Sanni Lahdenperä

Intense physical training decreases circulating antioxidants and endothelium-dependent vasodilatation in vivo

Physical training increases free radical production and consumes antioxidants. It has previously been shown that acute exercise markedly increases the susceptibility of LDL to oxidation but whether such changes are observed during physical training is unknown. We measured circulating antioxidants, lipids and lipoproteins, and blood flow responses to intrabrachial infusions of endothelium-dependent (acetylcholine, ACh, L-N-monomethyl-arginine, L-NMMA) and -independent (sodium nitroprusside, SNP) vasoactive agents, before and after 3 months of running in 9 fit male subjects. Maximal aerobic power increased from 53 +/- 1 to 58 +/- 2 ml/kg min (P < 0.02). All circulating antioxidants (uric acid, SH-groups, alpha-tocopherol, beta-carotene, retinol) except ascorbate decreased significantly during training. Endothelium-dependent vasodilatation in forearm vessels decreased by 32-35% (P < 0.05), as determined from blood flow responses to both a low (10.8 +/- 2.1 vs. 7.3 +/- 1.5 ml/dl min, 0 vs. 3 months) and a high (14.8 +/- 2.6 vs. 9.6 +/- 1.8) ACh dose. The % endothelium-dependent blood flow (% decrease in basal flow by L-NMMA), decreased through training from 37 +/- 3 to 22 +/- 7% (P < 0.05). Blood flow responses to SNP remained unchanged. The decrease in uric acid was significantly correlated with the change in the % decrease in blood flow by L-NMMA (r = 0.74, P < 0.05). The lag time for the susceptibility of plasma LDL to oxidation in vitro, LDL size and the concentration of LDL cholestetol remained unchanged. We conclude that relatively intense aerobic training decreases circulating antioxidant concentrations and impairs endothelial function in forearm vessels.

Endothelial Dysfunction in Men With Small LDL Particles

BACKGROUND It is unknown whether LDL particle size is, independent of other lipids and lipoproteins, associated with endothelial dysfunction in vivo. METHODS AND RESULTS We determined in vivo endothelial function in 34 healthy men by measuring forearm blood flow responses to intrabrachial artery infusions of acetylcholine (ACh, an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). LDL peak particle size was measured with gradient gel electrophoresis. Men with small LDL particles (LDL diameter </=25.5 nm, n=10) had a 39% lower blood flow response to ACh than men with large LDL particles (LDL diameter >25. 5 nm, n=24, blood flow 6.9+/-3.6 versus 11.4+/-5.1 mL/dL. min, P=0. 006). The groups had comparable LDL cholesterol concentrations (3. 9+/-0.6 versus 3.7+/-1.0 mmol/L, men with small versus large LDL particles), blood pressure, glucose concentrations, and body mass indexes. LDL size (r=0.45, P=0.01) but not HDL cholesterol (r=0.31, P=0.09) or triglycerides (r=-0.19, P=0.30) was significantly correlated with endothelium-dependent vasodilation. Serum triglyceride concentrations and LDL size were inversely correlated (r=-0.44, P=0.01). In multivariate regression analysis, LDL size was the only significant determinant of the ACh-induced increase in blood flow. Sodium nitroprusside-stimulated endothelium-independent vasodilation was similar in both groups. CONCLUSIONS Small LDL particles are associated with impaired in vivo endothelial function independent of HDL and LDL cholesterol and triglyceride concentrations. LDL size may therefore mediate adverse effects of hypertriglyceridemia on vascular function.

A marathon run increases the susceptibility of LDL to oxidation in vitro and modifies plasma antioxidants

Physical activity increases the production of oxygen free radicals, which may consume antioxidants and oxidize low-density lipoprotein (LDL). To determine whether this occurs during strenuous aerobic exercise, we studied 11 well-trained runners who participated in the Helsinki City Marathon. Blood samples were collected before, immediately after, and 4 days after the race to determine its effect on circulating antioxidants and LDL oxidizability in vitro. LDL oxidizability was increased as determined from a reduction in the lag time for formation of conjugated dienes both immediately after (180 +/- 7 vs. 152 +/- 4 min, P < 0.001) and 4 days after (155 +/- 7 min, P < 0.001) the race. No significant changes in lipid-soluble antioxidants in LDL or in the peak LDL particle size were observed after the race. Total peroxyl radical trapping antioxidant capacity of plasma (TRAP) and uric acid concentrations were increased after the race, but, except for TRAP, these changes disappeared within 4 days. Plasma thiol concentrations were reduced after the race. No significant changes were observed in plasma ascorbic acid, alpha-tocopherol, beta-carotene, and retinol concentrations after the marathon race. We conclude that strenuous aerobic exercise increases the susceptibility of LDL to oxidation in vitro for up to 4 days. Although the increase in the concentration of plasma TRAP reflects an increase of plasma antioxidant capacity, it seems insufficient to prevent the increased susceptibility of LDL to oxidation in vitro, which was still observed 4 days after the race.Physical activity increases the production of oxygen free radicals, which may consume antioxidants and oxidize low-density lipoprotein (LDL). To determine whether this occurs during strenuous aerobic exercise, we studied 11 well-trained runners who participated in the Helsinki City Marathon. Blood samples were collected before, immediately after, and 4 days after the race to determine its effect on circulating antioxidants and LDL oxidizability in vitro. LDL oxidizability was increased as determined from a reduction in the lag time for formation of conjugated dienes both immediately after (180 ± 7 vs. 152 ± 4 min, P < 0.001) and 4 days after (155 ± 7 min, P < 0.001) the race. No significant changes in lipid-soluble antioxidants in LDL or in the peak LDL particle size were observed after the race. Total peroxyl radical trapping antioxidant capacity of plasma (TRAP) and uric acid concentrations were increased after the race, but, except for TRAP, these changes disappeared within 4 days. Plasma thiol concentrations were reduced after the race. No significant changes were observed in plasma ascorbic acid, α-tocopherol, β-carotene, and retinol concentrations after the marathon race. We conclude that strenuous aerobic exercise increases the susceptibility of LDL to oxidation in vitro for up to 4 days. Although the increase in the concentration of plasma TRAP reflects an increase of plasma antioxidant capacity, it seems insufficient to prevent the increased susceptibility of LDL to oxidation in vitro, which was still observed 4 days after the race.

Initiate Insulin by Aggressive Titration and Education (INITIATE): A randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups

OBJECTIVE—Insulin is often postponed for years because initiation is time-consuming. We sought to compare initiation of insulin individually and in groups with respect to change in A1C and several other parameters in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A randomized (1:1), multicenter, two-arm, parallel design study with a recruiting period of up to 14 weeks and a 24-week treatment period. Either in groups of 4–8 or individually, using the same personnel and education program, 121 insulin-naive type 2 diabetic patients with an A1C of 7.0–12.0% were randomized to initiate bedtime insulin glargine. The patients visited the treatment center before and at the time of insulin initiation and at 6, 12, and 24 weeks. Patients self-adjusted the insulin dose to achieve a fasting plasma glucose 4.0–5.5 mmol/l. RESULTS—At 24 weeks, mean ± SE A1C had decreased from 8.7 ± 0.2 to 6.9 ± 0.1% in those treated individually and from 8.8 ± 0.2 to 6.8 ± 0.1% in those in groups (not significant [NS]). Insulin doses averaged 62 ± 5 IU and 56 ± 5 IU at 24 weeks (NS), respectively. The frequency of hypoglycemia was similar. The total time (visits and phone calls) spent in initiating insulin in the patients in groups (2.2 ± 0.1 h) was 48% less than in those treated individually (4.2 ± 0.2 h). Diabetes treatment satisfaction improved significantly in both sets of patients. CONCLUSIONS—Similar glycemic control and treatment satisfaction can be achieved by initiating insulin in groups and individually. Starting insulin in groups takes one-half as much time as individual initiation.

In Vivo Low Density Lipoprotein Oxidation Relates to Coronary Reactivity in Young Men

OBJECTIVES This study was undertaken to examine the relation of in vivo low density lipoprotein (LDL) oxidation and other lipid risk factors to coronary reactivity in normal subjects. BACKGROUND Experimental studies have shown that oxidized LDL (ox-LDL) particles are injurious to the vascular wall by impairing its normal vasodilator function. METHODS We used noninvasive positron emission tomographic (PET) imaging with intravenous dipyridamole to measure coronary flow reserve, a marker of coronary endothelial and smooth muscle function, in 30 healthy men (mean [+/-SD] age 34.4 +/- 3.2 years). As a marker of in vivo LDL oxidation, the autoantibody titer against ox-LDL was measured by the enzyme-linked immunosorbent assay method. RESULTS Plasma levels of autoantibody titer against ox-LDL were inversely associated with coronary flow reserve (r = -0.42, p = 0.023). High LDL cholesterol levels (above median > 3.0 mmol/liter) were associated with a low coronary flow reserve only in subjects expressing simultaneously high levels of ox-LDL titer (above median). Subjects with simultaneously high levels of LDL cholesterol and ox-LDL titer had lower coronary flow reserve values than subjects in other groups (3.89 vs. > 5.0 in other groups, p = 0.066). CONCLUSIONS These data provide evidence for the role of ox-LDL in affecting the coronary reactivity in vivo and support the concept that oxidative modification of LDL particles provides a mechanism by which high LDL concentrations exhibit injurious effects on the coronary vascular bed.

Regulation of low-density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides

SummaryAn increase of low-density lipoprotein triglycerides (LDL-Tg) was found to be an independent coronary artery disease (CAD) risk factor for non-insulin-dependent diabetic (NIDDM) patients in a recent prospective study. We examined the composition and size of LDL particles in 50 NIDDM men with angiographically verified CAD (NIDDM+ CAD+) and in 50 NIDDM men without CAD (NIDDM+ CAD−) as compared to 50 non-diabetic men with CAD (NIDDM− CAD+) and 31 non-diabetic men without CAD (NIDDM− CAD−). The groups had similar ranges of age and BMI LDL particle size was determined by gradient gel electrophoresis, and LDL was isolated by sequential ultracentrifugation for compositional analyses. Serum Tg was increased in NIDDM patients as compared to non-diabetic subjects (p<0.05), and in patients with CAD as compared to subjects without the disease (p<0.05). LDL cholesterol was lower in NIDDM patients than in non-diabetic subjects (p<0.001). Mean diameter of LDL particles was less than 255 å, but closely comparable in all groups. The presence of NIDDM was associated with increases of Tg and protein but lowering of free cholesterol in LDL (p<0.005 for all). In multivariate regression analyses neither NIDDM nor CAD were associated with LDL particle size, but serum Tg was the major determinant of LDL size in both NIDDM and non-diabetic subjects (p<0.001). When the patients were divided into quartiles according to fasting serum Tg levels, the LDL particle size and free cholesterol content decreased, but Tg and protein contents of LDL particles increased from the lowest to the highest Tg quartile (analysis of variance p<0.001 for all). When the subjects were categorized into two groups according to the median of VLDL-Tg (1.10 mmol/l) LDL size was associated with VLDL-Tg in the high but not in the low VLDL-Tg group. We conclude that in NIDDM patients with or without CAD serum Tg is the major determinant of the properties of LDL particles. The clinical implication is that in NIDDM serum Tg should be as low as possible to prevent atherogenic changes in LDL.

Changes of lipolytic enzymes cluster with insulin resistance syndrome

SummaryThe activities of hepatic and lipoprotein lipase and the levels of lipo- and apoproteins were compared in two groups of normoglycaemic men representing the highest (n=18) and lowest (n=15) fasting insulin quintiles of first degree male relatives of non-insulin-dependent diabetic patients. The high insulin group representing insulin-resistant individuals had significantly lower post-heparin plasma lipoprotein lipase activity than the low insulin group (14.2±4.0 vs 20±5.8 Μmol NEFA·ml−1·h−1, p<0.001); hepatic lipase activity did not differ between the two groups (24.2±11 vs 18.0±5.3 Μmol NEFA·ml−1·h−1, NS). The lipoprotein lipase/hepatic lipase ratio in the high insulin group was decreased by 66% as compared to the low insulin group (0.75±0.57 vs 1.25±0.65, p<0.01). In the high insulin group both total and VLDL triglycerides were higher than in the low insulin group (1.61±0.57 vs 0.86±0.26 mmol/l, p< 0.001 and 1.00±0.47 vs 0.36±0.16 mmol/l, p<0.001, respectively) whereas HDL cholesterol and HDL2 cholesterol were lower (1.20±0.30 vs 1.43±0.22 mmol/l, p<0.05 and 0.49±0.21 vs 0.71±0.17 mmol/l, p<0.05, respectively). Total cholesterol, LDL cholesterol or HDL3 cholesterol did not differ between the two groups. The mean particle size of LDL was smaller in the high insulin group than in the low insulin group (258±7 vs 265±6 å, p<0.05). We propose that the changes of lipoprotein lipase and lipoprotein lipase/hepatic lipase ratio cluster with insulin resistance and provide a possible mechanism to explain the lowering of HDL cholesterol and elevation of triglyceride concentrations observed in insulin-resistant subjects.

Effects of Gemfibrozil on Low-Density Lipoprotein Particle Size, Density Distribution, and Composition in Patients With Type II Diabetes

OBJECTIVE To study the effects of gemfibrozil treatment on LDL particle size, density distribution, and composition in NIDDM patients. RESEARCH DESIGN AND METHODS We performed LDL analyses on 16 NIDDM patients with stable glycemic control. They were randomly allocated to receive either gemfibrozil (n = 8) or a placebo (n = 8) for 3 mo in a double-blind study. The LDL particle size distribution and the particle diameter of the major LDL peak were measured with nondenaturing polyacrylamide gradient gel electrophoresis. The density distribution and composition of LDL were determined with the density gradient ultracentrifugation method. RESULTS In the gemfibrozil group the mean serum TG concentration decreased by 38%, HDL cholesterol concentration increased by 10%, and LDL cholesterol concentration by 17% (P < 0.05). During gemfibrozil therapy the mean particle diameter of the major LDL peak increased from 244 to 251 Å (P < 0.05), whereas in the placebo group the mean LDL particle diameter remained unchanged. We found an inverse correlation between the changes of serum TG and the particle diameters of the major LDL peak (r = 0.85, P < 0.01). Gemfibrozil produced a shift in the LDL density distribution toward lower density. The mean peak density decreased from 1.0371 to 1.0345 g/ml because of a significant rise in the light LDL concentration from 141.0 to 183.2 mg/dl (P < 0.05), whereas the concentration of dense LDL had a tendency to decrease. In the placebo group the LDL density distribution did not change. Gemfibrozil increased the CE-to-TG ratio in LDL core lipids by 27% (P < 0.05); otherwise, the LDL composition was only slightly affected. CONCLUSIONS The results indicate gemfibrozil-induced changes in LDL properties in NIDDM patients are similar to those previously reported in nondiabetic individuals and are related to changes in serum TG level.

Hormone replacement therapy lowers plasma Lp(a) concentrations. Comparison of cyclic transdermal and continuous estrogen-progestin regimens.

To study the responses of serum lipoproteins, apoproteins (apos), and lipoprotein(a) (Lp[a]) to two frequently used hormone replacement therapies (HRTs), 120 postmenopausal women were randomly allocated to receive either transdermal therapy consisting of 28-day cycles with patches that delivered 17 beta-estradiol (50 micrograms/d) combined with cyclic oral medroxyprogesterone acetate (10 mg/d for 12 days per cycle) or continuous oral 17 beta-estradiol (2 mg/d) together with norethisterone acetate (1 mg/d) for 12 months. Blood samples were taken before and at 6 and 12 months of HRT. Concentrations of serum total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol decreased by 14% (P < .001), 17% (P < .001), and 9% (P < .001) in the oral HRT group. Respective changes were 5.7% (P < .001), 4.8% (P < .05), and 4.7% (NS) in the transdermal group. Serum triglycerides remained unchanged in the oral group but decreased by 15.7% (P < .001) in the transdermal group. We observed only trivial changes in serum apo B levels. The changes in apo A-I levels paralleled those of HDL cholesterol in the oral HRT group. The concentration of serum Lp(a) decreased by 31% (P < .001) and 16% (P < .001) in the two groups. The combination of progestin and transdermal estrogen was not associated with any further change of Lp(a). The decrement in Lp(a) during therapy was positively associated with baseline Lp(a) levels in both groups (r = .96, P < .001 and r = .88, P < .001). Thus, both HRT regimens were highly effective in lowering elevated Lp(a) levels in postmenopausal women. The divergent responses of LDL and HDL cholesterol in the two HRT groups may influence the potential cardioprotective effects of the two HRT regimens. Prospective trials are needed to define the long-term effects with respect to coronary heart disease risk.

Phenotype expression in familial combined hyperlipidemia

Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.