Severe Heterozygous Familial Hypercholesterolemia Research Articles

CTCA in children with severe heterozygous familial hypercholesterolaemia: Screening for subclinical atherosclerosis

Familial hypercholesterolemia (FH) is one of the most common genetically inherited disorders in the world. Children with severe heterozygous FH (HeFH), i.e. untreated low-density lipoprotein cholesterol (LDL-C) levels above the 90th percentile for age and sex among FH mutation carriers, can have LDL-C levels that overlap levels of children with homozygous FH (HoFH), but treatment regimen and cardiovascular follow-up to prevent cardiovascular disease are less intensive in children with severe HeFH. In children with HoFH, subclinical atherosclerosis can already be present using computed tomography coronary angiography (CTCA). The question remains whether this is also the case in children with severe HeFH who have a high exposure to elevated LDL-C levels from birth onwards as well. We calculated the cumulative LDL-C exposure (CEtotal [mmol]) in four children with severe HeFH and performed computed tomography coronary angiography (CTCA). These children, aged 13, 14, 15 and 18 years, had CEtotal of 71.3, 97.8, 103.6 and 136.1 mmol, respectively. None of them showed abnormalities on cardiovascular imaging, despite high LDL-C exposure. The results of this study, do not give us an indication to recommend performing CTCA routinely in children with severe HeFH.

The effect of achieving LDL-C <1.8 mmol/L to prevent the first atherosclerotic cardiovascular events in the primary prevention settings of severe heterozygous familial hypercholesterolemia

Abstract Introduction The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. LDL-C <2.5 mmol/l is a recommended therapeutic goal for the primary prevention settings of severe FH. However, given that ESC guidelines recommends LDL-C <1.8 mmol/l in FH patients, this stricter goal may be better to prevent the first atherosclerotic cardiovascular disease (ASCVD) in severe FH patients. Purpose To determine whether achieving LDL-C<1.8 mg/dl is more beneficial to reduce the first ASCVD events. Methods A total of 148 severe FH subjects without any history of ASCVD were analyzed. Severe FH was defined as untreated LDL-C >10.3 mmol/l, LDL-C >8.0 mmol/l+ 1 high-risk feature, LDL-C >4.9 mmol/l + 2 high-risk features according to IAS proposed statement. The occurrence of ASCVD (all-cause death, CAD, ischemic stroke and lower extremity artery disease (LEAD)) were compared in those with on-treatment LDL-C < and ≥1.8 mmol/L. Results 10.1% (=15/148) of study subjects achieved on-treatment LDL-C <1.8 mmol/l. They were more likely to receive PCSK9 inhibitor (15.0 vs. 66.7%, p<0.01), whereas there was no significant difference in FH-related physical characteristics (tendon xanthomas: 72.2 vs. 93.3%, p=0.12) and causative genotypes (LDLR: 68.4 vs. 66.7%, p=1.00, PCSK9: 8.3 vs. 6.7%, p=1.00, LDLR/PCSK9: 3.8 vs. 6.7%, p=0.48), untreated LDL-C (7.3±1.7 vs. 7.9±1.8 mmol/l, p=0.22) and lipoprotein(a) (23 [11–42] vs. 25 [15–70] mg/dl, p=0.41) levels between two groups. During the observational period (median=7.0 years), severe FH achieving on-treatment LDL-C <1.8 mmol/l was associated with a lower likelihood of experiencing ASCVD events (Figure 1). Of note, any cardiovascular events did not occur in severe FH who achieved on-treatment LDL-C <1.8 mmol/l. In those with on-treatment LDL ≥1.8 mmol/L, CAD (76.5%=26/34) was more dominant component of ASCVD, followed by ischemic stroke (17.6%=6/34) and LEAD (5.9%=2/34). Conclusions A significantly lower frequency of ASCVD was observed in severe FH who achieved LDL-C <1.8 mmol/L in the primary prevention settings. Given that only 10.1% of severe FH patients achieved LDL-C <1.8 mmol/l, more actions are required to motivate physicians for further intensified management of LDL-C in severe FH patients in the primary prevention settings. Funding Acknowledgement Type of funding sources: None.

Comparison of plasma separation using centrifugation or filtration for MONET lipoprotein apheresis in patients with cardiovascular disease and severe dyslipidemia.

Homozygous or severe heterozygous familial hypercholesterolemia and elevated lipoprotein(a) levels may be treated with membrane filtration. The MONET system (Fresenius Medical Care, Bad Homburg, Germany) involves plasma separation by centrifugation or filtration. Whether the method of plasma separation affects lipoprotein lowering and treatment safety was investigated in a single-center retrospective study. The centrifugation-based plasma separation achieved a higher plasma flow and shorter time to treat 1L of plasma (46.2 ± 8.6min), than the filtration-based system (71.5 ± 40.0min; p=0.001). The mean reduction of LDL-cholesterol was 69% and 67% with centrifugation and filtration and was 75% for lipoprotein(a) with both plasma separation methods. A reduction of IgM by more than 60%, of albumin and total protein by approximately 20% and low frequency of side effects was observed. The efficacy of lowering atherogenic lipoproteins was comparable with both plasma separation methods. Centrifugation was more time-efficient compared to filtration.

Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia.

Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation. https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

Transcatheter aortic valve replacement in a patient with premature coronary artery disease and calcific aortic stenosis complicated by heterozygous familial hypercholesterolemia

We describe a case of a 59-year-old man with severe heterozygous familial hypercholesterolemia (FH) and elevated lipoprotein(a) presenting with severe aortic stenosis, treated with transcatheter aortic valve replacement (TAVR). His history also includes premature coronary artery disease requiring coronary artery bypass surgery at age 48 and a stroke at age 55. His pre-treatment lipid values include an LDL-Cholesterol (LDL-C) of 458 mg/dL, total cholesterol of 588 mg/dL, and lipoprotein (a) level of 351 nmol/L. Since his FH diagnosis, he has received several lipid-lowering agents including statins, bile acid sequestrants, nicotinic acid derivatives, and PCSK9 inhibitors. This case reflects the association of FH and elevated lipoprotein(a) with aortic stenosis and TAVR as a viable and effective treatment.

Management of Familial Hypercholesterolemia: Current Status and Future Perspectives.

Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia,” “diagnosis,” “management,” “guideline,” “consensus,” “genetics,” “screening,” “lipid lowering agents.” The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia

BackgroundProprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. ObjectivesThe aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). MethodsIn this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. ResultsIn total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was −21.2% (−59.8 mg/dl) in patients with HoFH and −54.9% (−104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from −19.6% at week 12 to −29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis. ConclusionsEvolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

Long-term lipoprotein apheresis in the treatment of severe familial hypercholesterolemia refractory to high intensity statin therapy: Three year experience at a lipoprotein apheresis centre.

Severe familial hypercholesterolemia (FH) individuals, refractory to conventional lipidlowering medications are at exceptionally high risk of cardiovascular events. The established therapeutic option of last choice is lipoprotein apheresis (LA). Herein, it was sought to investigate the clinical usefulness of LA in a highly selected group of severe heterozygous FH (HeFH), as recently described by the International Atherosclerosis Society (IAS), for their efficacy in lipid reduction and safety. Efficacy and safety of LA were investigated in 318 sessions of 7 severe HeFH females with cardiovascular disease, over a mean period of 26.9 ± 6.5 months. Relative reduction of low density lipoprotein cholesterol (LDL-C) ≥ 60%, clinical complications and vascular access problems were evaluated and compared between the direct adsorption of lipoproteins (DALI) and lipoprotein filtration (Membrane Filtration Optimized Novel Extracorporeal Treatment [MONET]). Additionally, lipoprotein (a) [Lp(a)], total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fibrinogen concentrations were investigated. The relative reduction of LDL-C, TC, TG and Lp(a) were 69.4 ± 12.9%, 59.7 ± 9.1, 51.5 ± ± 14.2% and 71.3 ± 14.4%, respectively. A similar efficacy was found in both systems in LDL-C removal. DALI system led to larger depletions of Lp(a) (80.0 [76-83]% vs. 73.0 [64.7-78.8]%; p < 0.001). The frequency of clinical side effects and vascular access problems were low (8.5%). Long-term LA in severe HeFH individuals is safe and efficiently reduces LDL-C and Lp(a). Higher efficacy of the DALI system than MONET in Lp(a) removal may indicate the need for individualized application of the LA system in severe HeFH individuals.

Lipoprotein-apheresis in familial hypercholesterolemia: Long-term patient compliance in a French cohort

Background and aimsLipoprotein apheresis (LA) is a complex therapeutic option and poor compliance can adversely affect treatment outcome. The aim of this study was to describe long-term compliance to treatment in patients undergoing regular LA therapy and to investigate factors related to low compliance. MethodsWe analysed 11,391 prescribed procedures of LA performed between 1990 and 2007 in 51 patients with familial hypercholesterolemia. Regular LA treatment was initiated in patients presenting with either homozygous familial hypercholesterolemia (n = 21), or severe heterozygous familial hypercholesterolemia (n = 30) with elevated LDL-cholesterol levels and who did not respond adequately to diet and drug therapy; the majority of these patients (n = 30) had cardiovascular disease at initiation of therapy. ResultsThe overall observed compliance rate based on the number of achieved/programmed procedures was 87.5%. Neither cardiovascular history nor subtypes of hypercholesterolemia was associated with compliance. In addition, there was no impact of patient demography on compliance. Treatment frequency alone significantly impacted non-compliance (i.e. patient with weekly procedures were less compliant). Interestingly, a non-significant decrease in compliance was observed among patients aged <20 years. ConclusionsDespite the complexity of the LA procedure and its impact on the organisation of patients' daily lives, overall compliance was very high. The choice of an appropriate and adequate frequency of treatment significantly impacted patient compliance.

Value of the Definition of Severe Familial Hypercholesterolemia for Stratification of Heterozygous Patients

Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol with co-dominant transmission and high risk of cardiovascular disease (CVD), although with high variability among subjects. Currently, CVD stratification tools for heterozygous FH (HeFH) are not available. A definition of severe HeFH has been recently proposed by the International Atherosclerosis Society (IAS), but it has not been validated. Our study aims to see clinical characteristics and prevalence of CVD in subjects defined as severe HeFH by IAS criteria. Probable or definite HeFH introduced in the Dyslipidemia Registry of Spanish Arteriosclerosis Society were analyzed by the IAS criteria. Univariate and multivariate analysis was used to assess the association of CVD with the IAS criteria. About 1,732 HeFH cases were analyzed. Severe HeFH had higher prevalence of familial history of CVD, personal history of tendon xanthomas, LDL cholesterol, and CVD than nonsevere HeFH. A total of 656 (77.1%) and 441 (50.1%) of men and women, respectively, fulfilled the IAS criteria of severe HeFH. In the univariate analysis, subjects defined as severe HeFH showed odds ratio 3.016 (95% CI 3.136 to 4.257, p <0.001) for CVD. However, when traditional risk factors were included in the multivariate analysis, only the presence of cholesterol >400mg/dl had a statistically significant association with CVD odds ratio 8.76 (95% CI 3.90 to 19.69, p <0.001). In conclusion, the IAS definition of severe HeFH is not significantly associated with CVD when adjusted for classic risk factors. Risk stratification in HeFH is an important issue, but the proposed criteria do not seem to solve this problem.

Impact of selective LDL apheresis on serum chemerin levels in patients with hypercholesterolemia.

BackgroundSelective low-density lipoprotein (LDL) apheresis is commonly used to treat patients with familial hypercholesterolemia (FH). Chemerin is an adipokine with putative roles in the regulation of lipid metabolism.MethodsIn our pilot study, we measured serum chemerin levels by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments using the technique of direct adsorption of lipoproteins (DALI).ResultsThe first treatment sessions decreased serum chemerin levels by an average of 27.26 %. While following one patient, 12 months of regular LDL apheresis resulted in a permanent reduction in his serum chemerin level. Changes in the lipoprotein subfractions measured by gel electrophoresis (Lipoprint) correlated with the reduction of chemerin levels. Furthermore, we eluted and then measured chemerin bound to the DALI column.ConclusionWe conclude that LDL apheresis decreases the circulating level of chemerin by binding the protein to the column and thus improves lipoprotein subfraction pattern.

Abstract 52: Efficacy and Safety of Mipomersen in Patients with Familial Hypercholesterolemia and Inadequately Controlled LDL-C Levels

Aim: Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein B-100 synthesis, FDA-approved to treat homozygous familial hypercholesterolemia. The primary objective of this study was to determine whether mipomersen significantly reduced atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (HeFH). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study comprised of two cohorts (NCT01475825). Cohort 1 had severe HeFH (LDL-C ≥200 mg/dL + coronary heart disease, or LDL-C ≥300 mg/dL) and Cohort 2 had milder HeFH (LDL-C ≥160 and &lt;200 mg/dL). For each cohort, patients were randomized 1:1 to 200 mg SC once weekly or 70 mg SC thrice weekly, then 2:1 to receive mipomersen or placebo for 60 weeks. The primary outcome was percent change from baseline in LDL-C in Cohort 1. The % change from baseline in LDL-C at Week 61 for mipomersen treated patients was compared to placebo using a mixed model for repeated measures (MMRM), as well as by ANCOVA on the value closest to 7 days post last treatment (LOCF). Results: Mean baseline LDL-C levels were 265 mg/dL in Cohort 1 (N=200) and 176 mg/dL in Cohort 2 (N=109). In Cohort 1, mipomersen 200 mg weekly reduced LDL-C levels by -29.7% (vs -7.9% placebo, P &lt;.001) in the mixed model, and by -36.3% (vs -7.6% placebo, P &lt;.001) using the LOCF. Analysis of LDL-C over time (Figure) showed a mean absolute reduction of 138 mg/dL in mipomersen patients who completed the blinded treatment period (n=32), achieving a mean level of 147 mg/dL from a mean 285 mg/dL baseline level. Tolerability to treatment and adverse events were similar between dose regimens. Adverse events were consistent with the drug’s known safety and tolerability profile. Conclusions: The primary analysis showed a significant reduction in LDL-C levels in patients with severe HeFH who received mipomersen 200 mg once weekly versus placebo. A highly relevant absolute reduction in LDL-C was achieved over time.

LDL apheresis in a woman with severe heterozygous familial hypercholesterolemia. Late, but not too late.

Familial hypercholesterolemia (FH) is an under-recognized and undertreated common lipid metabolism disorder [1, 2]. Early and intensive treatment reduces consequent mortality from coronary heart disease [3, 4]. A promising tool for retarding or arresting the atherosclerotic process in hypercholesterolemic patients refractory to maximally tolerated pharmacotherapy is LDL apheresis [5, 6].

Myocardial infarction from isolated coronary artery vasculitis in a young patient: A rare case

Symptomatic coronary artery disease (CAD) primarily occurs in patients over the age of 40, however younger men and women can also be affected. The pathophysiology of CAD in this group is often not due to atherosclerotic plaque rupture, except for those with genetically predetermined risk such as familial hypercholesterolaemia. In an autopsy study of victims aged 15–34years, advanced coronary atheromas were seen only in 2% of males aged 15–19years, and none in females [1]. Many of these cases may have had severe heterozygous familial hypercholesterolaemia (FH), which occurs with a frequency of 1:300–1:500 of the general population, and in which total cholesterol levels are very high (usually >8mmol/L) [2].

Familial hypercholesterolaemia.

Familial hypercholesterolaemia is associated with lifelong elevated cholesterol levels and is an important cause of premature coronary heart disease (CHD). This condition is often underdiagnosed and undertreated. Awareness of this condition is poor among nonlipid specialists. Treatment of elevated cholesterol levels with statins reduces the risk for CHD. The review will increase the awareness of this condition among nonspecialists. Recently, several guidelines have been produced by different countries, but a unified approach to this global problem is addressed through a recent guideline facilitated by the Familial Hypercholesterolaemia Foundation. Although the widespread use of statins has been successful in reducing the risk for CHD in familial hypercholesterolaemia, there have been difficulties in getting to targets, especially in those with established vascular disease. New therapies such as mipomersen, a second-generation antisense oligonucleotide, microsomal triglyceride transfer protein inhibitors that decrease the synthesis of apolipoprotein B-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 inhibitors hold promise in reducing cholesterol levels in those patients in whom low density lipoprotein cholesterol (LDL-C) reduction is required beyond the use of statins, especially in those with severe heterozygous familial hypercholesterolaemia or homozygous familial hypercholesterolaemia. Increased awareness and wider availability of guidance to treat familial hypercholesterolaemia will improve management of familial hypercholesterolaemia. New therapies, if they become available after appropriate outcome studies, will reduce LDL-C levels in both homozygous familial hypercholesterolaemia and severe heterozygous familial hypercholesterolaemia, thus reducing the risk for premature CHD.

Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: A study of a cohort of 14,000 mutation carriers

BackgroundSome recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with ‘severe heterozygous FH (HeFH)’. However, no uniform definition of ‘severe HeFH’ exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients. Methods and resultsWe analysed a cohort of 14,283 patients with molecularly defined HeFH, identified by the national FH screening programme in the Netherlands. Age and gender specific percentiles of untreated LDL-C were determined. The percentile corresponding to an LDL-C level of 8 mmol/L (309 mg/dL) in men aged 36–40 years (90th percentile) was selected as the cut-off value for severe HeFH. By applying this percentile-criterion to the whole cohort, 11% of the HeFH patients could be considered as having severe HeFH. Combined with an estimated HeFH prevalence of 1:300 in the Netherlands, this would translate into a prevalence of approximately 1:3,000 for severe HeFH. CVD risk was significantly increased in severe HeFH patients compared to non-severe HeFH patients (adjusted hazard ratio: 1.25 [95% CI: 1.05–1.51], p = 0.015). In line, male gender, increased age, increased BMI, smoking, hypertension, diabetes, high LDL-C and low high-density lipoprotein cholesterol were independent CVD risk factors in HeFH per se. ConclusionsWe changed the commonly used static LDL-C level of 8 mmol/L for the identification of severe HeFH into an age and gender corrected percentile. This definition would theoretically result in a prevalence of 1:3,000 for severe HeFH. Patients with severe HeFH are at increased CVD risk compared to non-severe HeFH patients, which underscores the need for more aggressive LDL-C lowering these patients.

Emerging low-density lipoprotein (LDL) therapies: Management of severely elevated LDL cholesterol—The role of LDL-apheresis

Low-density lipoprotein (LDL)-apheresis is a Food and Drug Administration-approved treatment for patients with homozygous familial hypercholesterolemia (FH) or severe heterozygous FH. Based on electrochemical principles, it selectively removes apolipoprotein B-containing lipoproteins through extracorporeal precipitation with either heparin (Heparin-induced Extracorporeal LDL Precipitation, ie, HELP) or dextran sulfate (Liposorber). LDL-apheresis can lead to an acute decrease in LDL cholesterol (LDL-C) of 70%-80%, but there is a rapid rebound to baseline levels within approximately 2 weeks. LDL-apheresis is typically performed once-a-week in patients with homozygous FH and every other week in those with heterozygous FH to produce time-average LDL-C reductions of ≈ 40%. Side effects associated with LDL-apheresis include hypotension (later found to be due to concomitant use of angiotensin-converting enzyme inhibitors), nausea/vomiting, flushing, angina, and fainting. Posttreatment bleeding can occur secondary to heparin used during the procedure. Challenges associated with LDL-apheresis include vascular access often requiring an arteriovenous fistula (fistulas may clot and require revision over time), the time associated with each treatment session (2-4 hours), the frequency of treatment, and the scarcity of medical centers which perform LDL-apheresis. Given the nature of LDL-apheresis, randomized placebo controlled trials are nearly impossible, and virtually all studies of clinical benefit have been non-randomized investigations of small numbers of subjects. Nonetheless, results from those studies support the benefits of LDL-C reduction for reducing coronary atherosclerosis and cardiovascular events.

Early diagnosis and treatment of familial hypercholesterolemia: improving patient outcomes

Familial hypercholesterolemia (FH) is the most frequent inherited disorder associated with premature coronary artery disease. Early identification and treatment of patients will reduce cardiovascular outcomes. Identification of index cases and then cascade testing in first-degree relatives using lipid levels and genetic test is the most cost-effective strategy implemented in some countries. FH patients are considered at high cardiovascular risk. Imaging techniques such as coronary computed tomography angiography could identify subjects that will require more intensive treatments. Recent guidelines recommend an LDL-C below 100 mg/dl or at least 50% LDL-C reduction if the first goal is not attained as treatment targets in heterozygous FH. Statins are the first-line agents in almost all patients, and several options exist to obtain larger LDL-C reductions like the addition of ezetimibe and/or colesevelam. Novel agents like microsomal triglyceride transfer protein inhibitors, apolipoprotein B100 antisense or PCSK9-specific monoclonal antibodies, if approved by regulatory agencies, will reduce LDL-C levels and potentially reduce cardiovascular risk in homozygous and severe heterozygous FH patients.

Pathophysiology of Severe Familial Hypercholesterolemia

Abstract Familial hypercholesterolemia (FH) is a commonly inherited autosomal-dominant disorder. As discussed in this presentation, the four principal defects occur as mutations in the genes encoding for the low-density lipoprotein cholesterol receptors, ApoB, PCSK9, or LDL RAP1, or in other as-yet unidentified genes. Severe heterozygous FH occurs in between 1 in 10,000 and 1 in 50,000 people in the United States, with the pathology resulting in lifelong elevations of the serum low-density lipoprotein cholesterol levels and in patients developing coronary heart disease prematurely compared with individuals who inherit heterozygous FH. This Journal of Clinical Lipidology open-access eCME activity (accessed at http://multimedia.lipidjournal.com/2012/SevereFH/ ) underscores that the pathophysiology of severe heterozygous FH is not different from the pathophysiology of other forms of atherosclerosis; it simply manifests more severely and decades earlier, requiring physicians to be aware of the lipid markers for this condition and of the necessity for an aggressive therapeutic response. McGowan MP. J Clin Lipidol. 2012;6(6). Accessible at http://lipidjournal.com .

O-21 DOUBLE FILTRATION PLASMAPHERESIS IN THE MANAGEMENT OF A CRIMEAN-CONGO HEMORRHAGIC FEVER CASE

regular LDL-apheresis therapy and to factors related to low compliance. We analysed 12,269 prescribed procedures of LDL-apheresis performed between 1990 and 2007 in patients with familial hypercholesterolemia (n =51). Regular LDL-apheresis treatment was initiated in patients presenting with either homozygous familial hypercholesterolemia (n =29), or severe heterozygous familial hypercholesterolemia (n =22) with elevated LDL-cholesterol levels and who did not respond adequately to diet and drug therapy; the majority of these patients (n = 29) presented cardiovascular disease at initiation of therapy. Results: The overall observed compliance rate based on the number of achieved/programmed procedures was 87.6%. Neither cardiovascular history nor subtypes of hypercholesterolemia were associated with compliance. In addition, there was no impact of patient demography on compliance. Treatment frequency alone significantly impacted noncompliance (i.e. patient with weekly procedures are less compliant). Interestingly, a no significant fall in compliance was evident among patients aged <20 years. Conclusion: Despite the complexity of the LDL-apheresis procedure and its impact on the organisation of our patients’ daily lives, overall compliance was very high. The choice of an appropriate and adequate frequency of treatment significantly impacted patient compliance.