Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low-density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report.

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m2 ) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic-pump inhibitor. In the absence of specific lipid-lowering therapy, plasma lipid levels at first visit were: total-cholesterol = 522 mg/dL, LDL-cholesterol = 434 mg/dL, HDL-cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24-week treatment, the LDL-cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL-apheresis (H.E.L.P.system) was started as add-on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL-cholesterol was reduced by 49.4%, thus reaching an inter-apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein-apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.

Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort.

BACKGROUND AND AIMS: The efficacy and safety of lomitapide as adjunct treatment for adults with homozygous familial hypercholesterolaemia (HoFH) have been confirmed in a phase 3 trial. Given the small number of patients (N = 29), and variations in patient characteristics, examining individual cases provides additional details regarding patient management with lomitapide. Here, we examine the details of the Italian patient cohort in the phase 3 trial. METHODS AND RESULTS: The methodology of the multinational, single-arm, open-label, 78-week, dose-escalation, phase 3 trial has been previously reported. The current report details the Italian cohort of six patients (three males, three females) based on individual patient data, individual patient histories and narratives, and by mean data ± SD. Lomitapide was administered according to the dose-escalation protocol. At Week 78, concentrations of low-density lipoprotein-cholesterol were decreased by a mean of 42.6 ± 21.8% compared with baseline. Lomitapide was similarly well tolerated in the Italian cohort as in the entire study population. The most common adverse events were gastrointestinal symptoms. One patient showed an increase in liver transaminases >5× upper limit of normal that resolved after lomitapide treatment was reduced and maintained at a lower dose. CONCLUSION: The efficacy, safety and tolerability of lomitapide demonstrated in the Italian subgroup of patients are consistent with findings in the entire study population, and illustrate the broad applicability of lomitapide therapy across genotypes and clinical phenotypes. These data also provide an insight into the management of lomitapide use in a cohort of patients within a clinical trial protocol. Clinicaltrials.gov Identifier: NCT00730236.

How new imaging techniques can aid in defining the cardiovascular profile of the high-risk patient.

Cardiovascular prevention has been developed in the last eight years producing an ever increasing amount of data requiring frequent updating. Studies using angiography to determine change in coronary obstruction have indicated progression, stabilization, or regression of coronary lesions associated with changes in plasma lipids and lipoproteins. Moreover, the guidelines on arterial hypertension published in 2007 listed the risk factors affecting prognosis but even by 2009 an update modified not only the list of risks, but even the philosophy behind the thought process which introduced as essential element in the prognosis of hypertension the ascertained existence of a damaged organ. Thus, the documentation of atherosclerotic vascular disease (plaques) and the quantification of its extension in the arterial tree became a determinant in the definition of cardiovascular risk. Magnetic Resonance (MRI) and coronary computed tomography (coro CT) applied to the heart and large vessels are the most promising methods.

The lipid- and lipoprotein- [LDL-Lp(a)] apheresis techniques. Updating.

Therapeutic plasmapheresis allows the extracorporeal removal of plasmatic lipoproteins (Lipid-apheresis) (LA). It can be non selective (non specific), semi - selective or selective low density lipoprotein-lipoprotein(a) (specific [LDL- Lp(a)] apheresis) (Lipoprotein apheresis, LDLa). The LDL removal rate is a perfect parameter to assess the system efficiency. Plasma-Exchange (PEX) cannot be considered either specific nor, selective. In PEX the whole blood is separated into plasma and its corpuscular components usually through centrifugation or rather filtration. The corpuscular components mixed with albumin solution plus saline (NaCl 0.9%) solution at 20%-25%, are then reinfused to the patient, to substitute the plasma formerly removed. PEX eliminates atherogenic lipoproteins, but also other essential plasma proteins, such as albumin, immunoglobulins, and hemocoagulatory mediators. Cascade filtration (CF) is a method based on plasma separation and removal of plasma proteins through double filtration. During the CF two hollow-fiber filters with pores of different diameter are used to eliminate the plasma components of different weight and molecular diameter. A CF system uses a first polypropylene filter with 0.55 µm diameter pores and a second one of diacetate of cellulose with 0.02 µm pores. The first filter separates the whole blood, and the plasma is then perfused through a second filter which allows the recovery of molecules with a diameter lower than 0.02 µm, and the removal of molecules larger in diameter as apoB100-containing lipoproteins. Since both albumin and immunoglobulins are not removed, or to a negligible extent, plasma-expanders, substitution fluids, and in particular albumin, as occurs in PEX are not needed. CF however, is characterized by lower selectivity since removes also high density lipoprotein (HDL) particles which have an antiatherogenic activity. In the 80's, a variation of Lipid-apheresis has been developed which allows the LDL-cholesterol (LDLC) (-61%) and Lp(a) (-60%) removal from plasma through processing 3 liters of filtered plasma by means of lipid-specific thermofiltration, LDL immunoadsorption, heparin-induced LDL precipitation, LDL adsorption through dextran sulphate. More recently (90's) the DALI®, and the Liposorber D® hemoperfusion systems, effective for apoB100- containing lipoproteins removal have been developed. All the above mentioned systems are established LDL-apheresis techniques referable to the generic definition of LDLa. However, this last definition cannot describe in an appropriate manner the removal of another highly atherogenic lipoprotein particle: the Lp(a). Thus it would be better to refer the above mentioned techniques to the wider scientific and technical concept of lipoprotein apheresis.

Cytokines profile in serum of homozygous familial hypercholesterolemia is changed by LDL-apheresis.

OBJECTIVE: The effects of LDL-apheresis (LDLa) with dextran sulphate on plasma cytokines in 6 homozygous familial hypercholesterolemic (HozFH) patients, were evaluated. METHODS: Plasma IL-1α; IL-1ra; IL-4; IL-6; IL-10; IL-12(p40); IL-12(p70); TNF-α, sTNF-R, VEGF, VEGF-R1, E-Selectin (ESEL), and P-Selectin (PSEL) concentrations were measured before and after LDLa on three consecutive sessions for each patient. RESULTS: TNF-α was significantly reduced (-60%; P=0.01), while TNF-R was only slightly increased (+15%), although not significantly. Plasma VEGF was significantly reduced (-57%; P=1.87301E-05), while VEGF-R1 was significantly increased (+56%; P=0.05). ESEL and PSEL were reduced but not to a statistically significant extent (-19%, -15%, respectively). IL-1α level was dramatically reduced (-87%; P=0.0001). IL-1ra concentration was only slightly increased in plasma, but not significantly. IL-4 and IL-10 levels were significantly reduced in plasma after apheresis (-50%; P=0.03, and -55%; P=0.004, respectively). On the contrary, IL-6 concentration showed a slight decrease (-8%). Plasma IL-12p40 was significantly increased (+47%; P=0.0004). On the other hand, IL-12p70 was reduced, but the difference (-31%) was not statistically significant. CONCLUSIONS: Plasma cytokines imbalance is associated with inflammation and atherogenesis. In this study LDLa changed several circulating cytokines inducing anti-inflammatory and anti-atherogenic changes in cytokines plasma profile in HozFH patients with/without pre-existing angiographically demonstrated coronary heart disease (CHD) and aortic valvular disease (AVD).

Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis.

BACKGROUND: Hyperlipidemic pancreatitis (HP) is caused by severe hypertriglyceridemia (SHTG). Evidence of SHTG refractoriness to standard medical treatment but not to therapeutic apheresis has increased in the last years. METHODS: Described is the timing of clinical events and the sequence of therapeutic plasma-exchange (TPE) procedures to treat pancreatitis due to SHTG in a male patient, Caucasian, aged 49years, referred to emergency for severe epigastric pain. There was no history of alcohol consumption, a pre-existing mild hyperlipidemia was treated with diet alone, and biliary imaging was normal. Physical examination revealed epigastric tenderness. Laboratory investigation revealed marked hypertriglyceridemia (11,355mg/dL; range: 30-150), and hypercholesterolemia (941mg/dL; range: 80-200). Serum amylase (Amy) and lipase (Lip) were increased: 160UI/L (range: 20-100) and 175UI/L (range: 13-60), respectively. A computerized tomography (CT) scan of the abdomen revealed a picture compatible with acute pancreatic phlogosis. It was diagnosed as "acute secondary pancreatitis (AP) and SHTG". RESULTS: The patient was successfully submitted to three sessions of TPE in emergency. He was released from hospital after 13 days of hospitalization. The levels of lipids and lipoproteins in his plasma were as follows: triglycerides (TG) 185mg/dL; total cholesterol (TC) 179mg/dL; HDL-cholesterol (HDLC) 22mg/dL; LDL-cholesterol (LDLC) 120mg/dL. CONCLUSIONS: The decision to submit the patient with clinical evidence of HP caused by SHTG to apheresis was correct. The improvement in the clinical picture was fast and the recovery was complete.

The 2009 2nd Italian Consensus Conference on LDL-apheresis.

The '2009 2nd Italian Consensus Conference on LDL-apheresis' was held in Rome, Italy, 15 May 2009. The latest scientific evidence and the information processed in more than two decades of LDL-apheresis application require new guidelines. Experts were invited by the Consensus Panel to give a scientific specific contribution in their clinical area of specialty. The experts of interdisciplinary affiliation participated in the extension of 'The new guidelines and recommendations for the indications and the appropriate use of LDL-apheresis'. The summary statement describing the frame and the lines of action of the scientific event and a supplementary document inherent to the Consensus available online at http://ees.elsevier.com/nmcd/ are reported.

Treatment of symptomatic hyperLp(a)lipidemia with LDL-apheresis vs. usual care.

BACKGROUND/AIMS: To assess LDL-apheresis efficacy to lower Lp(a) and to compare the effects of Usual Medical Care (UMC) a 12-months study was carried out. The incidence of new coronary artery disease (CAD) events/need of revascularization, was also monitored. METHODS: Twenty-one patients with hyperLp(a)lipidemia and angiographically documented CAD were randomly assigned to LDL-apheresis every week, or the UMC. RESULTS: LDL-apheresis group, averaged an Lp(a) reduction of 57.8+/-9.5% vs. basal values (P<0.001). In the UMC group Lp(a) increased in 1 year to 14.7+/-36.5% (P=0.66). Stepwise multivariate regression analysis for predictors of Lp(a) including: type of treatment, smoking, hypertension, age, age at first cardiovascular event, initial Lp(a), LDL, and BMI values, was performed. Only the type of treatment was co-related (P<0.001): Lp(a) variation (beta)=0.863. The model has R2 adjusted relative risk of 0.725. CONCLUSION: LDL-apheresis could be the first line treatment of isolated hyperLp(a)lipidemia when CAD is established. New CAD events/cardiac interventions were not observed.

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high density lipoprotein cholesterol lower (-5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients >30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors.

Platelet entropy is increased in familial hypercholesterolemia and in type 2 diabetic patients.

AIM: A plethora of abnormalities in platelet function have been described in diabetic patientsas well in familial hypercholesterolemia. This paper investigates the use of computerized fractal analysis for objective characterization of the entropy of the platelet surface of circulating platelets collected from healthy individuals, from type 2 diabetic patients and from familial hypercholesterolemic subjects, in order to search a structural biomarker to distinguish between them. METHODS: Circulating platelets were collected from 11 type 2 diabetic patients, from 6 familial hypercholesterolemic patients and 5 healthy subjects as platelet rich plasma. Platelet boundaries were observed by transmission electron microscopy and extracted by means of automatically image processing. The information dimension (entropy of the platelet contour) was automatically calculated. RESULTS: Platelet boundary observed by electron microscopy is fractal. Entropy of the platelet surface in the circulating platelets is significantly increased in the diabetic patients in comparison to healthy subjects (P<0.001), as well in familial hypercholesterolemic patients (P<0.01), with 100% correct classification in selected subjects. In vitro activated platelets from healthy subjects show an analogous increase of platelet entropy. CONCLUSION: Computerized shape analysis of circulating platelets observed by transmission electron microscopy provides accurate, quantitative, data to study platelet activation at morphological level in atherosclerosis-linked condition, as diabetes mellitus and familial hypercholesterolemia, able to distinguish the activated platelets of the patients from the platelets of healthy subjects. This method may be promising to follow the platelet activation in the circulating blood at morphological level in pathophysiological condition linked to platelet activation and after administration of drugs or other therapeutic procedures.

First on-line survey of an international multidisciplinary working group (MightyMedic) on current practice in diagnosis, therapy and follow-up of dyslipidemias.

The MightyMedic (Multidisciplinary International Group for Hemapheresis TherapY and MEtabolic DIsturbances Contrast) Working Group has been founded in 2013. The leading idea was to establish an international network of interdisciplinary nature aimed at working to cross national borders research projects, clinical trials, educational initiatives (meetings, workshops, summer schools) in the field of metabolic diseases, namely hyperlipidemias, and diabetes, preventive cardiology, and atherosclerosis. Therapeutic apheresis, its indications and techniques, is a parallel field of investigation. The first on-line survey of the Group has been completed in the first half of 2014. The survey included # 24 Centers in Italy, Germany, Greece, UK, Sweden, Japan and USA. Relevant data have been collected on current practice in diagnosis, therapy and follow-up of dyslipidemias. 240 subjects with hyperlipidemia and treated with lipoprotein apheresis have been reported in the survey, but a large percentage of patients (35%) who could benefit from this therapeutic option are still treated by conventional drug approach. Genetic molecular diagnosis is performed in only 33% of patients while Lipoprotein(a) (Lp(a)) is included in cardiovascular disease risk assessment in 71% of participating Centers. New detailed investigations and prospective multicenter studies are needed to evaluate changes induced by the impact of updated indications and strategies, as well as new treatment options, targeting standardization of therapeutic and diagnostic approaches.

The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial.

OBJECTIVE: Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide. METHODS: Existing lipid-lowering therapy, including apheresis, was to remain stable from Week -6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5 mg to 60 mg a day (maximum). The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the impact of apheresis on LDL-C reductions in patients receiving lomitapide. RESULTS: Of the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week 26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (-48%) and not treated (-55%) with apheresis (p = 0.545). Changes in Lp(a) levels were modest and not different between groups (p = 0.436). CONCLUSION: The LDL-C lowering efficacy of lomitapide is unaffected by lipoprotein apheresis.

Therapeutic apheresis in low weight patients: technical feasibility, tolerance, compliance, and risks.

The use of therapeutic apheresis in very low weight patients is generally thought to have limitations, because of possible severe adverse reactions, potential risk related to the extracorporeal procedure, due to the low weight of the young patients. A careful therapeutic approach using appropriate precautions, and also introducing modifications to the standard procedure, can minimise the risk without compromising the efficacy of the plasmapheresis. The aim of the study was to evaluate apheresis tolerance and acceptability in children [Artif. Organs. 21 (1997) 1126] and infants [J. Clin. Apheresis 5 (1989) 21] with inherited lipid metabolism disorder, familial hypercholesterolemia (FH), primary hyperlipoproteinemia (lipoprotein phenotype I), and acute leukemia, weighing on average 20.55 kg. One thousand one hundred twenty three aphereses were completed. Three types of apheresis were performed: leukapheresis, plasma exchange, dextran sulphate cellulose (DSC) low density lipoprotein (LDL)-apheresis. Three different types of continuous flow systems were used. Technical adaptation depending on patients blood volume, body mass index, hematocrit, type of system used, permitted us to perform complete aphereses, obtaining a high degree of tolerance and acceptability of the treatment. The use of plasmapheresis is regarded to be an extreme therapeutic measure in children. However, when the need for such treatment is undebatable, plasmapheresis must be done. A well-trained and experienced team can overcome the technical difficulties in order to complete the procedures without complications. The most frequently observed adverse effects are vascular relative access insufficiency (2.0%), and mild hypotension (2.0%).

Immunoadsorption apheresis (Selesorb) in the treatment of chronic hepatitis C virus-related type 2 mixed cryoglobulinemia.

In this short-term open label clinical pilot study, conducted at one center, the immune complex dextran sulphate adsorber (Selesorb) was used to treat four female patients aged 59-69 with HCV-related cryoglobulinaemia, vasculitis and/or neuropathy. The primary trial objective was to assess the clinical efficacy of the immunoadsorber. The secondary objective of the trial was to determine the safety of the adsorber and to investigate the adsorption capacity, measured as the adsorption of cryoglobulin-related immune complexes and the resulting influence on plasma components of the immune system. The patients have been submitted to treatment with the immunoadsorber, at approximately 1-3 days intervals, completing six sessions. The follow-up was one month. In the patients treated with Selesorb, we observed a statistically significant decrease in plasma of all classes of immunoglobulins (IgA: 5-28%; IgG: 14-44%; IgM: 8-38%). In two patients with peripheral neuropathy secondary to cryoglobulinemia, the symptomatology was improved. In a third patient the neurological involvement was substantially unchanged, and the same unsuccessful outcome was observed for Sjögren syndrome is concerned. Nevertheless, the two patients with lower extremity vasculitis showed an appreciable improvement. We failed to observe significant side effects directly related to the use of this immunoadsorbent.

Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood.

This study was a 1-year clinical study on 16 (7 males and 9 females) pediatric patients with heterozygous familial hypercholesterolemia treated with hypocholesterolemic diet only, or with diet plus drug (simvastatin 10 mg/day). According to the study protocol, the children were submitted to a 3-month washout (free diet). Then they were given a diet (American Heart Association, step 2) for 6 months. After 6 months they were divided into two groups matched for sex, age and body mass index (BMI). Diet only was given to group A (n = 8); simvastatin (10 mg/daily) was given to group B, for 1 year. All patients were examined at baseline, and monitored for safety during the study by pediatricians. All patients were submitted to noninvasive cardiovascular examinations (exercise electrocardiogram, echocardiography). After 12 months of treatment with simvastatin, total cholesterol (TC) and low density lipoprotein cholesterol (LDLC) showed a statistically significant reduction (group B). The decrease of TC and LDLC in patients on diet only was 4% and 3% (all) and 17% and 4% (group A) after 6 and 12 months, respectively.

Treatment of homozygous and double heterozygous familial hypercholesterolemic children with LDL-apheresis.

Within the framework of a seven-year clinical experience on treatment of severe hyperlipoproteinemia with/without associated coronary heart disease, with therapeutic plasmapheresis (APO B-100-containing lipoprotein-apheresis), we focused the present report on two young patients aged 7 and 11 years, respectively. The older patient is a boy treated since 1990 by plasma-exchange, cascade filtration-low density lipoprotein apheresis (LDL-apheresis), and dextrane sulphate-LDL apheresis. Over the treatment period the patient was submitted to three consecutive coronary angiographies. The second is a girl first submitted to a coronary angiography and then treated with dextrane sulphate-LDL apheresis. Up to now, a total of one-hundred therapeutic plasmaphereses have been performed. The interval of treatment was of fifteen days, and a volume of 2-3000 ml of plasma was processed at each session. The systems used were the following: DIDECO Vivacell BT 798-A, DIDECO Vivacell BT 798-A + BT 803, DIDECO BT 985 (Dideco, Mirandola, Italy), KANEKA MA-01 (Kanegafuchi, Osaka, Japan). Mean (SD) plasma apo B-100-containing major lipoprotein-LDL, Lp(a)-levels during treatment, are reported below: [table: see text] The treatment was very well tolerated. Rare, moderate hypotensive events occurred. Nevertheless, all procedures were regularly completed. A mild hypochromic anemia, regressed using drug treatment, was observed in the boy. Along with the improvement of plasma atherogenic profile, a regression of skin xanthomas and unchanged favourable coronary angiograms, were obtained in the above mentioned patient.

Efficacy, safety and tolerability of combined low-dose simvastatin-fenofibrate treatment in primary mixed hyperlipidaemia.

OBJECTIVE: In order to assess the long-term (12 months) efficacy and safety of fenofibrate administered with simvastatin in the treatment of primary mixed hyperlipidaemia, we conducted a study that compared increasing dosages of these drugs in subgroups of men and women belonging to a clinical sample of out-patients. DESIGN: This was an open study carried out in patients with primary mixed hyperlipidaemia (lipoprotein phenotype IIb) who needed a combined therapeutic approach because of their poor response to a single-drug regimen with an HMG-CoA reductase inhibitor (simvastatin). Thus, a fibrate (fenofibrate) was added to the therapy. The study lasted 12 months. PATIENTS: Forty-five patients (mean age: 58.9 +/- 11.3 years) with primary mixed hyperlipidaemia who showed a poor response to the single-drug hypolipidaemic treatment were enrolled. Their average plasma triglyceride level was consistently above 300 mg/dL and low-density lipoprotein cholesterol (LDL-C) was over 160 mg/dL after at least 6 months of a single hypolipidaemic drug (simvastatin) regimen plus antiatherogenic dietary treatment. INTERVENTIONS: Five patients received simvastatin 10mg once daily in addition to fenofibrate 200mg; 26 patients received simvastatin 20mg once daily plus fenofibrate 200mg; 11 patients received simvastatin 20mg once daily plus fenofibrate 300mg; and three patients received simvastatin 30mg once daily plus fenofibrate 200mg. The patients were allocated to treatment groups on the basis of their relative response to the therapy. Those making up the progressively higher agent/dose groups were the individuals at higher cardiovascular risk according to the total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) values. RESULTS: The double-drug regimen given for 12 months to four different groups, according to the different combined dosages of simvastatin and fenofibrate, resulted in a reduction in total cholesterol of 18% (p

[Isolated jejunal angiomatosis. A rare cause of intestinal hemorrhage]. / Angiomatosi digiunale isolata. Una causa rara di emorragia intestinale.

The Authors report a case of solitary small bowel angiodysplasia and emphasise the rarity of this site. The importance of angiography is stressed in terms of its fundamental role in the diagnostic process and in its ability to evaluate not only the site but the extension of this type of lesion, thus enabling a surgical approach to be defined.

[Some historical considerations on the inflammatory theory of atherosclerosis]. / Una breve riflessione storica sulla teoria infiammatoria dell'aterosclerosi.

In the past 20 years several clinical and experimental observations have led to the hypothesis that an inflammatory response can trigger some key processes during the development of atherosclerosis. Here we briefly review, from the historical viewpoint, the inflammatory theory of atherosclerosis, as proposed by the Berliner pathologist Rudolf Virchow in the XIX century. Contrary to this hypothesis, in the same period the Viennese Karl von Rokitansky recognized blood dyscrasia (particularly fibrin-induced alterations) as the promoting factor in the process of atherogenesis. Moreover, we outline the relationship between atherosclerosis and arthritis, by reporting some passages from two scientific works published in the late XIX century, the former by the Italian Achille De Giovanni ("Sull'arterite. Sue forme cliniche e sua patogenesi", 1882) and the latter by the French Theophile Guyot ("L'arthritis. Maladie Constitutionnelle", 1890).

[First prenatal diagnosis of familial hypercholesterolemia by a molecular biology technic]. / La prima diagnosi prenatale di ipercolesterolemia familiare mediante tecniche di biologia molecolare.

The first prenatal diagnosis for exclusion of homozygous familial hypercholesterolemia by using the so called technique of Restriction Polymorphism Fragment Length (RFLP's) on chorial villus DNA, was performed. The test was used when the mother of a seven-year-old child with homozygous familial hypercholesterolemia, became pregnant. Previous examination of DNA of both parents and of one hypercholesterolemic child, showed a mutation of the gene encoding for the synthesis of LDL-receptor. The comparison between first degree relatives RFLP's and the chorial villus RFLP's, showed the absence of a previously recognized mutation in the foetus. After a normal pregnancy, the child was born and his plasma cholesterol was within the "normal" range.