[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.

Long-Term Efficacy and Safety of Evinacumab in Patients with Homozygous Familial Hypercholesterolemia: Real-World Clinical Experience.

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by markedly elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations from birth and increased risk of premature atherosclerotic cardiovascular disease. Evinacumab is an inhibitor of angiopoietin-like 3 protein that offers a new approach for correcting high LDL-C in HoFH. Evinacumab was administered intravenously (15 mg/kg Q4W) for 24 months in 7 patients with genetically confirmed HoFH, receiving background lipoprotein apheresis (LA) and/or lipid-lowering treatment (LLT). Assessment of efficacy and safety were carried out before and after 24 months of evinacumab treatment. The LDL-C lowering effect of evinacumab without LA were also investigated in the 7 HoFH patients after a subsequent compassionate extension period. Twenty-four months of treatment with evinacumab against background LA and LLT resulted in a significant reduction in LDL-C (−46.8%; p < 0.001). LDL-C reduction with evinacumab was maintained during the compassionate extensions period in the absence of treatment with LA (−43.4%; mean follow-up of 208 ± 90 days). Evinacumab was well-tolerated, with no major adverse event reported or significant changes in liver and muscle enzyme concentrations. Our findings suggest that evinacumab is a safe and effective treatment for patients with HoFH receiving best standard of care in a routine setting.

Lipoprotein(a) concentration, genetic variants, apo(a) isoform size, and cellular cholesterol efflux in patients with elevated Lp(a) and coronary heart disease submitted or not to lipoprotein apheresis: An Italian case-control multicenter study on Lp(a).

BACKGROUND: Coronary artery disease (CAD) risk is greater with higher plasma lipoprotein(a)[Lp(a)] concentrations or smaller apoisoform size and putatively with increased cellular cholesterol loading capacity (CLC). The relationship between Lp(a) and CLC is not known. Information on Lp(a) polymorphisms in Italian patients is lacking. OBJECTIVE: The objective of this study was to determine relationships between Lp(a) and CLC, the impact of lipoprotein apheresis (LA), and describe the genetic profile of Lp(a). METHODS: We conducted a multicenter, observational study in Italian patients with hyperLp(a) and premature CAD with (n = 18)/without (n = 16) LA in which blood samples were analyzed for Lp(a) parameter and CLC. Genetic profiling of LPA was conducted in patient receiving LA. RESULTS: Mean macrophage CLC of the pre-LA serum was significantly higher than that of normolipidemic controls (19.7 ± 0.9 µg/mg vs 16.01 ± 0.98 µg/mg of protein, respectively). After LA, serum macrophage CLC was markedly lower relative to preapheresis (16.1 ± 0.8 µg/mg protein; P = .003) and comparable with CLC of the normolipidemic serum. LA did not significantly affect average apo(a) isoform size distribution. No anthropometric or lipid parameters studied were related to serum CLC, but there was a relationship between CLC and the Lp(a) plasma concentration (P = .035). DNA analysis revealed a range of common genetic variants. Two rare, new variants were identified: LPA exon 21, c.3269C>G, p.Pro1090Arg, and rs41259144 p.Arg990Gln, c.2969G>A CONCLUSIONS: LA reduces serum Lp(a) and also reduces macrophage CLC. Novel genetic variants of the LPA gene were identified, and geographic variations were noted. The complexity of these polymorphisms means that genetic assessment is not a predictor of CAD risk in hyperLp(a).

Aorta and coronary angiographic follow-up of children with severe hypercholesterolemia treated with low-density lipoprotein apheresis.

BACKGROUND: In this single-center, nonrandomized, prospective study, 11 children with severe genetic hypercholesterolemia, without previous cardiovascular disease events, were treated with low-density lipoprotein apheresis (LDLa). STUDY DESIGN AND METHODS: LDLa was given every 1 or 2 weeks for 2 to 17 years. Clinical cardiovascular events and coronary revascularization, as well as aortic and coronary angiographic findings and ejection fractions, were serially evaluated for 2 to 17 years. RESULTS: Total cholesterol (TC) and LDL cholesterol levels at baseline were 826.1 +/- 183.3 and 767.8 +/- 181.9 mg/dL, respectively. After LDLa, these levels decreased to 122.6 +/- 24.4 and 79.1 +/- 20.7 mg/dL, respectively (both differences, p < or = 0.001). There were no cardiac deaths, and 6 children were free from any coronary lesions. Nonfatal myocardial infarction was not observed, and coronary revascularization was not required in any patient. Regression of coronary stenosis in children with existing angiographically established lesions after treatment with LDLa was prospectively demonstrated. The statistical analysis applicable to a scoring model (overall atherogenic index [OAI]) highlighted a significant relation between values of 0 to 4 years relevant to the score (p < or = 0.018) and a weaker significant statistic for the value of OAI between 0 and 2 years (p < or = 0.03). The OAI score at baseline was significantly related to the basal values of TC (p = 0.015), LDL cholesterol (p = 0.015), and triglycerides (p = 0.01), but not of high-density lipoprotein cholesterol (p = 0.075) as demonstrated by the logistic regression analysis (Cox and Snell pseudo-R(2) of 0.67). CONCLUSION: LDLa interrupted the development of new aortic and coronary lesions in the native arteries and prevented cardiac events and the need for coronary revascularization in children without previous cardiovascular disease events.

LDL apheresis: a novel technique (LIPOCOLLECT 200).

Therapeutic means to lower Lp(a) are limited. The most effective method to reduce plasma Lp(a) concentration significantly is therapeutic apheresis, namely, low-density lipoprotein (LDL) lipoprotein(a) (Lp(a)) apheresis. A novel technique based on reusable LDL adsorber called Lipocollect 200 (Medicollect, Rimbach, Germany) allows the removal of both LDL and Lp(a) from plasma. Two male patients with hyperLp(a)lipoproteinemia and angiographically established progressive coronary heart disease, without rough elevation of LDL-cholesterol, who did not respond to diet and medication were submitted to 50 LDL Lp(a) aphereses with Lipocollect 200 LDL Lp(a)-adsorber at weekly and biweekly intervals. Total cholesterol and LDL cholesterol plasma levels fell significantly by 48.3% (+/-6.7) to 61.6% (+/-12.7) (first patient), and 42.5% (+/-6.3) to 60.6% (+/-14.3) (second patient), respectively (all differences: P < or = 0.001). High-density lipoprotein (HDL)-cholesterol concentration in plasma did not show statistically significant change. Plasma triglycerides were also significantly reduced by 43.6% (+/-24.4) (first patient) and 42.3% (+/-13) (second patient) (both differences: P < or = 0.001). Plasma Lp(a) showed a statistically significant percent reduction in plasma as expected: 64.7 +/- 9.5 (first patient), and 59.1 +/- 6.7 (second patient) (both differences: P < or = 0.001). Plasma fibrinogen concentration was decreased by 35.9% (+/-18.7) (P < or = 0.05) (first patient) and 41.8% (+/-11.5) (second patient) (P < or = 0.005). Considering the reduction rate between the first and the last procedures, we have compared the mean percent reduction of the first five treatments (from session #1 to #5) with the last five treatments (from session #21 to #25). We have observed an increasing reduction of all activity parameters on both patients apart from HDL-cholesterol (first patient) and triglyceride (second patient) that showed a decreasing reduction rate. Both patients followed the prescribed schedule and completed the study. Clinically, all sessions were well tolerated and undesired reactions were not reported. The Lipocollect 200 adsorber proved to have a good biocompatibility. In this study, the adsorber reusability for several sessions was confirmed.

Therapeutic plasma exchange in patients with severe hypertriglyceridemia: a multicenter study.

Extremely high plasma triglyceride (TG) concentration is a recognized risk factor for acute pancreatitis (AP). In order to evaluate the therapeutic efficacy of plasma-exchange plasmapheresis in treating patients with severe hypertriglyceridemia (sHTG), 17 patients who had not responded to conventional medical therapy (fat-free diet plus pharmaceutical interventions) were referred for therapeutic plasma exchange (TPE) in a multicenter frame case series study. Two hundred seventeen TPE sessions were performed, and therapy is ongoing for five (30%) of the patients. After treatment, the mean plasma TG and total cholesterol concentrations were significantly reduced from 1929 and 510 mg/dL, to 762 and 227 mg/dL, respectively (P < or = 0.001 in both cases). In most cases, the interval between treatments was related to the clinical presentation and individual circumstances. The removal of TG-rich lipoproteins prevented relapses of AP. In this case series, TPE is confirmed as a safe and reliable method for treating patients with refractory sHTG when a severe complication, such as AP, is clinically demonstrated or can be actively prevented. Therefore, in cases where standard medical approaches fail to promote the clearance of TGs from plasma and a high risk of first or second hypertriglyceridemic pancreatitis persists, TPE provides a therapeutic option for preventing life-threatening sHTG.

Immunoadsorption apheresis and immunosuppressive drug therapy in the treatment of complicated HCV-related cryoglobulinemia.

The immunosuppressive drug therapy (IDT) is not always effective to avoid the development of complications in hepatitis C virus-related cryoglobulinemia (HCV-Cr). Removal of cryoglobulins by therapeutic plasmapheresis is currently accepted. In this randomized, parallel group study, 17 male and female patients aged 43-79 years, with complicated HCV-Cr, were submitted for 12 weeks (initial immunosuppressive therapy) to IDT (alpha-interferon, pegylated-interferon alpha-2a, cyclophosphamide, methylprednisolone, prednisone, cyclosporine, ribavirin, and melphalan). Then, they were randomly assigned to two parallel groups: A # 9 patients treated by immunoadsorption apheresis (Selesorb((R))) (IA) plus IDT, and B # 8 patients submitted to IDT only, for further 12 weeks. # 187 IA aphereses were performed. No adverse reactions or complications were observed. A Clinical Score (CS) was adapted from a pre-existing scoring model to evaluate signs and symptoms inherent to the underlying immunologic disorder. The CS was calculated at baseline (CS0), after the initial immunosuppressive therapy (CS1 = 12 weeks) when patients were treated only with IDT, and at the end of the study (24 weeks) in the group A (CSA; IA plus IDT) and B (CSB; IDT only). The score did not change significantly from CS0 to CS1. However, statistically significant differences were observed between CS1 and CSA (P < 0.001), and CSA versus CSB (P = 0.03), respectively. The changes observed were favorable to the patients assigned to the IA plus IDT group (A): in most case relief of symptoms and complications have been obtained.

A complicated pregnancy in homozygous familial hypercholesterolaemia treated with lipoprotein apheresis: A case report.

BACKGROUND AND AIMS: During pregnancy total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels increase significantly and lipoprotein apheresis (LA) is considered the most effective therapy in homozygous familial hypercholesterolaemia (HoFH) for modulating lipid and lipoprotein levels and reducing maternal and foetal complications. CLINICAL CASE: A primigravida 28 years old Caucasian female patient, previously diagnosed as to be HoFH, was admitted at our outpatient service at the beginning of pregnancy. METHODS: The patient was continuously submitted to LA every two weeks without foetal complication. During pregnancy two methods have been utilised: selective apheresis, and later plasma exchange. At 33 weeks gestational age the patient developed progressively hypertension, associated to LDL-C levels increase. Weekly LA was favoured. RESULTS: At 34 weeks +5 days patient suddenly experienced acute chest pain and abnormal electrocardiogram heart tracing and cardiac enzymes increase. An emergency caesarean section was performed without complications and the foetus was healthy. The patient was immediately transferred to Coronary Intensive Care Unit, where she was diagnosed non-ST elevation myocardial infarction (NSTEMI). Notwithstanding the patient improved in few days and was quickly discharged in fair clinical condition. CONCLUSIONS: LA is a safe and effective tool in HoFH subjects even in pregnancy. Evidence based guidelines for the management of these patients during pregnancy are still lacking.

A successful term pregnancy with severe hypertriglyceridaemia and acute pancreatitis. Clinical management and review of the literature.

BACKGROUND AND AIMS: Acute hyperlipidaemic pancreatitis (HP) may develop in pregnancy in patients with genetic predisposition. There are no accepted guidelines for the management of this rare but life-threatening condition in pregnancy. Plasma exchange (PEX) was suggested as a suitable option to treat HP in pregnancy; however, further evidence from case reports/case series are needed. METHODS: Three PEX procedures (2000 ml of plasma replaced with 5% albumin) were performed in one week in a pregnant patient at 25 weeks of gestational age with severe HP. Triglyceride related genes (LPL, APOA5, APOE, GPIHBP1, GPD1, LMF1, CREB3L3) were screened by DNA sequencing. Medline and Embase databases were searched electronically in January 2018 using different combinations of the relevant medical subject headings for "pancreatitis in pregnancy" and "therapeutic apheresis". RESULTS: Gene profiling assessed a combined heterozygous state for the variants pSer19Trp of the APOA5 gene and pCys130Arg of the APOE (allele E4) gene. PEX led to significant and progressive reduction of triglyceride plasma levels along with cholesterol and C-reactive protein. Meanwhile a fast improvement of pregnant clinical condition was observed. This allowed the delivery at term of a healthy newborn without gestational complications. An outcome hardly achievable in patients managed exclusively by a pharmacological approach. CONCLUSIONS: PEX led to a positive maternal outcome in absence of foetal and gestational complications in a case of severe HP in pregnancy. As clinical trials are lacking, case reports still represent the best way to reasonably implement clinical management of this rare but life-threatening disease.

A cross-national investigation of cardiovascular survival in homozygous familial hypercholesterolemia: The Sino-Roman Study.

BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) is a rare inherited disorder characterized by extreme elevation of low-density lipoprotein (LDL) cholesterol, accelerated coronary artery disease, and premature death. Aggressive LDL-lowering therapies are important for survival, but these are not available worldwide. OBJECTIVE: The aim of the study was to compare and contrast cardiovascular outcomes and mortality of hoFH patients in 2 countries with disparate use of lipoprotein apheresis (LA) and modern therapies for lowering LDL cholesterol. METHODS: A retrospective study was undertaken comparing cardiovascular disease (CVD)-free survival and mortality in 44 hoFH patients who were treated with statins but not LA, from a center in Beijing, China, and 18 hoFH patients who were treated with LA and novel therapies from an early age, from a center in Rome, Italy. RESULTS: CVD-free survival and survival were significantly reduced in Chinese patients compared with the Italian patients after 30 years of follow-up (log-rank P < .01). In a pooled analysis, cardiovascular survival was significantly increased with earlier age at treatment, longer duration of treatment, and lower on-treatment LDL cholesterol concentrations (P < .05). In addition, the probability of a CVD event and death were increased in patients that carried a null mutation in the LDLR or had elevated lipoprotein(a). CONCLUSIONS: We show that coronary artery disease outcomes in patients with hoFH can be significantly improved with earlier and potent LDL cholesterol lowering with pharmacotherapies and LA. This has major implications for countries, such as China, where the models of care for hoFH remains underdeveloped.

Optical coherence tomography of retinal and choroidal layers in patients with familial hypercholesterolaemia treated with lipoprotein apheresis.

PURPOSE: Detect and quantify morpho-functional alterations of the retina and choroid in patients affected by familial hypercholesterolemia (FH) treated with lipoprotein apheresis (LA) using optic coherence tomography (OCT) and optic coherence tomography-angriography (OCTA). DESIGN: Observational study. SUBJECTS: To be diagnosed: A group of 20 patients (40 eyes) being clinically and genetically diagnosed as FH and under treatment (FH-Group)", for at least 2 years, was compared to a control group of 20 healthy subjects (40 eyes), with a normal lipid profile and no ocular disease (CT-Group). METHODS: Participants were studied with the slit lamp, binocular indirect fundoscopy, OCT and OCTA. MAIN OUTCOME MEASURES: Best corrected visual acuity (BVCA), spherical equivalent (SE), intraocular pressure (IOP), central macular thickness (CMT), choroidal thickness (CHT), retinal nerve fiber layer in four quadrants (RNFL (Superior = Sup; Inferior = Inf; Nasal = Nas Temporal = Temp), and the mean value across the four quadrants (RNFL G), foveal avascular zone (FAZ) and vascular density (VD). RESULTS: FH subjects had smaller RNFL superiorly (108 ±â€¯19,38 µm OD/111 ±â€¯16,56 µm OS FH-Group vs 127 ±â€¯7,42 µm OD/129 ±â€¯14,64 µm OS CT-Group; P < 0,001 for both OD and OS) and inferiorly (108 ±â€¯23,58 µm OD/115 ±â€¯17,33 µm OS FH-Group vs 128 ±â€¯18,15 µm OD/133 ±â€¯17,38 µm OS CT-Group; P = 0,002 OD; P = 0,001 OS). G RNFL was consequently smaller (93 ±â€¯12,94 µm OD/94 ±â€¯10,49 µm OS FH-Group vs 101 ±â€¯9,01 µm OD/101 ±â€¯10,20 µm OS CT-Group; P = 0,03 OD; P = 0,02 OS). FH subjects had a larger FAZ (0,31 ±â€¯0,08 mm2 OD/0,33 ±â€¯0,10 mm2 in OS FH-Group vs 0,21 ±â€¯0,05 mm2 OD/0,21 ±â€¯0,07 mm2 OS CT-Group; P < 0,001 OD; P = 0,002 OS). CONCLUSIONS: Early signs of retinal vessel damage in FH patients can be detected and quantified with OCT and OCTA.

Effects of low-dose atorvastatin and rosuvastatin on plasma lipid profiles: a long-term, randomized, open-label study in patients with primary hypercholesterolemia.

BACKGROUND AND OBJECTIVE: Despite the favorable effects of reduction of low-density lipoprotein-cholesterol (LDL-C) levels in decreasing the risk of coronary heart disease, many patients treated with lipid-lowering HMG-CoA reductase inhibitors (statins) do not achieve goal LDL-C levels. This may be due to high doses of statins prescribed that could potentially induce adverse effects and compromise patient safety and compliance with considerable expense in the long-term. We compared the actions of rosuvastatin and atorvastatin, administered at the low dosages of 10 and 20 mg/day, respectively, in reducing plasma LDL-C levels and their effects on other components of the atherogenic lipid profile in patients with primary hypercholesterolemia. METHODS: In this randomized, parallel group, open-label clinical study, 106 patients with LDL-C >200 mg/dL were treated with rosuvastatin 10 mg/day (group A; n = 52), or atorvastatin 20 mg/day (group B; n = 54) for 48 weeks. RESULTS: At 48 weeks, rosuvastatin 10 mg/day was associated with a significantly greater reduction in plasma LDL-C levels compared with atorvastatin 20 mg/day (-44.32% vs -30%; p < 0.005). Compared with atorvastatin, rosuvastatin also produced a greater reduction in plasma total cholesterol, triglycerides, and non-high-density lipoprotein-cholesterol (non-HDL-C) levels (p < 0.005). Plasma HDL-C levels were not affected significantly, independent of the drug used. CONCLUSION: In high-risk patients with primary hypercholesterolemia, rosuvastatin 10 mg/day was more efficacious than atorvastatin 20 mg/day in reducing plasma LDL-C levels, enabling goal LDL-C levels to be achieved and improving other lipid parameters. Both treatments were well tolerated over 48 weeks.

Monascus purpureus for statin and ezetimibe intolerant heterozygous familial hypercholesterolaemia patients: A clinical study.

BACKGROUND: Hypercholesterolaemia is a major risk factor for cardiovascular disease and requires effective therapy in affected patients. Statins, the mainstay of lipid-lowering therapy, can cause side effects, including myalgia, in some patients. Ezetimibe, is frequently used as an add-on therapy for statins, and is also used as a monotherapy in statin-intolerant patients, however elevations in liver transaminases can occur. We examined the lipid-lowering efficacy of the natural fungal product Monascus purpureus (MP), which contains the natural statin monacolin K. METHODS: Fifty-five patients with familial hypercholesterolaemia who had discontinued statins due to muscle symptoms. Patients were placed on a lipid-lowering diet cholesterol-lowering diet (1500-1800 kcal daily, 30% lipids, 19% proteins and 52% carbohydrates). MP was added to the diet at a dose of 300 mg (providing monacolin K 10 mg). Patients were followed for 12 months. Lipid profiles and adverse event data were collected in the normal course of patient care. RESULTS: After 6 months of treatment with MP and diet therapy, statistically significant changes in low-density lipoprotein cholesterol were evident (-17% for males, -16% for females; p < 0.005) Levels fell to -24% and -27% respectively at 12 months. No patients experienced elevated serum aminotransferases or C-reactive protein levels. CONCLUSIONS: MP is a viable option for lipid-lowering therapy in statin-intolerant patients with hypercholesterolaemia, with good efficacy and safety profiles.

Lipoprotein apheresis downregulates IL-1α, IL-6 and TNF-α mRNA expression in severe dyslipidaemia.

BACKGROUND AND AIMS: Dyslipidaemias are associated with cardiovascular mortality and morbidity, driven by unstable atherosclerotic plaques with inflammatory infiltrates. Levels of messenger RNA (mRNA) for pro-inflammatory cytokines have been positively correlated with atherosclerotic disease progression. Therapeutic lipoprotein apheresis (LA) reduces plasma lipid levels and reduces inflammation. We evaluated the effects of LA on expression of mRNA coding for key pro-inflammatory cytokines in patients with dyslipidaemia, homo-/hetero-zygous familial hypercholesterolaemia (HoFH, HeFH) or hyperlipoprotein(a)aemia [hyperLp(a)] and associated coronary artery disease (CAD). APPROACH: Ten patients (five males and five females, mean age 47 ± 9.2 years) were enrolled, all with HyperLp(a) or confirmed genetic diagnoses of dyslipidaemia, HoFH, or HeFH; all had associated CAD. mRNA determinations were via reverse transcriptase polymer chain reaction (RT-qPCR). RESULTS: LA was associated with downregulation of mRNA expression for IL-1α, IL-6 and TNF-α, starting after the first LA session. The observed reduction was progressively enhanced during the interval between the first and second LA sessions to achieve a maximum decrease by the end of the second session (IL-1α: -49%, p < 0.001; IL-6: -35%, p < 0.001; TNF-α: -56%, p < 0.001). CONCLUSIONS: LA suppresses the expression of IL-1α, IL-6 and TNF-α mRNA in patients with dyslipidaemias. This may contribute to the arterial anti-inflammatory effect of LA.

Management of homozygous familial hypercholesterolemia in real-world clinical practice: A report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, genetically determined condition of highly elevated low-density lipoprotein cholesterol (LDLC) levels. If untreated, patients do not typically survive beyond the second decade of life. Traditional lipid-lowering therapies (statins and ezetimibe) are largely ineffective in HoFH patients, and extracorporeal lipoprotein apheresis (LA) forms the mainstay of treatment. Lomitapide is a microsomal triglyceride transfer protein inhibitor approved for the treatment of HoFH as an adjunct to LA. We undertook to examine the efficacy and safety of lomitapide in 7 HoFH patients treated with LA in the Lipid Clinic and Therapeutic Apheresis Unit in Rome, Italy outside a clinical trial setting. METHODS: Seven patients with genetically determined HoFH were treated with lomitapide in the normal course of their therapy. All patients received LA either weekly or biweekly. Lomitapide was administered according to the approved European Union prescribing information. LDLC levels, liver enzymes, and hepatic fat were monitored. Length of follow-up varied between 12 and 50 weeks. RESULTS: After titration, lomitapide doses ranged from 10 to 30 mg/d for most (5/7) patients. One patient received lomitapide 60 mg/d and another 5 mg/d. Three patients achieved LDLC reductions of >50%. The patient on the lowest lomitapide dose did not gain significant benefit. Gastrointestinal adverse events (AEs) were managed via alterations to dietary fat intake. CONCLUSION: Lomitapide is an effective adjunct to LA in patients with HoFH. AEs are manageable; gastrointestinal AEs can be managed with a low-fat eating plan.

Cyclophosphamide and immunoadsorption apheresis treatment of lupus nephritis nonresponsive to drug therapy alone.

In this report we present a 28-year-old male patient with systemic lupus erythematosus (SLE) that was treated with immunoadsorption apheresis (IA) and cyclophosphamide for lupus nephritis (proliferative glomerulonephritis, class IV-B) after proving nonresponsive to drug therapy alone. Before starting the therapeutic cycle with IA, the patient was administered prednisone 25 mg/d, hydroxychloroquine 200mg twice/d, ACE inhibitors 5 mg/d, aspirin 100 mg/d, furosemide 50 mg/d, and intravenous (IV) albumin (20%) 50 mL. Deteriorating clinical conditions necessitated a renal biopsy, and thereafter an increase in medication. The patient was given a bolus of IV cyclophosphamide 1 g/d for 1 day and IV methylprednisone 500 mg/d for 3 days. This was not followed by any improvement and the renal functions worsened. Thus, 3 weeks after the more aggressive pharmacologic treatment with cyclophosphamide, which had been prescribed to improve renal function, and given the young age of the patient, the decision was made to administer IA (Selesorb). IA selectively removes IgG and IgM immune complexes from the plasma, thereby reducing the complications induced by the pathogenic autoimmune reaction. The treatment was administrated twice a week for the first 15 days, once a week for a further 5 weeks, and biweekly in the last month with a bolus of cyclophosphamide (average 250-100 mg) after each session. After twelve sessions of IA over 3 months, renal function was completely restored and the patient discharged. Although it is not proven, the concomitant use of cyclophosphamide could presumably improve the final clinical outcome.

Italian multicenter study on low-density lipoprotein apheresis Working Group 2009 survey.

We present results of the second survey of the Italian Multicenter Study on Low-Density Lipoprotein Apheresis (IMSLDLa-WG/2). The study involved 18 centers in 2009, treating 66 males and 35 females, mean age 47 ± 18 years. Mean age for initiation of drug treatment before low-density lipoprotein apheresis (LDLa) was 31 ± 18 years, mean age to the first LDLa was 37 ± 20 years and average duration of treatment was 9 ± 6 years. The techniques used included direct adsorption of lipids, dextran sulfate cellulose adsorption, heparin-mediated low-density lipoprotein (LDL) precipitation, cascade filtration, and plasma exchange. The mean treated plasma/blood volumes/session were 3127 ± 518 mL and 8666 ± 1384 mL, respectively. The average plasma volume substituted was 3500 ± 300 mL. Lipid therapy before LDLa included ezetimibe, statins, ω-3 fatty acids and fenofibrate. Baseline mean LDL cholesterol (LDLC) levels were 386 ± 223 mg/dL. The mean before/after apheresis LDLC level decreased by 67% from 250 ± 108 mg/dL (P = 0.05 vs. baseline) to 83 ± 37 mg/dL (P = 0.001 vs. before). Baseline mean Lipoprotein(a) [Lp(a)] level was 179 ± 136 mg/dL. Mean before/after apheresis Lp(a) level decreased by 71% from 133 ± 120 mg/dL (P = 0.05 vs. baseline) to 39 ± 44 mg/dL (P = 0.001 vs. before). Major and minor side effects occurred in 27 and 62 patients, respectively. Among patients with coronary artery disease (CAD), 62.3% had coronary angiography and 50.4% coronary revascularization before LDLa. Single vessel, double vessel and triple vessel CAD occurred in 19 (30.1%), 15 (23.8%) and 29 (46%) patients, respectively. Both CAD and extra-CAD occurred in 41.5%, 39% had hypertension, 9.9% were smokers, 9.9% consumed alcohol and 42% were physically active. Ischemic cardiovascular events were not observed in any patient over 9 ± 6 years of treatment. Two centers have also treated 34 patients (females: 17/males 17; no. sessions: 36; average plasma volume treated: 3000 mL) for sudden hearing loss (SHL). Relief of symptoms was obtained, independently of the system used (HELP; cascade-filtration).

A three month-old infant with severe hyperchylomicronemia: molecular diagnosis and extracorporeal treatment.

OBJECTIVE: Chylomicronemia syndrome presenting in childhood is a rare recessive disorder due to mutations of lipoprotein lipase (LPL) and more rarely of APOC2, APOA5, GPIHBP1 or LMF1 genes. It often requires urgent and suitable treatment to avoid acute pancreatitis. The aim of this study was the molecular characterization and treatment of a 3 month-old infant with plasma triglycerides (TG) > 300 mmol/L. METHODS: All candidate genes were sequenced. The patient was submitted to one plasma-exchange (PEX) procedure and subsequently to a rigid lipid-lowering diet (milk: Monogen(®)). RESULTS: The proband was homozygous for a novel LPL mutation (c.242G > A, p.G81D) which in silico results pathogenic. After PEX, which was well tolerated, TG dropped to 64 mmol/L. During 5-month follow-up there was a clear trend towards lower and stable TG values. CONCLUSION: PEX is applicable in subjects with very low body weight when the extreme severity of the clinical picture has no therapeutic alternatives.

Combined treatment with Dif1stat and diet reduce plasma lipid indicators of moderate hypercholesterolemia more effectively than diet alone: a randomized trial in parallel groups.

An open-labeled randomized trial with parallel groups was carried out to study the effects of Dif1stat (Monascus purpureus-Linear aliphatic alcohols-Niacin) in the treatment of primary moderate hypercholesterolemia. The trial lasted 8 months. The patients, males and females, were assigned to two groups: A (#130), treated with diet, and B (#110) submitted to diet + Dif1stat. After 4 months, group A did not show significant changes in Total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC) or non-HDL-cholesterol (non-HDLC). The same group, showed a reduction in TC (-22%), LDLC (-30%) and non-HDLC (-27%) after 8 months (P < or = 0.001). After 4 months, TC (-21.3%), LDLC (-29%), and non-HDLC (-26%) were significantly lowered in group B (P < or = 0.001). In group B, TC, LDLC and non-HDLC showed a further reduction after 8 months: -29.4, -38 and -37%, respectively (P < or = 0.001). Even triglycerides (TG) decreased significantly (-33%) (P < or = 0.001). After 8 months, group B showed a significant reduction of TG (-33%) (P < or = 0.001), when compared to group A. Some safety parameters were significantly reduced in both groups: AST and gamma-GT in group A after 4 and 8 months, as well as ALT, AST and gamma-GT in group B after 8 months (P < or = 0.001). Dif1stat, given with a suitable diet, was well tolerated in the long-term and induced an anti-atherogenic plasma lipid and lipoprotein profile, in patients with moderate hypercholesterolemia.