Familial hypercholesterolemia and young patients' thoughts on own condition and treatment.

OBJECTIVES: Familial hypercholesterolemia (FH) is a hereditary and usually asymptomatic condition characterized by elevated blood cholesterol and increased risk of premature cardiovascular disease. It is treated with dietary modifications and lipid lowering drugs. The objective was to learn about young FH patients' perceptions and choices regarding treatment. METHODS: Data were collected through in-depth interviews with 24 patients (ages 16-35), and analysed according to Grounded Theory. RESULTS: The findings are presented as theoretical concepts describing the participants' way of handling their condition. The core category was identified as "Thoughts of consequences vs. Postponing thoughts of consequences", which could be described through the following subcategories: 1. Normalising the condition, 2. Belittling of treatment vs. Committed to treatment and 3. Trust in advice vs. Avoid unnecessary interference. The participants' position regarding these categories was described to affect motivation and challenges with treatment. CONCLUSIONS: Participants who postpone the thoughts of consequences, belittle the treatment and avoid unnecessary interference represent a challenge to health care practitioners. PRACTICAL IMPLICATIONS: Practitioners should explore aspects such as thoughts of consequences, view of treatment and the feeling of interference to be able to better understand illness behaviour, adjust their communication and hopefully improve adherence.

FAMILIAL COMBINED HYPERLIPIDEMIA: CURRENT KNOWLEDGE, PERSPECTIVES, AND CONTROVERSIES.

Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).

Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism.

Familial hypercholesterolaemia, familial combined hyperlipidaemia (FCH) and elevated lipoprotein(a) are common, inherited disorders of apolipoprotein B metabolism that markedly accelerate the onset of atherosclerotic cardiovascular disease (ASCVD). These disorders are frequently encountered in clinical lipidology and need to be accurately identified and treated in both index patients and their family members, to prevent the development of premature ASCVD. The optimal screening strategies depend on the patterns of heritability for each condition. Established therapies are widely used along with lifestyle interventions to regulate levels of circulating lipoproteins. New therapeutic strategies are becoming available, and could supplement traditional approaches in the most severe cases, but their long-term cost-effectiveness and safety have yet to be confirmed. We review contemporary developments in the understanding, detection and care of these highly atherogenic disorders of apolipoprotein B metabolism.

Long-term therapeutic efficacy of lipoprotein apheresis on circulating oxidative stress parameters--A comparison of two different apheresis techniques.

BACKGROUND: A chronic lipoprotein apheresis therapy leads to an expressed reduction in the incidence of cardiovascular events in high-risk patients. In addition to the elimination of atherogenic lipoproteins such as LDL and lipoprotein(a), an antioxidative effect of lipoprotein apheresis has been suspected. OBJECTIVES AND METHODS: We investigated long-term biochemical effects in sixteen patients undergoing lipoprotein apheresis - lipid filtration (LF, n = 7) or dextran sulfate adsorption (DSA, n = 9). Systemic oxidative stress markers (blood phagocyte chemiluminescence, levels of oxidized LDL and antioxLDL antibodies) were examined at the 1st, 40th and 80th apheresis sessions. RESULTS: In DSA patients, the 80th apheresis session was associated with significantly higher LDL cholesterol removal and lower HDL cholesterol deprivation as compared to LF patients. In contrast to LF patients, DSA patients showed a long-term progressive decrease in circulating oxidant generating activity as evaluated by whole blood chemiluminescence (p < 0.05). Moreover, a single LF apheresis session was associated with higher systemic generation of reactive oxygen species over time. CONCLUSION: Compared to LF, long-term DSA apheresis is associated with a gradual reduction of circulating oxidative burden and may be considered a beneficial molecular mechanism of this technique.

[Familial combined hyperlipidemia: consensus document]. / Hiperlipidemia familiar combinada: documento de consenso.

Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease. It is transmitted in an autosomal dominant manner, although there is not a unique gene involved. The diagnosis is performed using clinical criteria, and variability in lipid phenotype and family history of hyperlipidemia are necessaries. Frequently, the disorder is associated with type2 diabetes mellitus, arterial hypertension and central obesity. Patients with FCH are considered as high cardiovascular risk and the lipid target is an LDL-cholesterol <100mg/dL, and <70mg/dL if cardiovascular disease or type 2 diabetes are present. Patients with FCH require lipid lowering treatment using potent statins and sometimes, combined lipid-lowering treatment. Identification and management of other cardiovascular risk factors as type 2 diabetes and hypertension are fundamental to reduce cardiovascular disease burden. This document gives recommendations for the diagnosis and global treatment of patients with FCH directed to specialists and general practitioners.

[Familial combined hyperlipidemia: consensus document]. / Hiperlipidemia familiar combinada: documento de consenso.

Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease. It is transmitted in an autosomal dominant manner, although there is not a unique gene involved. The diagnosis is performed using clinical criteria, and variability in lipid phenotype and family history of hyperlipidemia are necessaries. Frequently, the disorder is associated with type2 diabetes mellitus, arterial hypertension and central obesity. Patients with FCH are considered as high cardiovascular risk and the lipid target is an LDL-cholesterol <100mg/dL, and <70mg/dL if cardiovascular disease or type 2 diabetes are present. Patients with FCH require lipid lowering treatment using potent statins and sometimes, combined lipid-lowering treatment. Identification and management of other cardiovascular risk factors as type 2 diabetes and hypertension are fundamental to reduce cardiovascular disease burden. This document gives recommendations for the diagnosis and global treatment of patients with FCH directed to specialists and general practitioners.

Familial combined hyperlipidemia: from molecular insights to tailored therapy.

PURPOSE OF REVIEW: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). RECENT FINDINGS: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. SUMMARY: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.

[LDL apheresis: an update and overview. LDL apheresis in Sardinia, Italy (SMILDLa)]. / LDL-aferesi: aggiornamenti e stato dell'arte. Studio Multicentrico Italiano LDL-Aferesi (SMILDLa).

LDL apheresis (LDLa) is an invasive therapeutic tool to control qualitative and quantitative disorders of lipid metabolism. It is aimed at achieving a metabolic balance in association with lipid-lowering drugs in patients with severe, genetically determined or acquired dyslipidemia who do not reach clinically adequate LDL-cholesterol (LDL-C) levels (<70 mg/dL) despite appropriate lipid-lowering drug treatment. A poorly known dyslipidemia is constituted by elevation of lipoprotein (a) [Lp(a)], which appears to be genetically determined and not influenced by diet or lipid-lowering medication. An Lp(a) level exceeding 30 mg/dL is an independent risk factor for premature cardiovascular disease and cerebrovascular disease. Numerous data support the notion that cardiovascular risk reduction is related to the degree of reduction of LDL-C, and the progression of atherosclerosis can be delayed or reversed by intensive and continuous cholesterol-lowering treatment. After the introduction of HMG-CoA reductase inhibitors (statins), the clinical benefit of cholesterol-lowering treatment has received significant confirmation. However, this treatment has shown poor results in the most severe, genetically determined forms. LDLa is an intensive extracorporeal cholesterol-lowering treatment approach with well documented efficacy and safety. It has also shown effects not directly correlated with its lipid-lowering activity, such as antioxidant effects on oxidized LDL and antiinflammatory effects on the cytokine network, the endothelium and the coagulation system. Finally, data acquired by the Italian Multicenter Study on LDLa Working Group were highlighted and the new evidence in the literature discussed.

Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events.

Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non-HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterol-lowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin+fibrate should be considered second-line therapy until the efficacy and safety are established.

The first results demonstrating efficiency and safety of a double-column whole blood method of LDL-apheresis.

LDL-apheresis is a treatment for familial hypercholesterolemia in addition to diet and drug therapy. In the past, LDL-apheresis techniques consisted in separating plasma from blood and adsorbing plasma LDL-C whereas recent methods remove LDL-C directly from whole blood. The whole blood system developed by Kaneka consists of a single-column (Liposorber DL-75) treatment (SCWB) but a double-column whole blood (DCWB) method has recently been developed (Liposorber DL-50 x 2). When 1.6 blood volumes (plus 1l) were processed, acute reductions of total cholesterol and LDL-C were 67.9+/-6% and 80.2+/-4.5%, respectively. The performances of the DCWB method were compared to other LDL-apheresis methods. Assessed in 10 patients, the DCWB method is more efficient than the SCWB method with higher reduction rates of LDL-C (79.7+/-4.9 vs. 68.2+/-5.0% p<0.0001) and apolipoprotein-B (79.5+/-5.4 vs. 67.4+/-5.4% p<0.0001). In a sub group of five patients having the highest LDL-C baseline levels, the LDL-C reduction rates obtained by the DCWB method are equivalent to those obtained by the conventional LDL-apheresis method consisting of preliminary plasma separation followed by plasma LDL-C adsorption and used as first line apheresis therapy (80.5+/-4.5 vs. 79.0+/-5.9%). The safety of DCWB was demonstrated in 12 patients with only a low frequency of mild and transient adverse effects (4%). In conclusion, the DCWB LDL-apheresis method provides efficient removal of LDL-C, a low level of adverse effects, and a shortened duration of the procedure.

Low density lipoprotein adsorption on sol-gel derived alumina for blood purification therapy.

Among the clinical treatments of Familial Hyper cholesterolemia patients to reduce the concentration of low density lipoprotein (LDL), blood purification therapy is most suitable in which a blood-compatible adsorbent is employed. In the present study, alumina powders were prepared via a sol-gel route to develop a LDL-adsorbent Aluminum tri2-propoxide was hydrolyzed and subsequently calcined up to 1200 degrees C. Surface charge density and pore size distribution were measured, and the phases were identified. The alumina calcined above 400 degrees C had excellent blood compatibility in terms of endogenous clotting parameters, i.e., partial thromboplastin time: (PTT), prothrombin time: (PT), and the amount of fibrinogen: (Fib). The amount of LDL-adsorption (DeltaW(LDL)) increased with the calcining temperature, showing a good linear correlation to surface charge density. The 1200 degrees C sample consisted only of alpha-alumina, and was greatest in DeltaW(LDL). All samples involved pores smaller than 20 nm but not the pores large enough to accommodate LDL molecules (20-25 nm). From those results, it was concluded for the present alumina particles that the surface charge density was the primary factor and that the chemical activity of alpha-alumina also contributed to the excellent LDL-adsorption for the 1200 degrees C sample, while entrapping LDL in the pores was not an active mechanism.

Primary hemostasis in patients treated with LDL-apheresis for severe familiar hypercholesterolemia: a prospective pilot trial using PFA-100 analysis to rationalize therapeutic LDL-apheresis procedure.

UNLABELLED: LDL-apheresis is a method of extracorporeal elimination of serum LDL-cholesterol used for treating patients with severe hyperlipidemia resistant to diet and pharmacotherapy. A practically applicable marker that may possibly be used to ascertain the efficacy of this treatment in lowering the activity of atherosclerosis are still to be found and remains an unresolved problem. Activity of primary hemostasis plays an important role in the process of developing atherosclerotic complications. This fact led us to hypothesize that the investigation of primary hemostatic activity might be a useful marker for monitoring LDL-apheresis efficacy. The aim of this work was to verify this hypothesis. METHODS AND PATIENTS: Commercial analyzer Dade Behring PFA-100, Germany (PFA, platelet function analysis) was used for all investigations. This analyzer enables quantitative measurement of platelet-mediated hemostasis in uncoagulated (citrated) blood. The method simulates platelet activation by mechanical stress (shear stress), and also simulates contact of platelets with collagen. A total of nine long-term treated patients with familial hypercholesterolemia were included in the study group (4 females and 5 males). Ages ranged from 17 to 59 years (average 46.4, median 55). Two patients had homozygous hypercholesterolemia. Eighteen sample pairs were examined using collagen/epinephrine (COL/EPI) membrane and 17 pairs were examined using collagen/ADP (COL/ADP) membrane, the total number of samples amounted to 70. RESULTS: Closure time (CT) values were prolonged after separation in all cases but CT prolongation was not statistically significant (p < 0.14). No differences between homozygous and heterozygous patients were found (p < 0.05). CONCLUSION: Investigation of primary hemostasis using PFA-100 analyzer is not a suitable marker and should not be used to determine the optimal intensity of individual LDL-apheresis procedures.

Influence of LDL apheresis on LDL subtypes in patients with coronary heart disease and severe hyperlipoproteinemia.

Epidemiologic studies and in vitro experiments indicate that low density lipoprotein (LDL) subtypes differ concerning their atherogenic potential. Small, dense LDL are more atherogenic than large, buoyant LDL. LDL apheresis is a potent therapeutic modality to lower elevated LDL-cholesterol. It is unknown whether such therapy induces a shift in the LDL subtype distribution. In this study we evaluated the influence of LDL apheresis on the LDL subtype distribution in patients with CHD and familial hypercholesterolemia (FH, n = 22), combined hyperlipidemia (CHLP, n = 6), or Lp[a]-hyperlipoproteinemia (Lp[a]-HLP, n = 4) regularly treated by LDL apheresis (immunoadsorption (n = 14), HELP apheresis (n = 8), dextran sulfate adsorption (n = 7), cascade filtration (n = 3)). On the basis of 6 LDL subfractions (d 1.020;-1.057 g/mL) isolated by density gradient ultracentrifugation the LDL-density profile was determined in each patient before and after apheresis. There was a relative increase of LDL-subfractions 1, 2, and 3 (P < 0.01, P < 0. 05, and P < 0.01, respectively) and a concomitant decrease of LDL subfractions 5 and 6 (P < 0.05) after apheresis. Subgroup analysis indicates that the degree of the small, dense LDL reduction was much more prominent in patients with CHLP compared to patients with FH or Lp[a]-HLP, whereas the type of apheresis technique had no effect. The extent of small, dense LDL reduction correlated with the preapheresis concentrations of small, dense LDL and triglycerides but not with the extent of triglyceride reduction.We conclude that LDL apheresis not only decreases LDL mass, but also improves LDL-density profile, particularly in patients with CHLP.

[Negative aspects of the Western life style and possibilities of intervention in patients with familial combined hyperlipidemia]. / Negativní aspekty západního zivotního stylu a moznosti intervence u pacientu s familiární kombinovanou hyperlipidémií.

BACKGROUND: Evaluation of the effect of intervention on changes in the lifestyle of patients with combined familial hyperlipidaemia (CFH). METHODS AND RESULTS: The group comprised 154 patients with CFH where changes in the lipid profile, diet, basic anthropometric data and smoking were recorded 3-6 months following intervention. In addition to little willingness to have a check-up examination the authors recorded significant shortcomings in the lifestyle of these patients with a high cardiovascular risk: a large number of smokers (51%), serious shortcomings in the composition of the diet (excessive intake of animal fats a proteins, inadequate intake of vegetable proteins, dietary fibre and vitamins, in particular E and C), overweight and a high percentage of body fat. CONCLUSIONS: While the attention devote to pharmacotherapy with hypolipidaemic agents is justified we should not forget systematic intervention as regards changes in lifestyle. This appeal is even more urgent in conjunction with the low motivation and willingness of patients to change their lifestyle. Special attention should be focused on smokers (in addition to effect on lipids also greater cumulation of risk factors).

Changes of autoantibodies against oxidatively modified low density lipoproteins during long-term LDL-apheresis.

The oxidation of low-density lipoproteins (LDL) is considered a key event in the initiation of atherosclerosis. The aim of this study was to follow-up the biological marker of in vivo LDL oxidation (oxidatively modified LDL autoantibody titres) during long-term LDL-apheresis treatment. A patient suffering from severe combined hyperlipidaemia underwent LDL-apheresis biweekly and was followed for two years. The significant reduction of baseline total cholesterol (58%), total triglycerides (80%), LDL-cholesterol (48%), apoprotein B (50%) and apolipoprotein (a) (61%) may be considered as a good response to the treatment. The titre of autoantibodies (IgG) against oxidatively modified LDL (malondialdehyde-derived LDL) was followed throughout the study and showed dynamic changes. The measured values were multiple compared as mean+/-SD over each semester of apheresis application: I semester 70.0+/-8.3 U/ml, n = 12; II semester 58.0+/-13.8 U/ml, n = 12; III semester 37.6+/-6.0 U/ml, n=12; IV semester 34.3+/-7.0 U/ml, n = 12; ANOVA: I vs. II semester p<0.083, II vs. III semester p<0.00053, III vs. IV semester p<0.248. In parallel to the changes in this biochemical parameter, regression of numerous xanthomas was clinically observed. In spite of this, the presence of oxidised-LDL (oxLDL) antibodies was enhanced in comparison to antibody titre detected in a group of age-matched normolipaemic healthy controls (n = 15; 19.4+/-8.6; p<0.01). Classical lipoprotein parameters were correlated with the titre of autoantibodies against oxLDL and showed low correlation coefficients: total cholesterol vs. oxLDLab, r = 0.36; triglycerides vs. oxLDLab, r = 0.43; LDL cholesterol vs. oxLDLab, r = 0.14; HDL cholesterol vs. oxLDLab, r = -0.33; apo B vs. oxLDLab, r = 0.25; apo (a) vs. oxLDLab, r = -0.05. Our study showed an additional benefit of LDL-apheresis therapy. The production of autoantibodies against oxLDL was reduced during the treatment, indicating a lower level of the atherogenic antigen.