Hyperlipidemias: Pauciullo P

Gaddi A, Galetti C, Pauciullo P, Arca M. · Centro per lo Studio dell'Arteriosclerosi e delle Malattie Dismetaboliche Giancarlo Descovich, Servizio di Gerontologia, Policlinico S. Orsola-Malpighi, Bologna, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #10765523 No free full text.

Abstract: The Atherosclerosis and Dysmetabolic Disorders Study Group, headed by Prof. Rodolfo Paoletti, decided in 1994 to compose a committee of experts to formulate a clear description of familial combined hyperlipoproteinemia (FCH), a disorder illustrated in the literature, but still unknown to most physicians in spite of its severity and relative diffusion. The Committee consists of experts from the Lipid Clinics of the Universities of Ancona, Bari, Bologna, Ferrara, Genoa, Milan, Naples, Padua, Palermo, Perugia, Rome, Sassari, Turin, Verona and Venice. It has held several meetings coordinated by the national secretary at the "Giancarlo Descovich" Atherosclerosis Centre of the University of Bologna. This paper summarizes its conclusions.

Rubba P, Iannuzzi A, Faccenda F, De Leo F, Pauciullo P. · Dipartimento di Medicina Clinica e Sperimentale, Università Federico II, Via S. Pansini 5, 80131 Napoli, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #12063770 No free full text.

Abstract: Atherosclerosis is a lifelong disease process that begins in childhood and may lead to cardiovascular disease in middle age or later. Non-invasive methods for vascular diagnosis help identify hypercholesterolemic children to treat with dietary or pharmacological intervention on the basis of anatomical or functional markers of arterial pathology. It would be unethical to assess these markers using angiographic or other invasive procedures (such as intravascular ultrasound), but the measurement of intermediate vascular end-points using non-invasive techniques is feasible. We here review the methods and procedures of non-invasive vascular examination that have been demonstrated to be feasible and informative with regard to arterial pathology in hypercholesterolemic children. These include measuring carotid intima-media thickness (IMT) by means of B-mode imaging, Doppler evaluation of the transvalvular aortic pressure gradient, measuring coronary calcium by means of computed tomography, studying the elastic properties of arteries, detecting impaired vasodilation, and measuring arterial remodelling. Suggested operative guidelines could be to measure carotid IMT in all hypercholesterolemic children aged > 10 years. The measurement should be repeated each year if the IMT is in the upper tertile of distribution for that age. A progression in IMT or the development of new lesions during the study could be an indication for more aggressive treatment.

Sirtori CR, Calabresi L, Pisciotta L, Cattin L, Pauciullo P, Montagnani M, Manzato E, Bittolo Bon G, Fellin R. · Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #15871851 No free full text.

Abstract: BACKGROUND AND AIM: Elevation of plasma cholesterol and/or triglycerides, and the prevalence of small dense low density lipoproteins (LDL) particles remarkably increase the risk in patients with familial combined hyperlipidemia (FCHL). There are, at present, inconsistent data on the effects of different treatments on size and density of LDL particles in FCHL patients. METHODS AND RESULTS: A multicenter, randomized, double-blind, double-dummy, parallel group study was designed to evaluate the effect of 3 months' treatment with atorvastatin (10mg/day) or pravastatin (20mg/day) on the lipid/lipoprotein profile and LDL size in a total of 86 FCHL patients. Both statins significantly lowered plasma total and LDL cholesterol, with a significantly higher hypocholesterolemic effect observed with atorvastatin (-26.8+/-11.1% and -35.9+/-11.1%, respectively) compared to pravastatin (-17.6+/-11.1% and -24.5+/-10.2%). The percent decrease in plasma triglycerides was highly variable, but more pronounced with atorvastatin (-19.8+/-29.2%) than with pravastatin (-5.3+/-48.6%). Opposite changes in LDL size were seen with the 2 treatments, with increased mean LDL particle diameter with atorvastatin, and decreased diameter with pravastatin, and significant between treatment difference in terms of percent modification vs baseline (+0.5+/-1.6% with atorvastatin vs -0.3+/-1.8% with pravastatin). CONCLUSIONS: The present results support the evidence indicative of a greater hypocholesterolemic effect of atorvastatin compared to pravastatin, and in addition show a raising effect of atorvastatin on the size of LDL particles in FCHL patients.

Pauciullo P, Giannino A, De Michele M, Gentile M, Liguori R, Argiriou A, Carlotto A, Faccenda F, Mancini M, Bond MG, De Simone V, Rubba P. · Department of Clinical and Experimental Medicine, Ceinge, Italy. · Metabolism. · Pubmed #14624402 No free full text.

Abstract: The current study sought to investigate the role of low-density lipoprotein receptor (LDLr) mutations in assessing the risk profile of familial hypercholesterolemia (FH) patients, independently of major cardiovascular risk factors. FH due to LDLr mutations is associated with premature atherosclerosis. The variable clinical severity of the disease in heterozygotes has been related to cholesterol levels and the coexistence of other cardiovascular risk factors, but the independent role of different LDLr mutations is still unclear. cDNA of LDL gene was sequenced in 102 patients with clinical features of heterozygous FH. Carotid artery intima-media thickness (IMT) was measured by B-mode ultrasound imaging in all patients. Sixteen different mutations (5 never described) were found in 82 patients (49 families; mean age, 39 years; 53% women). One of the newly described mutations, the 2312-3 C-->A, was found in 24 patients (13 families). The mean of maximum thicknesses was significantly higher in the 2312-3 C-->A group than in patients with other LDLr mutations (P=.004 after adjustment for major cardiovascular risk factors). Similar results (P=.001) were obtained in the adjusted comparisons of probands only, and of the patients with similar baseline cholesterol (P=.002). This study indicates that the identification of an LDLr mutation can help to assess the risk profile of FH patients independently of the major cardiovascular risk factors.

Olsson AG, Pauciullo P, Soska V, Luley C, Pieters RE, Broda G, Palacios B, Anonymous00213. · Hälsouniversitet Institutionen för Internmedicin, Linköping, Sweden. · Clin Ther. · Pubmed #11219479 No free full text.

Abstract: BACKGROUND: A new extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia. OBJECTIVE: The purpose of this study was to compare the lipid-lowering efficacy and tolerability of fluvastatin ER (80 mg once daily) versus fluvastatin immediate-release (IR) (40 mg once or twice daily). METHODS: Following a 4-week placebo/dietary run-in period, patients with primary hypercholesterolemia type IIa or IIb (low-density lipoprotein cholesterol ILDL-C] > or = 160 mg/dL and triglycerides [TG] < or = 400 mg/dL) were randomized (2:1:1) to receive fluvastatin ER 80 mg once daily at bedtime (QPM), fluvastatin IR 40 mg QPM, or fluvastatin IR 40 mg BID for 24 weeks. Patients who had homozygous familial hypercholesterolemia; type I, III, IV, V, or secondary hyperlipoproteinemia; diabetes; or evidence of liver or renal impairment were excluded. At weeks 0, 2, 4, 8, 12, 16, 20, and 24 of the active-treatment period, levels of LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) were measured. RESULTS: Of the 1183 patients enrolled, 695 were randomly assigned to treatment--346 to fluvastatin ER 80 mg QPM, 174 to fluvastatin IR 40 mg QPM, and 175 to fluvastatin IR 40 mg BID. Patients were well matched between groups, with a mean age of approximately 56 years and body mass index of 27 kg/m2; 56.0% of patients (389/695) were female and 97.7% (679/695) were white. Fluvastatin ER 80 mg QPM lowered LDL-C levels significantly more than did fluvastatin IR 40 mg QPM (33.7% vs 24.4%; P < 0.001) and as effectively as fluvastatin IR 40 mg BID (33.9%). More than half of the patients administered fluvastatin ER 80 mg QPM and IR 40 mg BID achieved reductions in LDL-C levels of > or = 35%; more than half of those administered fluvastatin IR 40 mg QPM experienced reductions in LDL-C levels of > or = 25%. The mean reductions in LDL:HDL ratio, TC, and apolipoprotein B levels in the fluvastatin ER 80 mg QPM group were significantly greater than the reductions in the IR 40 mg QPM group (P < 0.001). In patients with mixed dyslipidemia, fluvastatin ER 80 mg reduced triglycerides by 21.8% (median 28%) and increased HDL-C by 14.5%. Fluvastatin ER 80 mg QPM was well tolerated, with incidences of clinically notable elevations in alanine aminotransferase, aspartate aminotransferase, and creatine kinase levels and musculoskeletal adverse events comparable to those in the IR 40 mg QPM group. CONCLUSION: The ER 80-mg formulation of fluvastatin is effective and well tolerated as a once-daily starting and maintenance treatment for primary hypercholesterolemia.

Pauciullo P, Borgnino C, Paoletti R, Mariani M, Mancini M. · Department of Clinical and Experimental Medicine, Medical School of the University 'Federico II', Via S. Pansini 5, 80131, Naples, Italy. · Atherosclerosis. · Pubmed #10856536 No free full text.

Abstract: Preliminary data suggest that fluvastatin may be safely combined with fibrates. The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia. A total of 333 patients were randomly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone (n=80), 400 mg bezafibrate (n=86), 20 mg fluvastatin+400 mg bezafibrate (n=85) or 40 mg fluvastatin+400 mg bezafibrate (n=82) for 24 weeks. Low-density lipoprotein (LDL)-cholesterol decreased >20% in all fluvastatin-containing regimens, with significantly greater decreases compared with bezafibrate alone (P<0.001). Bezafibrate alone and fluvastatin+bezafibrate combinations resulted in greater increases in high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides compared with fluvastatin alone (P<0.001). Fluvastatin (40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24%, a decrease in triglycerides of 38% and an increase in HDL-cholesterol of 22%. All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy, or between combination regimens. No clinically relevant liver (aspartate aminotransferase [ASAT] or alanine aminotransferase [ALAT]) greater than three times the upper limit of normal) or muscular (creatine phosphokinase (CPK) greater than four times the upper limit of normal) laboratory abnormalities were reported. This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia, and to be safe and well tolerated.

Vigna GB, Donega P, Passaro A, Zanca R, Cattin L, Fonda M, Pauciullo P, Marotta G, Fellin R, Gasparrini S, Piliego T. · Institute of Internal Medicine, University of Trieste, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #10656170 No free full text.

Abstract: BACKGROUND AND AIM: Impaired triglyceride-rich lipoprotein metabolism is most probably related to an enhanced cardiovascular risk, and may be associated with a pro-coagulant state. A double-blind, randomized study was undertaken to evaluate two widely utilized hypolipidemic drugs in the post-prandial phase and their impact on lipid, coagulation and fibrinolytic parameters. METHODS AND RESULTS: Thirty middle-aged men selected according to their low density lipoprotein-cholesterol (LDL-C) > or = 160 and < or = 240 mg/dl and borderline hypertriglyceridemia (110-220 mg/dl) after at least one month of a lipid-lowering diet received gemfibrozil (600 mg bid) or simvastatin (20 mg qd) and the corresponding placebo. On enrollment and after 2 months of drug treatment, they were tested with a standard oral fat load (OFL) (35 g fat/m2 body surface). On both occasions plasma total-cholesterol, LDL-C, HDL-C, triglycerides, lipoprotein[a] (Lp[a]), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (AT-III), plasminogen and fibrinogen were determined just before the meal (t0) and at times 2 hours, 4 h, 6 h, 8 h after it (t2-t8). A two-factor (time and visit) multivariate analysis for repeated measurements was performed to evaluate the data. Total cholesterol, and LDL-C were significantly diminished 2 months after both gemfibrozil and simvastatin, the latter being more active. Plasma triglycerides showed a marked reduction with gemfibrozil at all times, while simvastatin regimen yielded only minor modifications. HDL-C was only slightly increased by simvastatin; Lp[a] plasma levels were almost unaffected. Small fibrinogen (t0, t2, t6, t8), PAI-1 (t6) and AT III (t0-t8) increases were observed after gemfibrozil, while simvastatin did not significantly modify these parameters. CONCLUSIONS: In the post-prandial phase, gemfibrozil and simvastatin induce different metabolic effects that beneficially influence the lipid pattern, whereas fibrinolytic and coagulative parameters display minor variations of undetermined significance.

Postiglione A, Montefusco S, Pauciullo P, Mancini M, Piliego T. · No affiliation provided · Atherosclerosis. · Pubmed #10627271 No free full text.

This publication has no abstract.

Pauciullo P, Gentile M, Marotta G, Baiano A, Ubaldi S, Jossa F, Iannuzzo G, Faccenda F, Panico S, Rubba P. · Department of Clinical and Experimental Medicine, University Federico II Medical School, 80131 Naples, Italy. <> · Metabolism. · Pubmed #18328361 No free full text.

Abstract: It is unclear whether an association between familial combined hyperlipidemia (FCHL) and inflammatory markers exists, independently of age, sex, body weight, insulin resistance, and metabolic syndrome. Serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein 1, interleukin 6, tumor necrosis factor-alpha (TNF-alpha), and high-sensitive C-reactive protein were determined in 135 probands with FCHL and in 146 normolipidemic, normotensive, normoglycemic healthy subjects. Insulin resistance was evaluated using homeostasis model assessment (HOMA). All inflammatory parameters, except interleukin 6, were significantly higher in FCHL according to medians or mean comparisons. After adjustment for age, sex, body mass index, and HOMA, only TNF-alpha remained an independent predictor of FCHL status by binary logistic regression (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.07-1.31; P = .001). In particular, elevated levels of TNF-alpha (above the 90th and 95th percentiles of the value observed in the control group, 9.6 and 9.8 pg/mL, respectively) were independent predictors of FCHL status: for TNF-alpha above the 90th percentile, OR was 7.91 (95% CI, 3.27-19.13; P < .001), and for TNF-alpha above 95th percentile, OR was 13.08 (95% CI, 4.60-37.15; P < .0001). The independent role of TNF-alpha as predictor of FCHL status was confirmed after adjustment for components of the metabolic syndrome (P = .007 and P = .003, for TNF-alpha values above 90th and 95th percentiles, respectively). In conclusion, among the inflammatory markers most commonly measured, only TNF-alpha was associated with FCHL independently of age, sex, body mass index, and HOMA. The association of TNF-alpha with FCHL was also independent of the metabolic syndrome.

De Michele M, Iannuzzi A, Salvato A, Pauciullo P, Gentile M, Iannuzzo G, Panico S, Pujia A, Bond GM, Rubba P. · Division of Cardiology, Moscati Hospital, Aversa, Italy. · Heart. · Pubmed #16807271 No free full text.

Abstract: BACKGROUND: Familial combined hyperlipidaemia (FCHL) is associated with a markedly increased risk of premature coronary artery disease. This study was designed to evaluate whether preclinical atherosclerotic functional abnormalities are detectable in the arteries of patients with FCHL. METHODS: 60 subjects were recruited for the study: 30 probands of families with FCHL (mean (standard deviation (SD)) age 48 (10) years, 77% men), defined by fasting total plasma cholesterol or triglyceride concentration >250 mg/dl (>6.5 mmol/l cholesterol, >2.8 mmol/l triglyceride) and by the occurrence of multiple lipoprotein phenotypes within a family, and 30 age-matched and sex-matched healthy controls. All subjects underwent high-resolution B-mode ultrasound examination and the brachial arterial reactivity, a marker of endothelial function, was measured by a semiautomated computerised program. Lipid profile, resting blood pressure, body mass index (BMI), smoking status, insulin and homocysteine levels were also determined. RESULTS: Compared with controls, patients with FCHL had significantly higher BMI, diastolic blood pressure and insulin levels. No difference was observed in baseline brachial diameter between the two groups (mean (SD) 3.45 (0.51) mm for FCHL v 3.60 (0.63) mm for controls; p = 0.17). In response to flow increase, the arteries of the controls dilated (mean (SD) 8.9% (4.9%), range 2.3-20.8%), whereas in the patients with FCHL, brachial arterial reactivity was significantly impaired (5.5% (2.5%), range 0-10.1%; p = 0.002). In multivariate linear regression analysis, apolipoprotein B and BMI were independent determinants of brachial artery response to reactive hyperaemia. CONCLUSIONS: The findings of our study suggest that vascular reactivity is impaired in the arteries of patients with FCHL.

Celentano A, Crivaro M, Roman MJ, Pietropaolo I, Greco R, Pauciullo P, Lirato C, Devereux RB, de Simone G. · Department of Clinical and Experimental Medicine, Federico II University Hospital, School of Medicine, Naples, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #11887428 No free full text.

Abstract: AIMS: To investigate the effect of hypercholesterolemia on total arterial compliance and left ventricular (LV) geometry in the absence of arterial hypertension and diabetes. METHODS: One hundred and fifty-two normotensive, non-diabetic patients (109 men) aged 52 +/- 10 years with plasma cholesterol > 240 mg/100 mL, and 282 normotensive controls (154 men) aged 42 +/- 10 years (p < 0.0001) with plasma cholesterol < 200 mg/100 mL were studied by means of echocardiography. The stroke volume/pulse pressure ratio as a percentage of the value predicted by individual age, body weight and heart rate was used as a prognostically-validated index of total arterial compliance. Central pulse pressure (PP) was estimated using a regression equation obtained in a non-overlapping population. RESULTS: Although within the "normal" range, systolic pressure, PP and estimated central PP were higher in the hypercholesterolemic patients even after controlling for differences in age, body mass index (BMI) and race (all p < 0.0001). After controlling for differences in systolic pressure, age, BMI and race, LV mass and the prevalence of hypertrophy were comparable between the two groups, whereas relative diastolic wall thickness was greater (0.36 + 0.06 vs 0.33 + 0.05) and percent SV/PP (stroke volume/PP) lower in the hypercholesterolemic patients (96 +/- 19% vs 102 +/- 18%; both p < 0.005). After considering the covariates, there was still an independent negative correlation between relative wall thickness and percent SV/PP (r = -0.37, p < 0.0001). CONCLUSIONS: Hypercholesterolemia in normotensive non-diabetic adults is independently associated with a mildly concentric LV geometry and a reduced index of total arterial compliance.

Liguori R, Bianco AM, Argiriou A, Pauciullo P, Giannino A, Rubba P, De Simone V. · CEINGE and Dept. of Biochemistry and Medical Biotechnology, University of Napoli "Federico II", Italy. · Hum Mutat. · Pubmed #11317362 No free full text.

Abstract: 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.

Iannuzzi A, Rubba P, Pauciullo P, Celentano E, Capano G, Sartorio R, Mercuri M, Bond MG. · Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy. · Metabolism. · Pubmed #9920145 No free full text.

Abstract: Arterial stiffness may be an indicator of early vascular changes signaling the development of vascular disease, while hypercholesterolemia is a well-recognized promoter of atherogenesis. It has been shown that hypercholesterolemic children have a thicker intima-media in the carotid artery than children with normal cholesterol. The aim of this study was to assess the stiffness of the abdominal aorta in children with hypercholesterolemia. Noninvasive imaging evaluation of the aorta was performed in 85 outpatient children (age, 3 to 14 years) with and without high cholesterol levels ((and) 247 mg/dL [6.4 mmol/L], respectively). Ultrasound imaging of the abdominal aorta that allowed diameter measurements was available in 67 children. Using an image-processing workstation, the maximum and minimum internal diameter of the aorta was measured, and the following indices of elastic properties of the abdominal aorta were derived: arterial strain, pressure-strain elastic modulus, and stiffness. No statistical difference for aortic strain, stiffness, and elastic modulus was found in normocholesterolemic compared with hypercholesterolemic children. The effect of age on the elastic modulus was different in the two groups: in normal children, the elastic modulus increased linearly with age (y = -0.020+0.003 x age [months], P<.001), while the high-cholesterol group had a weak increase in this parameter with age (y = 0.118+0.0009 x age, P = .051). The slope of the regression equations (elastic modulus vage) was significantly different in the two groups (t = 2.45, P = .017). The behavior of arterial stiffness with respect to age was similar, y = 0.677+0.018 x age (P = .002) in normocholesterolemic children and y = 2.06+0.00198 x age (P = .66) in hypercholesterolemic children. The slope of the regression equations (stiffness v. age) was significantly different in the two groups (t = 2.37, P = .021). The present study demonstrates an influence of hypercholesterolemia on age-related modification in the elastic properties of the aorta. A remodeling of the aortic wall in hypercholesterolemic children (cholesterolemia >247 mg/dL) could explain the different age-dependent increase in aortic elastic modulus and stiffness.