Hyperlipidemias: Hanefeld M

Hanefeld M. · Centre for Clinical Studies, GWT Technical University, Dresden, Germany. · Int J Clin Pract Suppl. · Pubmed #17594390 links to  free full text

Abstract: Type 2 diabetes is characterised by a gradual decline in glycaemic control and progression from oral glucose-lowering monotherapy to combination therapy and exogenous insulin therapy. Functional decline of the insulin-secreting beta-cells is largely responsible for the deterioration in glycaemic control. Preservation of beta-cell functionality, in addition to maintaining glycaemic control and reducing insulin resistance, is now regarded as a key target for long-term management strategies. Early, aggressive intervention with combination therapy is emerging as a valid approach to optimise long-term outcomes and combining agents with differing modes of action and secondary effect profiles should prove valuable. Sulfonylureas and thiazolidinediones exert their glucose-lowering effect through differing mechanisms of action - the sulfonylureas by stimulating insulin secretion, whereas the thiazolidinediones are insulin sensitisers. Both agents offer excellent improvements in glycaemic control when given as monotherapy or in combination. The thiazolidinediones protect beta-cell structural and functional integrity and functionality and complement the sulfonylureas by inducing and maintaining improvements in insulin resistance, the abnormal lipid profile associated with type 2 diabetes and other cardiovascular risk factors. Thus, there is a strong rationale to support the addition of thiazolidinediones to sulfonylureas as a treatment option for type 2 diabetes. This combination may be particularly effective in the early stages of the disease when beta-cell function is at its highest, allowing maximal benefit to be obtained from the insulin secretion-promoting abilities of the sulfonylureas and the beta-cell-protective effects of the thiazolidinediones.

Temelkova-Kurktschiev T, Hanefeld M. · Centre for Clinical Studies, Technical University Dresden, Germany. · Exp Clin Endocrinol Diabetes. · Pubmed #15031770 No free full text.

Abstract: Cardiovascular disease is the major cause of morbidity and mortality in type 2 diabetes mellitus. Among the established risk factors, the lipid triad (elevated triglycerides, decreased high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol) is a powerful risk factor for atherosclerosis in type 2 diabetes. The prevalence of hypertriglyceridaemia (HTG) in type 2 diabetes is two to three times higher than in non-diabetics. The Copenhagen Male study, the AMORIS study, and several other trials showed hypertriglyceridaemia to be an independent predictor of coronary heart disease (CHD). HTG may promote risk both directly and indirectly through association with alterations of lipoprotein size and composition. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) demonstrated that raising high-density lipoprotein cholesterol (HDL-C) in patients with low (HDL-C) and low-density lipoprotein cholesterol (LDL-C) is associated with a significant reduction in CHD risk. It was shown in the Diabetes Intervention Study, AFCAPS/TexCAPS, and PROCAM studies that decreased HDL-C and elevated triglycerides are independent risk factors for atherosclerosis, particularly in patients with diabetes mellitus. Several epidemiological studies demonstrated that total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratios or low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratios could be better predictors of atherosclerosis than any single lipid parameter. Intima-media thickness (IMT), a well established marker of early atherosclerosis, is associated with HTG/low HDL-cholesterol. In the Risk factors in IGT for Atherosclerosis and Diabetes (RIAD) study total and HDL-cholesterol were independent determinants of IMT in subjects at risk for type 2 diabetes. Postprandial HTG was also shown to be correlated with increased IMT in type 2 diabetic patients.

Hanefeld M. · Centre for Clinical Studies GWT, Technical University of Dresden, Germany. · Int J Clin Pract. · Pubmed #11501230 No free full text.

Abstract: Coronary heart disease (CHD) is the leading cause of death worldwide, and effective treatment of hyperlipidaemia can prevent development of CHD and significantly reduce the risk for cardiovascular events and mortality in this disease. The advent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has revolutionised the treatment of hyperlipidaemia, but many patients receiving these drugs still do not achieve their therapeutic goals. Rosuvastatin (Crestor; formerly ZD4522) is a new, potent and long-lasting inhibitor of HMG-CoA reductase that is highly selective for hepatocytes. Its pharmacokinetics permit once-daily dosing, and a lack of oxidative hepatic metabolism results in a reduced potential for drug-drug interactions. Preliminary clinical results indicate that it produces rapid dose-related reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B that may exceed those achieved with other currently available statins. Increases in high-density lipoprotein cholesterol have also been observed. Rosuvastatin is also well tolerated, with no evidence of either hepato- or myotoxicity. It is hoped that new agents such as rosuvastatin may help to reduce the high global morbidity, mortality and associated costs of CHD and related vascular disorders.

Hanefeld M, Deslypere JP, Ose L, Durrington PN, Farnier M, Schmage N. · Institute and Polyclinic for Clinical Metabolism Research, University Clinic Carl Gustav Carus of the Technology University, Dresden, Germany. · J Int Med Res. · Pubmed #10505301 No free full text.

Abstract: This study examined the action of cerivastatin, a new statin, in subjects with primary hypercholesterolaemia. The effects of two oral doses of cerivastatin (400 micrograms/day or 300 micrograms/day) were compared with placebo in 349 patients using a multicentre, randomized, double-blind, placebo-controlled study design. Cerivastatin treatment lasted 8 weeks and produced significant reductions in low density lipoprotein-cholesterol (LDL-C) levels from baseline compared with placebo. The reduction in LDL-C was significantly greater with 400 micrograms than with 300 micrograms cerivastatin. When responder rates were examined, the higher (400 micrograms/day) cerivastatin dose was found to be more effective in producing larger (> 40%) reductions in LDL-C levels. Cerivastatin treatment was well tolerated. Only two withdrawals due to adverse events during active treatment occurred, neither of which was considered to be due to the study medication. In addition, no clinically relevant increases in the levels of creatine phosphokinase and hepatic transaminases (alanine transaminase and aspartate transaminase) compared with placebo were seen in this study. In conclusion, cerivastatin treatment produced a significant lowering of LDL-C levels, with the higher dose providing the greatest benefit.

Ansquer JC, Bekaert I, Guy M, Hanefeld M, Simon A, Anonymous00016. · Laboratoires Fournier S.A., Daix, France. · Am J Cardiovasc Drugs. · Pubmed #19331437 No free full text.

Abstract: BACKGROUND: Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). Fenofibrate significantly reduces TG and, more moderately, LDL-C, increases HDL-C and produces a shift from small to large LDL particle size; the main effect of ezetimibe is a reduction in LDL-C levels. Combined treatment with fenofibrate and ezetimibe may correct all the abnormalities of type IIb dyslipidemia. OBJECTIVE: To assess the efficacy and safety of coadministration of fenofibrate (NanoCrystal(R)) and ezetimibe in patients with type IIb dyslipidemia and the metabolic syndrome compared with administration of fenofibrate and ezetimibe alone (ClinicalTrials.gov Identifier: NCT00349284; Study ID: CLF178P 04 01). METHODS: This was a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Sixty ambulatory patients (mean age 56 years; 50% women, 50% men) were treated in each group. For inclusion in the study, patients were required to have LDL-C >or=4.13 mmol/L (>or=160 mg/dL), TG >or=1.71 mmol/L and <or=4.57 mmol/L (>or=150 mg/dL and <or=405 mg/dL), and at least two of the following National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome: low HDL-C or increased fasting plasma glucose, blood pressure, or waist circumference. Patients received fenofibrate 145 mg, ezetimibe 10 mg, or coadministration of both (fenofibrate/ezetimibe) daily for 12 weeks. The outcome measures were changes in lipids and related parameters, apolipoproteins, glucose metabolism parameters, and high-sensitivity C-reactive protein (hsCRP). Fenofibrate/ezetimibe was more effective than either fenofibrate or ezetimibe in reducing LDL-C (-36.2% vs -22.4% and -22.8%, respectively), non-HDL-C (-36.2% vs -24.8% and -20.9%, respectively), total cholesterol (TC) [-27.9% vs -18.9% and -17.1%, respectively], apolipoprotein B (-33.3% vs -24.5% and -18.7%, respectively), TC/HDL-C ratio (-34.2% vs -23.0% and -17.0%, respectively), and apolipoprotein B/apolipoprotein AI ratio (-37.5% vs -27.0% and -17.7%, respectively) [p < 0.001 for all comparisons between fenofibrate/ezetimibe and monotherapies]. RESULTS: Fenofibrate/ezetimibe was as effective as fenofibrate and more effective than ezetimibe in reducing remnant-like particle cholesterol (-36.2% and -30.7% vs -17.3%, respectively), and in increasing LDL size (+2.1% and +1.9% vs + 0.7%, respectively), apolipoprotein AI (+7.9% and +5.1% vs +0.2%, respectively) and apolipoprotein AII (+24.2% and +21.2% vs +2.7%, respectively). Fenofibrate/ezetimibe and fenofibrate were equally effective in reducing TG (both -38.3%) and in increasing HDL-C (+11.5% and + 7.9%, respectively; p = 0.282). Ezetimibe had minor effects on TG (-10.4%) and HDL-C (+2.2%). Among patients with low HDL-C at baseline (<1.29 mmol/L [<50 mg/dL] in women, <1.03 mmol/L [<40 mg/dL] in men), normalization of HDL-C was observed in 52.9% with fenofibrate/ezetimibe and in 58.8% with fenofibrate, compared with 20.0% with ezetimibe. Changes in hsCRP were -25.9% with fenofibrate/ezetimibe, -27.8% with fenofibrate, and -10.2% with ezetimibe (not statistically significant). None of the treatments altered glucose metabolism parameters. CONCLUSION: In patients with type IIb dyslipidemia and features of the metabolic syndrome, coadministration of fenofibrate 145 mg and ezetimibe 10 mg daily was more effective than either monotherapy in reducing LDL-C, non-HDL-C, apolipoprotein B, and cardiovascular risk ratios, and was as effective as fenofibrate 145 mg alone in reducing TG and in increasing HDL-C in patients with low baseline HDL-C levels.

Ott P, Benke I, Stelzer J, Köhler C, Hanefeld M. · Weisseritzel-Kliniken, Freital/Dippoldiswalde, Freital. · Dtsch Med Wochenschr. · Pubmed #19197810 No free full text.

Abstract: INTRODUCTION: The efficacy of a multifactorial intervention with antihypertensive drugs, statins and acetylsalicylic acid was shown in the STENO 2 trial of diabetic patients with microalbuminuria. But how good is clinical practice in Germany? The DIG (Diabetes in Germany) study was an prospective survey, analysing the quality of risk factor control and treatment patterns of type 2 diabetics over 4 years between 2002 and 2007. METHODS: A total of 4020 type 2 diabetics (aged 35 - 80 years) were recruited by 238 physicians across Germany. Their medical history, risk factor profile and clinical data were recorded. The quality of control of diabetes, hypertension or hyperlipidemia and the use of aspirin were assessed in 2914 patients at baseline and after 3,7 years. RESULTS: The mean HbA (1c) value was 6,98 % at baseline and 7,03 at the study end. 42,9 % at the beginning vs. 36,9 % at follow-up had HbA (1c) values above the target level of 6,5 %. Mean blood pressure was 139,3/80.0 compared with 137,3/79.9 mm Hg (p < 0,01), while 24,1 % and 27,0 %, respectively had values above the target level. Mean LDL-cholesterol levels were 3,23 mmol/l and 2,93 mmol/l, respectively, but only 23,2 % and 30,4 % of patients, respectively, reached target levels. There was a significant increase in the use of antihypertensive drugs, statins and acetylsalicylic acid over the four-year period. CONCLUSION: Type 2 diabetics in Germany received an acceptable level of treatment for hyperglycaemia, but still more than 60 % of the patients have HbA (1c) values higher than 6,5 %. There are serious deficits in the management of hypertension, hypercholesterolemia and the use of aspirin. Because intensive, multifactorial care of type 2 diabetics leads to reduced rates of death and cardiovascular disorders, these results indicate that the early and meticulous implementation of current treatment guidelines remains a major challenge.

Metzler W, Fücker K, Schwanebeck U, Hanefeld M, Julius U, Kindel B, Fischer S. · Medizinische Klinik (Leiter: U. R. Fölsch), Universitätsklinikum Schleswig-Holstein, Campus Kiel. · Dtsch Med Wochenschr. · Pubmed #14502445 No free full text.

Abstract: BACKGROUND: The relationship between the various degrees of glucose tolerance and metabolic parameters have already been examined in various studies. Whether and to what extent the triglycerides (TG) affect other metabolic parameters in the different degrees of glucose tolerance is not certain. We therefore studied the importance of the triglycerides within a defined glycemic state in patients with an elevated familial risk for metabolic diseases. METHODS: We examined 866 patients (380 men, 486 women, mean age 44,4 years) in the "Familial Metabolic Syndrome Study" (FAMES). The patients were assigned to various degrees of glucose tolerance, according to the result of an oral glucose tolerance test. All degrees were divided into subgroups in respect of the triglyceride level (TG < 1,7 or TG >/= 1,7 mmol/l). In these subgroups we measured various metabolic parameters like fasting glucose, insulin resistance, insulin and proinsulin levels, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), uric acid, HbA (1c), and free fatty acids (FFA). RESULTS: In patients with normal glucose tolerance the hypertriglyceridemia is already associated with other components of the metabolic syndrome like elevated HbA (1c), free fatty acids, proinsulin and insulin levels, worsened insulin sensitivity, elevated uric acid and LDL-C levels as well as a lowered HDL-C level. The patients with diabetes and hypertriglyceridemia also showed higher levels of FFA, proinsulin and insulin, a lower HDL-C level and a more prominent insulin resistance. CONCLUSION: Hypertriglyceridemia is an indicator for insulin resistance and elevated levels of other components of the metabolic syndrome within the various degrees of glucose tolerance.

Kopprasch S, Pietzsch J, Kuhlisch E, Fuecker K, Temelkova-Kurktschiev T, Hanefeld M, Kühne H, Julius U, Graessler J. · Department of Internal Medicine 3, Carl Gustav Carus Medical School, University of Technology Dresden, Germany. · Diabetes. · Pubmed #12351454 links to  free full text

Abstract: Oxidized LDL (oxLDL) is a key mediator in atherogenesis and a marker of coronary artery disease (CAD). Type 2 diabetes is associated with excessive cardiovascular morbidity and mortality. Because atherogenesis starts before diabetes is diagnosed, we investigated whether circulating oxLDL levels are increased in impaired glucose tolerance (IGT). OxLDL levels were measured in 376 subjects with normal glucose tolerance (NGT), 113 patients with IGT, and 54 patients with newly diagnosed type 2 diabetes. After correction for age and BMI, serum levels of oxLDL were significantly increased in IGT versus NGT subjects (P = 0.002). OxLDL levels were not associated with the following parameters of the oxidative/antioxidative balance in the blood: total antioxidant capacity, urate-to-allantoin ratio, and circulating phagocyte oxygenation activity. In stepwise multivariate analysis, LDL cholesterol (P < 0.0005) and triglycerides (P < 0.0005) were the strongest predictors of circulating oxLDL levels, followed by HDL cholesterol (P = 0.003), 2-h postchallenge C-peptide (P = 0.011), fasting free fatty acids (P = 0.013), and serum paraoxonase activity (P = 0.035). The strong correlation of oxLDL with LDL cholesterol and triglycerides indicates that LDL oxidation in IGT is preferentially associated with dyslipidemia. OxLDL increase may explain the high atherogenic potency of dyslipidemia in the prediabetic state.

Kaiser M, Temelkova-Kurktschiev T, Hanefeld M. · Center for Clinical Studies, Technical University Dresden, Germany. · Ann N Y Acad Sci. · Pubmed #12079884 No free full text.

Abstract: Familial defective apolipoprotein B-100 (FDB) is a genetic disorder characterized by a decreased binding of low-density lipoprotein (LDL) particles to the LDL receptor due to defective apo B-100. Impaired LDL clearance could also be due to defects of the LDL receptor (familial hypercholesterolemia, FH). FDB was suggested to be clinically indistinguishable from classical FH. The measurement of the intima-media thickness (IMT) is an accepted method for the direct evaluation of early atherosclerosis. Thus, the aim of this study was to examine the IMT in patients with FDB in comparison to FH. Our data indicate that IMT in FDB does not differ from IMT in FH.

Henkel E, Temelkova-Kurktschiev T, Koehler C, Pietzsch J, Leonhardt W, Hanefeld M. · Centre of Clinical Studies-Metabolism and Endocrinology, Science and Technology Transfer GWT, Technial University Dresden, Germany. · Diabetes Nutr Metab. · Pubmed #12059096 No free full text.

Abstract: Post-prandial (pp) hypertriglyceridaemia (HTG) has an important role in the development of atherosclerosis in Type 2 diabetes. Impaired glucose tolerance (IGT) is associated with an increased risk of atherosclerosis and increased level of fasting triglycerides (TG). The aim of this study was to analyse pp HTG and the composition of TG-rich lipoproteins in carefully selected subjects with IGT in comparison to controls with normal glucose tolerance (NGT). Fifteen men with IGT and 27 men with NGT, aged 44 to 70 yr, were examined. All study participants were non-smokers and had fasting TG <4.6 mmol/l. The subjects underwent an oral glucose tolerance test (75 g glucose) and a lipid-glucose tolerance test (LGTT; 92 g fat, 126 g carbohydrate), that allowed the assessment of lipid and glucose tolerance in one test. HbA1C, plasma glucose and lipids were measured by routine methods. Lipoprotein subfraction analysis of VLDL (VLDL1: Sf60-400 and VLDL2: Sf20-60) was conducted in a fasting state, as well as 4 hr after the LGTT using a density gradient ultracentrifugation with a subsequent compositional analysis. No significant difference was found either for fasting or pp TG, or for area under curve (AUC) -TG (12.21 +/- 4.27 mmol/l x 6 hr vs 13.95 +/- 6.74 mmol/l x 6 hr; p>0.05) between the IGT and NGT. A highly significant correlation was found between the fasting TG and the AUC-TG (r=0.925; p<0.01). To avoid bias by differences in fasting plasma TG known to affect lipid tolerance we investigated 11 matched pairs for fasting TG. Also, the matched-pairs evaluation pp TG course did not differ significantly from the IGT and NGT. No significant difference for fasting or pp levels of VLDL1 and VLDL2, or for the TG content of chylomicron, VLDL1 and VLDL2 and for the percentage of TG in VLDL1 and VLDL2 was found between the IGT and NGT group. In conclusion, IGT subjects with a similar level of fasting TG do not exhibit lipid intolerance. Our data suggest that glucose intolerance should precede lipid intolerance.

Henkel E, Hanefeld M. · Zentrum Klinische Studien GWT-TU Dresden. · Herz. · Pubmed #11820155 No free full text.

Abstract: The lipid triad: hypertriglyceridemia, low HDL, small dense LDL represents a high risk group for excessive cardiovascular morbidity and mortality in type 2 diabetes. In poorly controlled diabetes LDL are increasingly oxydized and glycosylated whereas HDL degradation is accelerated. The high lipid risk in coincidence with the diseases of the metabolic syndrome leads to the conclusion that diabetes today is a cardiovascular disease demanding an aggressive correction of the lipid triad. The benefit of lipid lowering treatment has been proven not only for statins but there is more and more evidence also in favour of fibrates. Fibrates are particularly useful in the treatment of hypertriglyceridemia/low HDL. This also leads to a reduction in small dense LDL. In the case of insufficient correction of LDL a combination with a low dose of a statin is recommended. A definite answer with respect to the benefit/risk ratio of fibrates should be provided by large ongoing studies with these drugs in representative groups of diabetes patients (LDS, TrUMPET, FIELD).

Noack B, Jachmann I, Roscher S, Sieber L, Kopprasch S, Lück C, Hanefeld M, Hoffmann T. · Department of Periodontology, Medical Faculty of TU Dresden, Germany. · J Periodontol. · Pubmed #10914792 No free full text.

Abstract: BACKGROUND: During the last few years, risk assessment has become one of the main topics of periodontal research. Therefore, the aim of this study was to determine whether a predisposition to metabolic disorders such as diabetes mellitus (in the absence of diagnosed diabetic disease) or hyperlipidemia may be risk indicators for periodontitis. METHODS: One hundred patients ranging in age from 40 to 70 years were examined. The patients were classified as having impaired glucose tolerance (IGT) but no manifest diabetes (56 patients), hyperlipidemia (17 patients, HL), or normal metabolic status (27 control patients). Probing depth (PD), attachment level (AL), plaque index (PI), and gingival bleeding on probing (BOP) were recorded. Serum antibody titers (SAT) to A. actinomycetemcomitans (A.a.), P. intermedia (P.i.), and P. gingivalis (P.g.) were determined by enzyme-linked immunosorbent assay (ELISA). Pooled subgingival plaque samples were analyzed using indirect immunofluorescence to detect the same organisms. In addition, respiratory burst activity of peripheral polymorphonuclear leukocytes (PMN) was evaluated by chemiluminescence (CL). RESULTS: No significant differences were observed between the IGT group and normal controls in the following parameters: 1) percentage of sites exhibiting BOP; 2) mean PI; 3) mean PD and AL; 4) percentage of periodontal microorganisms; and 5) increased SAT. The IGT probands exhibited a significantly higher mean serum level of triglycerides, as well as higher formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated PMN chemiluminescence than the control group. Patients with hyperlipidemia (HL) showed a significantly higher number of sextants with increased PD (73.4%) than the control group (50.6%). Similar results were obtained when comparing the percentage of all sites with increased PD (HL = 16.7%, control 12.3%). The mean FMLP-stimulated CL in patients with hyperlipidemia was significantly higher than the control group. When looking at all patients, there was a small but statistically significant correlation between PD and lipid levels. In addition, a significant correlation was observed between lipid serum levels and the FMLP-stimulated chemiluminescence. CONCLUSIONS: These findings suggest that abnormal glucose tolerance, which is a predisposing factor for diabetes mellitus, does not appear to be a risk indicator for periodontal disease. On the other hand, impaired lipid metabolism does seem to be a risk indicator for periodontitis.

Gehrisch S, Kostka H, Tiebel M, Patzak A, Paetzold A, Julius U, Schroeder HE, Hanefeld M, Jaross W. · Institut für Klinische Chemie und Laboratoriumsmedizin, Medizinische Fakultät TU Dresden, Germany. · J Mol Med. · Pubmed #10606208 No free full text.

Abstract: Hepatic lipase is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of intermediate density lipoproteins and high-density lipoproteins. The search described here concentrated on mutations of the HL gene in 129 patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in 184 members of 19 families with familial combined hyperlipidemia. Controls were 100 subjects with favorable lipid values (age 46-51 years). Mutation screening and analysis were performed by temperature-gradient gel electrophoresis, allele-specific restriction genotyping, and sequencing. Six different missense mutations and four different silent mutations were found in the HL gene. The alleles Phe-267 and Gln-343 were detected only once in the patient group with hypertriglyceridemia and hyperalphalipoproteinemia and were not detected in the control group. The allele Met-383 was rare in both patients and controls. We found 9.3% of the patients and only 3.0% of controls to be carrying the Val-73-Met missense mutation. The allele Phe-334 was found in 5.43% of patients and in 2.0% of controls. The difference between the frequencies of these alleles was significant between male patients and male controls (Met-73 P=0.044; Phe-334 P=0.047). Also, the summarized odds ratio of 3.28 (95% confidence interval 1.23-8.73) demonstrates that mutation carriers are significantly more prevalent in the patients. Fifteen carriers of the Met-73 allele were found in six families of the familial combined hyperlipidemia group. Furthermore, six carriers of the Phe-334 allele were found in three families of the same group. In comparison to the controls the summarized odds ratio of 2.45 (95% confidence interval 0.89-6.71) barely missed the level of significance. The linkage between genotype and phenotype was incomplete. These results show an association of the missense mutations Val-73-Met and Leu-334-Phe as susceptibility alleles for combined forms of hyperlipidemia.

Scheuch K, Hanefeld M, Grässler J, Seibt R, Naumann HJ. · Institute and Out-Patient Department of Occupational and Social Medicine, University of Technology, Faculty of Medicine, Dresden, Germany. · J Hum Hypertens. · Pubmed #10455475 No free full text.

Abstract: OBJECTIVES: We investigated the significance of hypertriglyceridaemia (HTG) for associated components of the metabolic syndrome and stress reactivity in subjects with mild hypertension. METHODS: Seventeen asymptomatic subjects with mild hypertension assessed by 24-h blood pressure (BP) measurement plus HTG (TG >2.3 mmol/l) were recruited and compared with age- and sex-matched subjects with hypertension alone and healthy controls. Cardiovascular and hormonal stress reactivity were tested in a standardised programme consisting of 6 min mental stress, 3 min finger grip and a submaximal bicycle ergometry. RESULTS: The hypertensive patients with HTG exhibited significantly higher fasting insulin, uric acid and gamma-GT levels and lower HDL-cholesterol. The cardiovascular reactivity was similar in all three tests with respect to brachial and peripheral BP in the groups. Peripheral BP during the tests was found to be higher particularly in subjects with hypertension alone. The correlations between BP parameters were disturbed in hypertensives with HTG. Latter group showed significantly higher dopamine, noradrenaline, as well as ACTH levels and an increased ACTH/cortisol ratio. CONCLUSION: HTG in mild hypertension is indicative for insulin resistance accompanied by a modified vascular reactivity as well as elevated catecholamines and ACTH.

Leonhardt W, Hanefeld M, Schaper F. · Institute and Policlinic of Clinical Metabolic Research, Medical Faculty of the Technical University, Dresden, Germany. · Atherosclerosis. · Pubmed #10381283 No free full text.

Abstract: Oxidizability of low-density lipoproteins (LDL) in hypercholesterolemia is of clinical relevance, but previous studies revealed diverging results. Therefore, we studied ex vivo oxidation of LDL in plasma samples of 57 hypercholesterolemic and 20 normocholesterolemic volunteers. LDL were isolated by ultracentrifugation and analyzed for lipids and alpha-tocopherol. The formation of conjugated dienes, lipoperoxides and malondialdehyde was measured at 0.1 micromol/l LDL, 3.2 micromol/l CuSO4. We found prolongation of the lagtime (53.6/65.8/71.4 min) with tertiles (< or = 3.17/3.89/14.2 mmol/l) of LDL-cholesterol (LDL-C). Regression analysis revealed that the lagtime increased with the apparent concentrations of cholesterol (P = 0.003) and alpha-tocopherol (P = 0.001) in the oxidation assay. A multiple regression model with the apparent concentrations of alpha-tocopherol, triglycerides and cholesterol explained 40% of the variation in lagtime. The close relationship between plasma concentrations of LDL-C and LDL-alpha-tocopherol (P = 0.002) indicated that LDL contained more of this antioxidant in hypercholesterolemia. This might provide an explanation for the positive relationship between lagtime and LDL-C. The latter was independent of whether LDL-C or LDL-protein was chosen for standardization of the oxidation assay. The formation of conjugated dienes (P = 0.000), lipoperoxides (P = 0.038) and malondialdehyde (P = 0.001) increased with the cholesterol level in the assay. This may be due to the increased load of LDL with cholesterol esters as a substrate for oxidation in hypercholesterolemia. Our data do not support the opinion that hypercholesterolemia is characterized by increased susceptibility of LDL to oxidation.