). In conclusion, we found that greater reductions in LDL-C levels after MI were strongly associated with the presence and intensity of statin therapy, older age, male sex, hypertension, and better socioeconomic status. These findings support the use of intensive statin therapy in post-MI patients and provide estimates of the expected LDL-C changes after MI in a real-world population.

Hypolipidimic and antioxidant activities of virgin olive oil and its fractions in 2,4-diclorophenoxyacetic acid-treated rats.

OBJECTIVE: We examined the effects of extra virgin olive oil (EVOO) and its hydrophilic and lipophilic fractions on serum lipids, oxidative stress, and morphologic and functional liver damages induced by 2,4-diclorophenoxyacetic acid (2,4-D). METHODS: Male Wistar rats were divided randomly into eight groups: control; 2,4-D at a dose of 5 mg/kg of body weight (2,4-D); 2,4-D plus EVOO (2,4-D/EVOO); 2,4-D plus the hydrophilic fraction (2,4-D/OOHF); 2,4-D plus the lipophilic fraction (2,4-D/OOLF); only EVOO (EVOO); only the hydrophilic fraction (OOHF); and only the lipophilic fraction (OOLF). These components were administered daily by gavage for 4 wk. RESULTS: A hepatic architecture aberration, increased activities of aspartate and alanine aminotransferase enzymes, total and low-density lipoprotein cholesterol, and malondialdehyde (MDA) level, and a decreased antioxidant defense system were observed in the 2,4-D group. The administration of EVOO restored the damage caused by 2,4-D by a significant decrease of plasma total and low-density lipoprotein levels and a moderate increase of high-density lipoprotein cholesterol. The 2,4-D/OOHF group exhibited a pronounced enhancement of the antioxidant defense system by an increase of superoxide dismutase, catalase, and glutathione peroxidase levels and a decrease of plasma and liver MDA levels. However, less improvement in the liver histoarchitecture and antioxidant status was observed in rats supplemented with OOLF diet, despite its richness in α-tocopherol. CONCLUSION: Extra virgin olive oil may be a potential functional food source of antioxidants than can decrease the frequency of cardiovascular diseases and liver damage.

Effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein, lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia.

Inflammation, oxidative stress, and high concentration of serum lipoprotein (a) [Lp (a)] are common complications in hemodialysis patients. The present study was designed to investigate the effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein (CRP), Lp (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia [hyper Lp (a)]. This was an unblinded, randomized clinical trial. Thirty-six hyper Lp (a) hemodialysis patients (23 men and 13 women) were randomly assigned to either a carnitine or control group. Patients in the carnitine group received 1000 mg/d oral L-carnitine for 12 weeks, whereas patients in the control group did not receive any L-carnitine supplement. At baseline and the end of week 12, 5 mL of blood were collected after a 12- to 14-hours fast and serum free carnitine, CRP, interleukin-1ß, interleukin-6 (IL-6), tumor necrosis factor-α, Lp (a), and oxidized low-density lipoprotein were measured. Serum free carnitine concentration increased significantly by 86% in the carnitine group at the end of week 12 compared with baseline (P<0.001), while serum CRP and IL-6 showed a significant decrease of 29% (P<0.05) and 61% (P<0.001), respectively. No significant changes were observed in serum free carnitine, CRP, and IL-6 in the control group. There were no significant differences between the two groups in mean changes of serum interleukin-1ß, tumor necrosis factor-α, Lp (a), and oxidized low-density lipoprotein concentrations. L-carnitine supplement reduces inflammation in hemodialysis patients, but has no effect on hyper Lp (a) and oxidative stress.

Nutritional recommendations for preventing coronary heart disease in women: evidence concerning whole foods and supplements.

AIMS: Some food groups and supplements have been recommended for preventing coronary heart disease (CHD) in women. In this article, evidence on recommendations for some of these food groups (whole grains, fruits, vegetables, fish, nuts, and soy) and supplements (phytosterols, antioxidants, folic acid, and B-complex vitamins) is reviewed. Additionally, gender differences in nutritional requirements and recommendations are described. DATA SYNTHESIS: Studies of nutrition in women and those emphasizing gender differences in nutritional requirements were selected for this review. CONCLUSION: Observational data support the benefit of vegetables, fruits, and whole grains in CHD prevention. Trial data provide support for consuming fish at least twice a week, although women of childbearing age should limit their intake of fish that may contain high levels of mercury. Nuts are nutritious snacks but their caloric impact must be considered. Soy products do not affect low-density lipoprotein cholesterol (LDL-C) or CHD but may be beneficial in replacing high-fat meat. Foods supplemented with plant stanol/sterol-esters are recommended for reducing LDL-C. Antioxidant supplementation is not recommended for prevention of heart disease. A direct causal relationship between vitamin D deficiency and CHD has not been established. Homocysteine lowering through folic acid and B-complex vitamin supplementation has not been proven to improve CHD risk. More gender-specific analyses are needed to determine whether nutritional requirements differ between men and women.

[Medical nutrition prevention and medical nutrition therapy of lipid metabolism disorder].

High energetic density of nutrition, insufficient physical activity and smoking are the most common causes of obesity and lipid metabolism disorders (hyperlipoproteinemia and dyslipoproteinemia). Hyperlipoproteinemia and dislipoproteinemia are mass noncommunicable diseases and at the same time they are main causes of atherosclerotic cardiovascular diseases and cerebrovascular diseases, metabolic syndrome, hepatic diseases and some localization of malignant diseases. Cardiovascular diseases and malignant diseases are the leading causes of mortality in the world. Global Strategy on Diet, Physical Activity and Health Nutrition and The Second European Action Plan for Food and Nutrition Policy represent the World Health Organisation approach in prevention of risks of development, and treatment of mass noncommunicable diseases, first of all for hyperlipoproteinemia, cardiovascular diseases and cerebrovascular diseases. According to the previously mentioned health programmes, medical nutrition therapy of hyperlipoproteinemia and dislipoproteinemia should be applied on whole population and individual level as well. Medical nutrition therapy is managed on individual level. Eminent international organizations, such as the European Society of Atherosclerosis and the American Heart Association, give priority to medical nutrition prevention and medical nutrition therapy in their guides for prevention and therapy of hyperlipoproteinemia, cardiovascular diseases and cerebrovascular diseases.

Pregnancy-induced hyperlipoproteinemia: review of the literature.

It is well known that with the effect of hormonal changes during pregnancy, plasma lipid levels increase. Expected elevations for triglyceride and cholesterol levels during a normal gestational period usually do not exceed 332 mg/dL and 337 mg/dL, respectively (corresponding 95th percentile values). However, elevations over the 95th percentile values can be observed during pregnancy, and patients with levels over these expected adaptation levels can be divided into 2 groups: (1) supraphysiologic hyperlipoproteinemia during pregnancy and (2) extreme hyperlipoproteinemia limited to gestational period (triglyceride level >1000 mg/dL). Regarding the first group, some of these patients may develop hyperlipoproteinemia in their future life. What percentage of these women will translate into hyperlipoproteinemia later in life and how efficiently these women can be screened during pregnancy is an enigma. The underlying disorders in the second group of patients at least include dysbetalipoproteinemia, partial lipoprotein lipase deficiency, and apoprotein E3/3 genotype. Pregnancy had been reported to induce severe hyperlipoproteinemia that is limited to gestational period in these disorders. Dysbetalipoproteinemia, partial lipoprotein lipase deficiency, and apoprotein E3/3 genotype probably bring risks and implications to the future life of the carrying individuals although the true extent of the risks is yet to be defined. When disorders unique to gestational period such as gestational diabetes are considered, pregnancy may be accepted as an opportunity to identify women under risk of cardiovascular morbidity and mortality.

Aspectos clínico-epidemiológicos y enfoque preventivo de las dislipoproteinemias / Clinical-epidemiological aspects and preventive focus of dyslipoproteinemias

Describir algunos aspectos clínico-epidemiológicos de las principales entidades correspondientes a lasdislipoproteinemias primarias y secundarias, y abordar las acciones y políticas de salud que favorecen su prevención. Los variados estilos de vida en diferentes regiones del mundo, e incluso dentro de un mismo país, han hecho difícil establecer rangos de referencia universal para la medición de los lípidos y las lipoproteínas. Estas últimas, determinadas genéticamente y por factores de riesgo relacionados con diversas enfermedades y los estilos de vida. Las de causa genética son denominadas dislipoproteinemias primarias, que pueden ser de tipo familiar o esporádica, por trastornosmonogénicos o poligénicos. Es clara la importante interrelación entre los factores de riesgo referidos y los de la biología humana en el comportamiento clínico-epidemiológico de las dislipoproteinemias, así como el papel desempeñado por los factores del ambiente y los servicios de atención médica. El enfoque preventivo propuesto, permite actuar en los distintos niveles de atención de salud con posibilidades de resultados beneficiosos para el individuo, la familia, la comunidad y el país, apoyándose sobre todo en el nivel de atención primario (Médico y Enfermera de la familia, en Cuba), con la participaciónactiva de dietistas, nutriólogos, educadores y la intersectorialidad.Se evidenció la necesidad de llevar a cabo estudios de corte nacional, tanto en Cuba como en otros países, para identificar la prevalencia real de las dislipoproteinemias no sin antes uniformar los criterios diagnósticos, métodos de laboratorio y definiciones clínicas, para mejorar la comparabilidad de los resultados de las investigaciones(AU)

To describe some clinical-epidemiological aspects of the main entities corresponding to primary and secondary DLPs and to approach the actions and health policies that can favor their prevention. The varying lifestyles in different parts of the world, including those within the very same country, have on occasion made it difficult to establish universal reference ranges for lipid and lipoprotein measurements, the later, beingdetermined genetically and by risk factors related to lifestyle and various diseases. Those caused genetically aredesignated primary dyslipoproteinemias and can be related or sporadic, due to monogenic or polygenic disorders. Theimportant interrelation between the referred risk factors and human biology factors in clinical-epidemiological behavior of dyslipoproteinemias is clear, just as is the role played by the environmental protagonists and medical attention services. The proposed preventive focus permits action in the distinct levels of health care with the possibilities of beneficial resultsfor the individual, family, community and country, relying most of all on the primary level (in Cuba: the family practitioner and nurse) with the active participation of dieticians, nutritionists, educators and intersectoriality. The necessity to carry out studies at the national level, both in Cuba and abroad to identify the real prevalence of dyslipoproteinemias was proved, but not without first making the diagnostic criteria, laboratory methods andclinical definitions uniform in order to improve the comparability of the national and international investigation results.(AU)

Soy-tibolone combination - effect on lipids in postmenopausal monkeys and women.

OBJECTIVES: To determine whether co-administration of soy during tibolone treatment would prevent tibolone-induced dyslipoproteinemia in postmenopausal monkeys and women. METHODS: Surgically postmenopausal cynomolgus monkeys (n = 18) were assigned randomly to one of four dietary regimens in a Latin Square crossover design, such that all animals received all diets for 14 weeks with a 4-week washout period: (1) casein/lactalbumin (CL); (2) tibolone (Tib, 1.25 mg/day women's equivalent); (3) soy (138 mg isoflavones/day women's equivalent); (4) Soy + Tib. Postmenopausal women on tibolone treatment were randomized to receive soy powder (52 g of soy protein containing 112 mg isoflavones) or placebo (containing 52 g of milk protein) daily in a crossover trial for 8 weeks with a 4-week washout period. RESULTS: Monkeys given Tib alone had approximately 14% increase in plasma LDL + VLDL-C; whereas those given soy combined with tibolone had significant ( approximately 22%) reductions. Tib treated monkeys had reductions in plasma HDL-C of about 48% vs. no reductions in Soy + Tib. In postmenopausal women using tibolone, soy reduced plasma LDL-C concentrations by approximately 10% from baseline without a change in HDL-C. CONCLUSIONS: Co-administration of soy during tibolone treatment improved the lipoprotein profile in both monkeys and women; however, the effects were more robust in monkeys.

Study of resveratrol and antioxidant activity in Georgian brand red wines and a number of foreign red wines.

Today wine pricing is guided by content of useful substances such as resveratrol and catechines. Resveratrol [3,4',5-trihydroxystilbene (RESV)] is a compound found in the skin of red grapes and is a constituent of red wine. Clinical investigation demonstrated that resveratrol lowers the levels of catecholamines, inhibits lipid peroxidation of low-density lipoprotein; it has anti-inflammatory, antioxidant activity etc. In Georgia the highest concentration of resveratrol has been reported in wines prepared from Saperavi grapes. Resveratrol contents and antioxidant activity of Georgian brand red wines made from Saperavi grape variety and of foreign red wines available on Georgian market were assessed and compared. It was found that resveratrol content distinguishes foreign wines, particularly the French wine from the Georgian brand red wines. The research showed that resveratrol content is higher in non-brand Kakhetian style Saperavi (6.24 mg/ml) than in European or other Georgian brand wines. Proportion of trans-resveratrol is higher in "Saperavi" by "Badagoni" (94.5%), French wine (93.83%) and Saperavi by "TbilGhvino" (93.49%). Given that trans-resveratrol is characterized by higher biological activity and medical importance than cis-resveratrol, their proportion may be an important criterion to measure healing properties of wine. In terms of antioxidant activity, Georgian wines are like foreign wines. It is concluded that Georgian brand wines with few exceptions are behind the foreign wines in several parameters. Since polyphenolic substances define wine price through their positive effects on human health, more detailed studies on polyphenolic content of Georgian wines are needed.

Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications?

CONTEXT: Previous studies in postmenopausal women have demonstrated that, after oral administration of norethisterone, a small proportion of the compound is rapidly converted into ethinylestradiol. The shape of the concentration - time curve suggested that this occurred in the liver. The results were confirmed by in vitro investigations with adult human liver tissue. In 2002, it was shown that, after oral treatment of women with tibolone, aromatization of the compound occurred, resulting in the formation of a potent estrogen, 7 alpha-methyl-ethinylestradiol. The result has been called into question, because the adult human liver does not express cytochrome P450 aromatase, which is encoded by the CYP 19 gene. Moreover, it has been claimed that the serum level of 7 alpha-methyl-ethinylestradiol measured by gas chromatography/mass spectrometry was an artifact. REPLY: Aromatization of steroids is a complex process of consecutive oxidation reactions which are catalyzed by cytochrome P450 enzymes. The conversion of the natural C19 steroids, testosterone and androstenedione, into estradiol-17beta and estrone is dependent on the oxidative elimination of the angular C19-methyl group. This complex key reaction is catalyzed by the cytochrome P450 aromatase, which is expressed in many tissues of the adult human (e.g. ovary, fat tissue), but not in the liver. However, 19-nortestosterone derivatives are characterized by the lack of the C19-methyl group. Therefore, for the aromatization of these synthetic steroids, the action of the cytochrome P450 aromatase is not necessary and the oxidative introduction of double bonds into the A-ring can be catalyzed by other hepatic cytochrome P450 enzymes. The final key process in the formation of a phenolic A-ring, both in natural androgens and 19-nortestosterone derivatives, is the enolization of a 3-keto group to the C2-C3-enol or the C3-C4-enol moiety, which occurs without the action of enzymes. CONCLUSION: 19-nortestosterone derivatives (norethisterone, norethynodrel, tibolone) can readily be aromatized in the adult human liver. This leads to the formation of the potent estrogens ethinylestradiol from norethisterone or norethynodrel and 7 alpha-methyl-ethinylestradiol from tibolone. This may have clinical consequences, e.g. the elevated risk of venous thromboembolic disease in premenopausal women treated with high doses of norethisterone for bleeding disorders, or the elevated risk of stroke or endometrial disease in postmenopausal women treated with tibolone.

Treatment of diabetic dyslipoproteinemia.

Diabetes mellitus, specifically type 2, is often associated with disorders in lipid metabolism. Elevated levels of plasma free fatty acids play a pivotal role by contributing significantly to insulin resistance. In addition free fatty acids promote diabetic dyslipidemia through increasing VLDL synthesis in the liver, and by virtue of cholesterylester transfer protein, modifying LDL to increase small-dense LDL subfractions and to decrease HDL cholesterol. This atherogenic lipoprotein profile (elevated triglycerides, increased small-dense low-density lipoproteins, and decreased high-density lipoproteins), contributes to the development of atherosclerosis and increases the risk of experiencing cardiovascular events, the most common cause of death in type 2 diabetes. To decrease the risk of cardiovascular disease events in diabetics, dyslipidemia needs to be treated, as evidenced from epidemiology, from intervention trials, and from subgroup analyses of large intervention trials initiated to evaluate effects of lipid lowering treatment that also included patients with type 2 diabetes. Most measures used to counteract hyperglycemia, are also prone to ameliorate dyslipidemia: dietary intervention (medical nutrition) including omega-3 fatty acids as part of lifestyle changes that also comprise cessation of smoking, increases in physical activity and reduction in body weight. In addition insulin, biguanides, acarbose and glitazones applied for glycemic control also improve diabetic dyslipidemia. Additional pharmacological treatment of dyslipidemia if persisting after glycemic control relies on different drug classes. Fibrates effectively reduce free fatty acids, fasting and postprandial lipemia, shift the distribution of LDL particles towards less dense subfractions and increase HDL cholesterol, thus particularly addressing key components of diabetic dyslipidemia. For LDL cholesterol lowering statins are mainly used that decrease LDL cholesterol levels by competitive inhibition of the HMG-CoA reductase. As type 2 diabetes is found to be associated with a two- to fourfold increase in coronary heart disease risk and as the degree of glycemia is more related to microvascular complications, correcting dyslipidemia appears to be a major task in order to reduce macrovascular events in patients with type 2 diabetes.