F. Heller

The use of Achilles tendon ultrasonography for the diagnosis of familial hypercholesterolemia

Differentiating FH from other causes of hypercholesterolemia has important clinical and therapeutic implications but is often not possible by standard clinical criteria. As accumulation of cholesterol in tendon is generally considered as pathognomonic of FH, we evaluated the sensitivity and specificity of clinical and ultrasonographic tendon characteristics using the data of 127 genetically ascertained FH and 160 controls with various lipid profiles. Upon clinical examination, none of the controls and 29% of FH individuals (17% FH women and 38% FH men) presented with xanthomata in Achilles tendons, but no female and only 6% of male FH patients also showed xanthomata in the extensor tendon of the hand. Amongst all possible quantitative parameters (thickness, breadth, section and roundness) of Achilles tendon (AT) measured by ultrasonography, the thickness presented the best receiver operating curves. AT thickness above 5.8 mm was the most useful threshold for diagnosis of FH, procuring sensitivity of 75% and specificity of 85%. Analysis of variation of AT thickness with age and sex indicated that this clinical criterion performed better in females older than 45 and in males under 45. In patients carrying the APOB-R3500Q mutation, AT-thickness appeared significantly less important compared with those carrying LDLR mutations. In conclusion, this study recommends identification of possible FH individuals amongst hypercholesterolemic patients using a criteria of AT-thickness over 5.8 mm eventually associated with a specific genetic test for APOB-R3500Q mutation.

Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia

Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, we assessed whether patients with mutations of low‐density lipoprotein (LDL) receptor and apolipoprotein B genes related to familial hypercholesterolaemia (FH) have a different degree of atherosclerosis than those without such mutations.

Impact of genetic defects on coronary atherosclerosis in patients suspected of having familial hypercholesterolaemia

Background In the present study we assessed whether the presence of genetic mutations typical of familial hypercholesterolaemia (FH) was associated with greater atherosclerosis in the coronary vessels in patients with severe hypercholesterolaemia and a family history of early cardiovascular disease.

Short‐Term Effects of Beta Blockers Atenolol, Nadolol, Pindolol, and Propranolol on Lipoprotein Metabolism in Normolipemic Subjects

The short‐term effect of the blockade of the beta‐adrenergic receptors on serum lipoproteins and the plasma activities of the enzymes involved in the metabolism of the serum lipoproteins: lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT) was evaluated in ten healthy normolipemic and normotensive subjects. In the first part of the study, the first three‐day period of placebo was followed by another three‐day period during which propranolol (120 mg/d) was given. In the second, third, and fourth part of the study, the same schedule was used but pindolol (15 mg/d), nadolol (160 mg/d), atenolol (100 mg/d) were given respectively instead of propranolol. The four drugs induced a significant blockade of the beta‐adrenergic receptors as evaluated by the measurement of the double two‐step test of Master (‐45%). Despite similar blockade, the effect on serum lipid concentrations depended on the type of drug: propranolol induced an increase in triglycerides and apoprotein B‐concentrations and a decrease in serum high density lipoprotein cholesterol (HDL‐C) and apoprotein AI‐concentrations. Pindolol provoked only a slight decrease of serum HDL‐C concentration. Nadolol and atenolol elicited a lowering of the same magnitude in HDL‐C. Except for a possible slight increase in plasma LCAT activity on propranolol, there was no significant change in the plasma activities of LPL, HL, and LCAT during the blockade of the beta‐adrenergic receptors with the drugs used. It is difficult to draw firm conclusions in regard to the mechanism by which beta blockers given to patients for much longer periods of time alter lipoprotein metabolism from results obtained in normolipemic subjects receiving beta blockers for only three days. It seems that pindolol modifies the serum lipoprotein pattern less likely than propranolol, nadolol, or atenolol. This difference could be attributed to the intrinsic sympathomimetic activity of pindolol of which the other beta blocking drugs that were used are devoid. The mechanism by which the serum lipid changes can be induced by beta blockade does not involve a lower activity of any of the plasma enzymes regulating the intravascular metabolism of lipoproteins.

Fast separation of the three main plasma lipoprotein classes by ultracentrifugation using vertical rotor and multiple discontinuous density gradient

An ultracentrifugation technique for isolation of the various lipoprotein fractions using a vertical rotor is described. By the use of a multiple discontinuous density gradient, very low density lipoproteins, low density lipoproteins and high density lipoproteins are sharply separated, without contamination of other lipoproteins or albumin. Centrifugation time is 80 min. The densities, electrophoretic mobilities, electron microscopic appearance and chemical composition are those of the expected classes of lipoproteins. Two different gradients are used to enhance the separation of very low density lipoproteins from low density lipoproteins on one hand and high density lipoproteins from infranatant on the other.

Effect of fenofibrate and LF 2151 on hepatic peroxisomes in hamsters

Hamsters were given a diet containing fenofibrate (0.5% or 0.05%) or its metabolite, LF 2151 (0.15% or 0.015%) or a standard diet for a 3-week period. At the end of this period, the analysis of plasma lipids showed that the mean plasma triglyceride concentrations were not significantly different in the five groups of animals. The mean plasma cholesterol concentrations were significantly reduced in animals treated with both drugs but only when given at the high dosage. No consistent changes were noted in the liver weight/body weight ratio and the DNA content of the liver; the number of peroxisomes was increased in the hepatocytes of animals given fenofibrate at the high dosage. Liver homogenates were fractionated and the fractions rich in peroxisomes were used for assays of several enzymes involved in lipid metabolism. Compared with the control animals, activity of cyanide-insensitive fatty acyl-CoA (FA-CoA) oxidizing system was significantly increased by fenofibrate at the high dosage, carnitine acetyltransferase activity was markedly increased by both drugs at the high dosage and catalase activity remained unmodified. As there was a significant inverse correlation between the peroxisomal activity of FA-CoA oxidizing system and the plasma cholesterol concentrations, it is suggested that the increase of peroxisomal beta-oxidation activity can be involved in the hypocholesterolemic action of fenofibrate and LF 2151. This is further substantiated by the finding that fenofibrate and LF 2151 were present in the peroxisomal fraction only in hamsters displaying hypocholesterolemia and high activity of FA-CoA oxidizing system. The presence of fenofibric acid in the plasma of hamsters given LF 2151 suggested that hepatocytes are able to generate the parent drug from this metabolite, underlining that the pharmacokinetics of fenofibrate are rather complex in hamsters.

Silent ischaemia in familial hypercholesterolemia

In a cohort of 66 FH-men (age 25-55) prospectively recruited during a 2-years period, we estimated the incidence of coronary heart disease to 52% (N=34). Thirty-two percent (N=21) had earlier history of symptomatic ischaemic disease whereas 20% (N=13) had significant ST/T changes during exercise stress test. Amongst the 8 patients with positive exercise stress test who underwent coronary angiography, six had severe coronary artery disease. Because of the severity of the stenotic lesions, 4 of these 6 patients underwent coronary angioplasty or surgical bypass. We concluded that a great proportion of FH men suffered from myocardial ischaemia, either asymptomatic or symptomatic, and that even the silent form is associated with severe coronary stenosis. This advocates to systematically perform exercise testing in asymptomatic FH men after age 25.

Atorvastatin and the plasma activities of lipoprotein lipase, hepatic lipase and lecithin:cholesterol acyltransferase in patients with mixed hyperlipidemia

Abstract Background : Atorvastatin provokes a strong reduction in plasma total cholesterol (TC) and LDL-cholesterol (LDL-C), an effect attributed to the increase in the receptor-mediated catabolism of LDL and well-demonstrated for statins. In addition, atorvastatin induces a reduction in plasma triglycerides (TG), an effect that must be ascribed to another mechanism. Methods : Ten patients with mixed hyperlipidemia (TC and TG greater than 250 and 200 mg/dl, respectively) were treated with atorvastatin, 10 mg/day for 1 month and 20 mg/day for another month. The plasma activities of lecithin:cholesterol acyltransferase (LCAT), of lipoprotein lipase (LPL), and of hepatic lipase (HL) were measured before and at the end of treatment. The changes were analyzed in relation to changes in plasma lipids and in components of lipoproteins. Results : A marked increase (65%) in the plasma LCAT was observed, together with a slight (18.1%) decrease in the plasma HL activity. Plasma activity of LPL remained unchanged. Conclusions : In this uncontrolled study, atorvastatin provoked a marked increase in the turnover of cholesteryl esters in accordance with the well-known stimulating effect of statins on the receptor-mediated catabolism of LDL. The marked decrease in TG is explained not by an increased activity of LPL but probably by a reduced synthesis of VLDL by the liver. The results must be confirmed in a placebo-controlled study.

Atorvastatin and low-density lipoprotein subfractions profile in mixed hyperlipidaemia: a contributory effect of reduced hepatic lipase activity?

dialysis and hemodialysis. Am J Nephrol 1986; 6: 206-11 6 Jackson JM, Lee HA. L-carnitine and acetyl-Lcamitine status during hemodialysis with acetate in humans: a kinetic analysis. Am J Clin Nutr 1996; 64: 922-7 7 Reddi AS, Moquete M, Keshav G, DeAngelis B, Frank 0, Baker H. Plasma carnitine levels in patients undergoing hemodialysis. Nephron 1998; 80: 87-8 8 De Sousa C, English NR, Stacey TE, Chalmers RA. Measurement of L-carnitine and acylcarnitines in body fluids and tissues in children and in adults. Clin Chim Acta 1990; 187: 317-28 9 Takahashi M, Veda S, Misaki H, Sugiyama N, Matsumoto K, Matsuo N, et al. Carnitine determination by an enzymatic cycling method with carnitine dehydrogenase. Clin Chem 1994; 40: 817-21 10 Minkler PE, Hoppel CL. Quantification of free carnitine, individual shortand medium-chain acylcarnitines, and total carnitine in plasma by high-performance liquid chromatography. Anal Biochem 1993; 212: 510-8 II Beutler E, West e. The removal of leukocytes and platelets from whole blood. J Lab Clin Med 1976; 88: 328-33 12 Wanner C, Wackerle B, Boeckle H, Schollmeyer P, Horl WHo Plasma and red blood cell carnitine and carnitine esters during L-carnitine therapy in hemodialysis patients. Am J Clin Nutr 1990; 51: 407-10 13 Zilleruelo G, Novak M, Hsia S, Goldberg R, Abitbol C, Monkus E, et al. Effect of dialysate composition on the lipid response to L-carnitine supplementation. Kidney Int 1989; 27: 259-63 14 Alhomida AS. Influence of acetate and bicarbonate dialysate on blood shortand long-chain acyl carnitine in adult pyelonephritis patients. Ann Clin Biochem 1999; 36: 48-55

Effects of gemfibrozil on plasma lipoproteins, plasma activities of hepatic enzymes, and hemostatic variables in hypertriglyceridemic patients

In 15 patients with hypertriglyceridemia-defined as plasma triglyceride (TG) concentration >250 mg/dL-gemfibrozil 600 mg given twice daily for 4 months significantly reduced the mean plasma concentration of total cholesterol (TC) (-15%) and TG (-61%). In the low-density lipoprotein (LDL) fraction, the TC concentration was unchanged but the TG concentration was decreased. As the apoprotein B concentration also decreased, it is likely that the LDL particles were not only enriched with TC but also reduced in number. The increase in high-density lipoprotein cholesterol (HDL-C) was accounted for by an increase in the TC content of HDL(3). Most of these changes can be considered beneficial in terms of protection against atherosclerosis. The plasma activities of lecithin-cholesterol acyltransferase and hepatic lipase were not changed significantly by the drug, while that of lipoprotein lipase increased significantly (44.1%, P < 0.05). Thus the mechanism of action of gemfibrozil appears to mainly involve an increased catabolism of TG-rich lipoproteins, although the correlations between lipoprotein lipase and lipoprotein concentrations were only marginally significant, As significant correlations were found between hepatic lipase and HDL-C, gemfibrozil appears to also have some impact on hepatic lipase. Finally, gemfibrozil did not change the activity of the fibrinolytic system, while the fibrinogen concentration and the platelet count increased, The significance of the latter changes is unclear.