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Aims: Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism that causes an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although early diagnosis and treatment of FH can significantly improve the cardiovascular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to provide guidelines for FH diagnosis and treatment., Data Synthesis: Our guidelines include: i) an overview of the genetic complexity of FH and the role of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardiovascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treatment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C) levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inadequate response to cholesterol-lowering therapies., Conclusion: FH is a common, treatable genetic disorder and, although our understanding of this disease has improved, many challenges still remain with regard to its identification and management., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial., Methods and Results: The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively., Conclusion: The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment., Gov Identifier: NCT02476006., Competing Interests: Declaration of competing interest A.B.C. received a consultancy fee for writing the article that examines the Italian data of the ODYSSEY APPRISE study; has received grants and personal honoraria for consultancy and lecturing from Aegerion, Akcea, Alfasigma, Amryt Pharmaceuticals, Inc., and Sanofi. M.Av. has received grants and personal honoraria for consultancy from Aegerion, Akcea, Ionis, Alfasigma, Amgen, Amryt, Pfizer, Sanofi. KG and GT, Sanofi employee, may hold shares and/or stock options in the company. M.Ar. has received grants and personal honoraria for consultancy from Amgen, Sanofi. S.N., K.B., R.G., C.B., P.R., S.G., G.M., and M.P. have nothing to disclose., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 ( ANGPTL3 ) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia., Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24., Results: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups., Conclusions: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment., Objectives: This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH., Methods: This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment., Results: Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period., Conclusions: In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by pathogenic variants in genes encoding for LDL receptor (LDLR), Apolipoprotein B and Proprotein convertase subtilisin/kexin type 9 (PCSK9). Among PCSK9 variants, only Gain-of- Function (GOF) variants lead to FH. Greater attention should be paid to the classification of variants as pathogenic. Two hundred sixty nine patients with a clinical suspect of FH were screened for variants in LDLR and the patients without pathogenic variants were screened for variants in PCSK9 and APOB. Functional characterization of PCSK9 variants was performed by assessment of protein secretion, of LDLR activity in presence of PCSK9 variant proteins as well as of the LDLR affinity of the PCSK9 variants. Among 81 patients without pathogenic variants in LDLR, 7 PCSK9 heterozygotes were found, 4 of whom were carriers of variants whose role in FH pathogenesis is still unknown. Functional characterization revealed that two variants (p.(Ser636Arg) and p.(Arg357Cys)) were GOF variants. In Conclusions, we demonstrated a GOF effect of 2 PCSK9 variants that can be considered as FH-causative variants. The study highlights the important role played by functional characterization in integrating diagnostic procedures when the pathogenicity of new variants has not been previously demonstrated.

Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration ≥4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin ± ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p < 0.001), Dutch Lipid Clinic Network score ( p < 0.001), independently of age, gender, smoking habits and systolic blood pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events.

Background: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples., Methods: We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII)., Results: Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C., Conclusions: A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis., (© 2014 American Association for Clinical Chemistry.)

Objective: Autosomal dominant hypercholesterolemias are due to defects in the LDL receptor (LDLR) gene, in the apolipoprotein B-100 gene or in the proprotein convertase subtilisin/kexin type 9 gene. The aim of this study was to identify and functionally characterize mutations in the LDLR gene that account for most cases of familial hypercholesterolemia (FH)., Methods: We enrolled 56 unrelated patients from Southern Italy with a clinical diagnosis of FH. The mutation screening was performed by direct sequencing of the promoter and the 18 exons of the LDLR gene and by multiplex ligation-dependent probe amplification (MLPA) analysis to search for large rearrangements., Results and Conclusion: We found 5 new mutations, the causative role of which was demonstrated by functional characterization performed by quantification of fluorescent LDL uptake in EBV-transformed B lymphocytes. These results enlarge the spectrum of FH-causative LDLR mutations. Lastly, screening for large rearrangements is highly recommended for the genetic diagnosis of FH., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

We screened a group of patients from southern Italy with clinically diagnosed familial hypercholesterolemia (FH) for mutations of the LDL receptor (LDLR) gene. RNA from each proband was analysed by RT-PCR followed by complete cDNA sequencing. Among 51 unrelated FH families we detected 17 mutations affecting the coding region of the LDLR gene. Five of these mutations, designated R395P, L783fsinsG, IVS15-3C>A, IVS3+5G>A, and 1698-1704delCACCCTAinsGCCCAAT (ITL545MPN), have not yet been reported in the literature. Interestingly, the novel IVS15-3C>A splicing mutation was detected in 20% of our unrelated FH families, suggesting an unusually high prevalence in our local population. Hum Mutat 17:433, 2001., (Copyright 2001 Wiley-Liss, Inc.)

Background and Purpose: Homocystinuria due to cystathionine beta-synthase deficiency and familial hypercholesterolemia are inherited disorders of metabolism that are associated with premature development of cardiovascular disease. This study addresses the possibility that different patterns of carotid wall damage and cerebral blood flow hemodynamics are present in these two metabolic diseases., Methods: Twelve patients with homocystinuria due to cystathionine beta-synthase deficiency (mean age, 24 years), 10 patients with homozygous familial hypercholesterolemia (mean age, 26 years), and 11 healthy control subjects (mean age, 26 years) underwent a vascular examination by noninvasive methods. B-mode ultrasound imaging was used to obtain measurements of intima-media thickness of common carotid, bifurcation, and internal carotid arteries as an index of atherosclerosis. Cerebral blood flow velocity was estimated from vascular examination of the middle cerebral artery by transcranial Doppler. Systolic, diastolic, and mean velocities were measured. Pulsatility index, a possible indicator of vascular resistance in the cerebral circulation, was also calculated., Results: Mean maximum intima-media thickness was 1.4 mm in patients with familial hypercholesterolemia, 0.6 mm in patients with homocystinuria, and 0.6 mm in control subjects. The difference between hypercholesterolemic and homocystinuric patients or control subjects was statistically significant (P < .001). Diastolic blood flow velocities were significantly reduced in the middle cerebral arteries of hypercholesterolemic patients compared with homocystinuric patients or control subjects (P < .05), whereas systolic or mean velocities did not differ. The pulsatility index, a possible indicator of vascular resistance in the cerebral circulation, was significantly higher in hypercholesterolemic patients compared with homocystinuric patients or healthy control subjects (P < .01). A direct relation was demonstrated between pulsatility index of the middle cerebral artery and mean maximum intima-media thickness of carotid arteries on the same side (P < .001)., Conclusions: Familial hypercholesterolemia is responsible for diffuse and focal thickening of carotid arteries and possibly also for hyperlipidemic endothelial dysfunction extending to small resistance arteries and leading to a disturbed cerebral blood flow. Patients with homocystinuria due to homozygosis for cystathionine beta-synthase deficiency seldom have plaques in their carotid arteries. They are similar to healthy control subjects with regard to both intima-media thickness and blood flow velocity in the middle cerebral artery. Therefore, it is unlikely that typical atherosclerotic lesions precede thrombotic events in homocystinuria. However, it is possible that arterial dilatations caused by medial damage lead to thrombosis in homocystinuric patients.

Background and Purpose: Low-density lipoprotein apheresis is currently used for the treatment of familial hypercholesterolemia, an inherited disorder of metabolism associated with premature development of cardiovascular disease. We wanted to evaluate cerebral blood flow velocity, cardiac output, and systemic vascular resistance in patients with familial hypercholesterolemia before and after low-density lipoprotein apheresis., Methods: Ten patients (age range, 14 to 46 years; 4 males, 6 females) with familial hypercholesterolemia (8 homozygotes, 2 heterozygotes) and 10 healthy control subjects of comparable age and sex distribution participated in the study. Low-density lipoprotein apheresis by dextran sulfate was performed in 8 patients (7 homozygotes, 1 heterozygote). Six patients (4 homozygotes, 2 heterozygotes) underwent a procedure of extracorporeal erythrocyte filtration with the same extracorporeal volume as for low-density lipoprotein apheresis, but with the exclusion of the passage of plasma through the dextran sulfate column. Cerebral blood flow velocity (transcranial Doppler), cardiac output, and systemic vascular resistance (electric bioimpedance cardiography) were determined by noninvasive techniques before and 1 day and 7 days after low-density lipoprotein apheresis or extracorporeal erythrocyte filtration. Plasma and blood viscosities were measured at the same time., Results: Before apheresis, mean and diastolic cerebral flow velocities were abnormally low in hypercholesterolemic patients (P < .01 and P < .02 vs healthy control subjects, respectively). After apheresis, low-density lipoprotein cholesterol was lowered by 40% to 60% from baseline, and cerebral blood flow velocities (mean, systolic, and diastolic velocities) were increased (P < .01). Cardiac output, systemic vascular resistance, and viscosity values were not significantly modified. Extracorporeal erythrocyte filtration (without passage of plasma through the dextran sulfate column) did not modify serum lipids, hemodynamic parameters, or viscosity values., Conclusions: Low-density lipoprotein apheresis produces potentially useful hemodynamic effects. They are not adequately explained by changes in blood viscosity alone and might reflect a restoration of endothelium-mediated vasodilation, which is inhibited by high concentrations of low-density lipoprotein.

It is well known that hypercholesterolemia is correlated with coronary atherosclerosis, but no definite information is available on its association with cerebrovascular atherosclerosis. We studied 10 young patients (age 3-32 years) with homozygous familial hypercholesterolemia (FH), together with 3 normal relatives as healthy controls. Extra- and intracranial Doppler examination, MRI and cerebral blood flow by SPECT and 99mTc-HM-PAO were performed on all. Six out of 10 patients already had signs and symptoms of coronary heart disease, but all patients were free from ischemic brain lesions, as small as detectable at MRI, and had normal cerebral blood flow. Two patients presented significant stenosis of the carotid arteries at Doppler examination. Young patients with homozygous FH have early and clinically evident coronary atherosclerosis, while overt disease in the cerebral district is delayed despite the extremely elevated plasma cholesterol concentration. This was also confirmed by the autopsy of two patients, who died after the study and whose cerebral arteries were totally free from atherosclerotic lesions. The age, at which flow-reducing atherosclerotic lesions develop in hypercholesterolemic patients, differs with regard to the arterial district involved.

The aim of this study was to measure noninvasively by Doppler ultrasound the blood flow velocity at the level of the aortic root in patients with homozygous familial hypercholesterolemia (FH) to detect abnormal pressure gradients. Seven patients with homozygous FH and seven healthy controls matched for age and sex were included in the study. Continuous-wave Doppler (2 MHz) was used to measure the highest detectable velocity from the aortic root; the probe was positioned in the suprasternal notch. When an abnormal velocity was detected, the corresponding pressure drop was calculated from the formula: Delta P = 4Vmax2. Each FH patient had an abnormal aortic velocity consistent with a pressure gradient across the valvular area. All the controls had normal aortic velocities (p less than 0.01). The measurement of the pressure drop across the aortic valvular area in FH patients gives an estimate of the lesions produced by cholesterol deposition in a crucial area of the cardiovascular system near the origin of coronary arteries. The noninvasivity of this method makes it an excellent method for obtaining parameters for follow-up and clinical trials.

Repeat low density lipoprotein (LDL) apheresis and blood flow determinations in the forearm and leg were performed in 10 patients (age range, 13-49 years; four male, six female) with familial hypercholesterolemia (eight homozygous, two heterozygous). To perform LDL apheresis, plasma was first separated by a polysulphone hollow fiber filter; then, LDL was selectively removed from plasma by dextran sulphate cellulose beads packed in columns. Blood flows in the forearm and leg were determined at rest and during a reactive hyperemia test (peak flow). This test was performed noninvasively by a strain-gauge plethysmograph with semicontinuous registration of arterial blood flow variables before the first apheresis and 3 weeks after the last of six procedures for apheresis. Resting arterial blood flows in the forearm and leg were slightly increased after repeat LDL apheresis (p less than 0.05). Peak blood flow in the leg significantly increased (+34%, p less than 0.01). No change in peak blood flow in the forearm was observed. Systolic blood pressures were slightly but significantly reduced (p less than 0.05); forearm peripheral resistances were also reduced (p less than 0.05). Flow response was not related to LDL receptor status. Blood and plasma viscosities were determined before and 7 days after the last apheresis. Blood viscosity was significantly reduced after LDL apheresis at shear rates of 11.25-450 sec-1. Plasma viscosity did not change.

Common and internal carotids have been studied by noninvasive method (echo-Doppler) in 30 normotensive patients with familial hypercholesterolemia (FH). Vascular lesions were detected in 14 patients (46%), who presented one or more lesions of different degree (between 1-15% and 16-49%). In one case, only one carotid had stenosis greater than 50%. Severity and number of stenosis were related to age and levels of hypercholesterolemia. FH patients with carotid lesions showed a significantly higher LDL-cholesterol (p less than 0.01) and plasma apolipoprotein B (p less than 0.001) concentrations and a significantly lower HDL-cholesterol (p less than 0.05) and plasma apolipoprotein A (p less than 0.001) levels as compared to those with normal echo-Doppler findings. These data indicate that investigation of arterial districts other than coronaries are useful in quantitative evaluation of atherosclerotic involvement.

Ultrasound methods have been used for the vascular examination of middle-aged patients with insulin-dependent diabetes mellitus (IDDM, n = 44) or heterozygous familial hypercholesterolemia (FH, n = 37); they were compared with 50 healthy controls. To define the localization of the early arterial lesions in these two conditions, the determination of ankle pressure by Doppler ultrasound and the detection of flow disturbances in the iliac arteries by echo-Doppler technique have been combined in a single vascular investigation. There were no major differences in mean age, degree of overweight, sex distribution, blood pressure, or smoking habits among the three groups. Total serum cholesterol in patients with FH was almost double compared with diabetics and controls. Triglyceride, HDL cholesterol, and blood pressure values did not differ. Nine of 88 limbs of patients with IDDM had an abnormally low ankle-arm pressure ratio (less than 0.97), and there were three cases of low ratio of 100 limbs in the control subjects (P less than .02). The corresponding figure for heterozygous FH was of three of 74 limbs (not different from controls). Echo-Doppler abnormalities suggesting lesions in the iliac arteries were significantly increased (P less than .01) in FH patients (13 limbs with lesions of 74) compared with controls (four of 100 limbs). The proportion of echo-Doppler abnormalities in IDDM (four of 88 limbs) was practically the same as compared to the controls.

Mesoglycan extracted from calf aorta was orally administered (96 mg/day) to 15 patients with primary hyperlipoproteinemia: 4 type IIA, 4 type IIB, 6 type IV and one type V. In the seven hypertriglyceridemic patients the drug after two months of treatment reduced total and VLDL-triglyceride from 701 mg/dl to 423 mg/dl (p less than 0.025) and from 562 mg/dl to 377 mg/dl (p less than 0.025) respectively and increased lipoprotein lipase activity from 19.7 mumol/l/min to 27.8 mumol/l/min (p less than 0.05). No change was observed in the group with type IIA-IIB hyperlipoproteinemia.

By using a non-invasive methodology of vascular diagnosis, ECG-triggered strain-gauge plethysmography, 5 patients with familial hypercholesterolemia (FH) (3 homozygous, 2 heterozygous) were evaluated before and during the 1st and 2nd week after plasma exchange (PE). In order to obtain data on the responsiveness to vasodilating stimuli in FH patients undergoing PE, reactive hyperemia test and peak flow determination were also performed. Resting arterial flow over the calf was found to be significantly enhanced after PE. Reactive hyperemia test demonstrated persistent improvement of peak flow following exchange. This study demonstrates useful hemodynamic effects of PE in patients with FH.

There is conflicting evidence on the relationship between increased low density lipoprotein (LDL) concentration in Type II hyperlipoproteinemia and premature development of peripheral atherosclerosis of the lower limbs. We evaluated the early signs of iliac artery involvement in patients with asymptomatic Type II hyperlipoproteinemia. Of these, 23 were Type IIA, 12 were Type IIB. Thirty-five consecutive patients, ages 40 to 60 years, with asymptomatic Type II hyperlipoproteinemia (LDL cholesterol greater than or equal to 3.80 mmol/liter, 147 mg/dl) and 54 normocholesterolemic controls (plasma cholesterol less than 5.70 mmol/liter, 220.6 mg/dl) from a random sample of clinically healthy, 50-year-old men had a noninvasive examination to detect common and external iliac artery stenosis. Both Type II patients and the controls were examined by the echo-Doppler technique (Duplex Scanner III-ATL Mark V) with spectral analysis of the Doppler signals. This method is sensitive not only to severe stenosis or occlusion but also to non-flow-reducing stenosis (less than 50% narrowing of the lumen diameter) and to minor wall irregularities (1%-15% stenosis). In Type II patients, 19 of 70 limbs (27%) were abnormal as compared to 6 of 108 limbs (6%) in the controls (p less than 0.001). The premature development of an obliterating disease of the iliac arteries was demonstrated in persons asymptomatic for Type II hyperlipoproteinemia.

Leg blood flow was measured before and 1 and 7 days after plasma exchange by venous occlusion plethysmography in a 9-year-old girl with homozygous familial hypercholesterolemia and in a 41-year-old man with heterozygous familial hypercholesterolemia. In the first patient the plasma cholesterol level was reduced from 890 mg/dl to 532 mg/dl and 666 mg/dl 1 and 7 days after plasma exchange. In the second patient plasma cholesterol decreased from 596 mg/dl to 342 mg/dl and 480 mg/dl, respectively. Leg arterial flow increased from 8.5 ml/min/l of leg volume to 19.1 and 19.5 ml/min/l in the first patient and from 6.6 ml/min/l to 18.0 and 21.8 ml/min/l in the second. No change was observed in haematocrit and total globulin concentration, which are known to play an important role in blood viscosity and flow. It is concluded that plasma exchange, possibly by decreasing plasma cholesterol concentration in patients with familial hypercholesterolemia, is associated with improved arterial flow to lower limbs and it is suggested therefore that some beneficial effect might be found also in other vascular beds.

Sixty-two patients (31 males, 31 females) with familial hypercholesterolemia (FH) underwent a vascular examination by Doppler ultrasound. The ankle/arm systolic pressure index was determined, and serum lipoproteins were analyzed. Eight of 124 legs examined (6.5%) showed an ankle/arm pressure index less than 0.95, suggesting flow reducing stenosis. Common carotid, internal carotid, and iliac arteries were evaluated by echo Doppler examination with spectral analysis. Forty-five of the 372 arteries examined (12.1%) had detectable abnormalities at echo Doppler examination. Iliac and internal carotid artery lesions were significantly (P less than 0.01) more frequent among FH patients than in a control group (30 men, 20 women) comparable for sex and age. The mean age of the patients with heterozygous FH and detectable arterial lesions was 45.3 years and that of those without lesions 30.7 years (P less than 0.05). When 14 patients with heterozygous FH and arterial lesions were compared to another 14 without lesions and matched for age and gender, it was found that patients with lesions had on average lower concentrations of HDL-cholesterol, and that 10 of 14 cases were actual smokers.