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apoE4 allele and the natural history of cardiovascular risk factors.
Scuteri, A, Najjar, SS, Muller, D, Andres, R, Morrell, CH, Zonderman, AB, Lakatta, EG
American journal of physiology. Endocrinology and metabolism. 2005;(2):E322-7
Abstract
The aims of the present study were to compare the longitudinal changes in traditional cardiovascular (CV) risk factors (blood pressure, BMI, total and HDL-cholesterol, triglycerides, and blood glucose) in men with and without the apolipoprotein (apo)E4 allele. Three hundred six men from the Baltimore Longitudinal Study of Aging, ranging in age from 20 to 92 yr, were studied. Repeated measurements of CV risk factors were performed over a median follow-up time of 7 yr (maximum 14.3 yr) for men. Longitudinal changes in these CV risk factors were analyzed by linear mixed-effects models. The prevalence of the apoE4 allele was 25.5%. apoE4 was independently associated with accelerated changes over time in fasting plasma glucose (+9.5% vs. no change in those without apoE4 in the 6th age-decade over 10 yr). No significant effect of apoE4 on longitudinal changes in total or HDL-cholesterol, triglycerides, or blood pressures was observed. In conclusion, apoE4 influences fasting plasma glucose and its changes over time. This could explain, in part, the increased CV risk associated with the apoE4 genotype observed in men.
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Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia.
van Wissen, S, Smilde, TJ, Trip, MD, de Boo, T, Kastelein, JJ, Stalenhoef, AF
Heart (British Cardiac Society). 2003;(8):893-6
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Abstract
BACKGROUND Raised plasma lipoprotein(a) (Lp(a)) is associated with increased risk of cardiovascular disease. It is unknown whether increased Lp(a) is an additional risk factor for coronary artery disease in familial hypercholesterolaemia (FH) or whether statin treatment can reduce Lp(a) concentrations in the long term. OBJECTIVE To investigate Lp(a) concentrations in relation to statin treatment and the progression of atherosclerosis in a large cohort of FH patients. DESIGN A two year, randomised, double blind trial (the ASAP trial). PATIENTS 325 heterozygous FH patients. INTERVENTION Treatment with 80 mg atorvastatin or 40 mg simvastatin. MAIN OUTCOME MEASURE Change in Lp(a) concentrations and intima-media thickness of carotid artery segments at one year and two years. RESULTS At baseline, median Lp(a) concentrations were 327 mg/l and 531 mg/l in the atorvastatin and simvastatin arms, respectively (p = 0.03). In the atorvastatin arm, Lp(a) concentrations decreased to 243 mg/l after one year (p < 0.001) and to 263 mg/l after two years (p < 0.001). In the simvastatin arm, Lp(a) concentrations decreased to 437 mg/l after one year (p < 0.001) and to 417 mg/l after two years (p < 0.001). The difference in Lp(a) reduction between the two treatment arms was significant after one year (p = 0.004), but not after two years (p = 0.086). Lp(a) concentrations at baseline were not related to cardiovascular events at baseline. There was no correlation between baseline Lp(a) concentrations and low density lipoprotein cholesterol concentrations or intima-media thickness at baseline. Change in Lp(a) concentrations was not correlated with change in intima-media thickness after one or two years. CONCLUSIONS Long term statin treatment significantly lowers Lp(a) in FH patients. However, this reduction was unrelated to changes in intima-media thickness and casts doubt on the importance of Lp(a) in the progression of atherosclerotic disease in these patients.
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The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.
Chertow, GM, Raggi, P, McCarthy, JT, Schulman, G, Silberzweig, J, Kuhlik, A, Goodman, WG, Boulay, A, Burke, SK, Toto, RD
American journal of nephrology. 2003;(5):307-14
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BACKGROUND We recently determined that in hemodialysis patients, the use of calcium salts to correct hyperphosphatemia led to progressive coronary artery and aortic calcification as determined by sequential electron beam tomography (EBT) while the use of the non-calcium-containing binder sevelamer did not. Whether the specific calcium preparation (acetate vs. carbonate) might influence the likelihood of progressive calcification was debated. METHODS To determine whether treatment with calcium acetate was specifically associated with hypercalcemia and progressive vascular calcification, we conducted an analysis restricted to 108 hemodialysis patients randomized to calcium acetate or sevelamer and followed for one year. RESULTS The reduction in serum phosphorus was roughly equivalent with both agents (calcium acetate -2.5 +/- 1.8 mg/dl vs. sevelamer -2.8 +/- 2.0 mg/dl, p = 0.53). Subjects given calcium acetate were more likely to develop hypercalcemia (defined as an albumin-corrected serum calcium > or =10.5 mg/dl) (36 vs. 13%, p = 0.015). Treatment with calcium acetate (mean 4.6 +/- 2.1 g/day - equivalent to 1.2 +/- 0.5 g of elemental calcium) led to a significant increase in EBT-determined calcification of the coronary arteries (mean change 182 +/- 350, median change +20, p = 0.002) and aorta (mean change 181 +/- 855, median change +73, p < 0.0001). These changes were similar in magnitude to those seen with calcium carbonate. There were no significant changes in calcification among sevelamer-treated subjects. CONCLUSION Despite purported differences in safety and efficacy relative to calcium carbonate, calcium acetate led to hypercalcemia and progressive vascular calcification in hemodialysis patients.
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Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hypercholesterolaemia (the DAPHNE study). Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands.
Hoogerbrugge, N, de Groot, E, de Heide, LH, de Ridder, MA, Birkenhägeri, JC, Stijnen, T, Jansen, H
The Netherlands journal of medicine. 2002;(9):354-61
Abstract
BACKGROUND Observational studies suggest a synergistic effect of hypertension and hyperlipidaemia on the progression of atherosclerosis. The alpha-blocker doxazosin has favourable effects on plasma lipids, insulin resistance and blood pressure, while the diuretic hydrochlorothiazide (HCTZ) principally affects blood pressure and increases insulin resistance. METHODS A randomised double-blind study over 36 months was performed to compare the effects of doxazosin and HCTZ on fasting lipids and on progression of peripheral atherosclerosis. Eighty males (45 to 70 years) with peripheral atherosclerotic disease and increased cholesterol levels (5.2-8.0 mmol/l) were treated for essential hypertension with either doxazosin (n = 41) or HCTZ (n = 39). Main outcome measures were arterial intima-media thickness (IMT) of the carotid and femoral arteries and fasting lipid parameters. RESULTS In the doxazosin-treated group, significant changes were observed in the concentration of triglycerides (-13.7%, p < 0.01), HDLc (+25.7%, p < 0.05) and IDLc (-30.1%, P < 0.05). In the HCTZ-treated group no significant changes in plasma lipid levels were observed. On follow-up visits systolic blood pressure in the doxazosin-treated group was 6 mm higher than in the HCTZ group. Nevertheless, the groups treated with doxazosin or HCTZ showed no differential effect on IMT after three years of treatment (p = 0.8). A significant reduction of the IMT of combined carotid and femoral arterial walls was shown in both treatment groups (p < 0.005). CONCLUSIONS Hypertension treatment with doxazosin or HCTZ resulted in a comparable change in arterial IMT after three years, in spite of differences in effect on plasma lipids. The study emphasises the importance of blood pressure control in patients with peripheral vascular disease and hypercholesterolaemia.
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Acute effect of pegvisomant on cardiovascular risk markers in healthy men: implications for the pathogenesis of atherosclerosis in GH deficiency.
Muller, AF, Leebeek, FW, Janssen, JA, Lamberts, SW, Hofland, L, van der Lely, AJ
The Journal of clinical endocrinology and metabolism. 2001;(11):5165-71
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Abstract
Cardiovascular risk is increased in GH deficiency (GHD). GHD adults are frequently abdominally obese and display features of the metabolic syndrome. Otherwise healthy abdominally obese subjects have low GH levels and show features of the metabolic syndrome as well. We investigated in healthy nonobese males the effect of the GH receptor antagonist pegvisomant in different metabolic conditions. This is a model for acute GHD without the alterations in body composition associated with GHD. We compared the effect of pegvisomant with that of placebo before and after 3 d of fasting. In addition, we investigated the effect of pegvisomant under normal, i.e. fed, conditions. Three days of fasting as well as pegvisomant alone decreased serum free IGF-I levels (1.0 +/- 0.15 vs. 0.31 +/- 0.05 ng/ml and 0.86 +/- 0.23 vs. 0.46 +/- 0.23 ng/ml, respectively). Fasting in combination with pegvisomant also decreased serum free IGF-I levels (1.0 +/- 0.15 vs. 0.31 +/- 0.07 ng/ml). Treatment with pegvisomant had no additional influence on the decline of free IGF-I induced by fasting. Pegvisomant alone had no influence on insulin sensitivity. The increase in insulin sensitivity induced by fasting was comparable to the increase in insulin sensitivity induced by fasting combined with pegvisomant. Among serum lipid concentrations, only serum triglycerides increased significantly as a result of pegvisomant alone (1.0 +/- 0.2 vs. 1.6 +/- 0.4 mmol/liter). The changes in lipid concentrations induced by fasting alone or pegvisomant were not different from those induced by pegvisomant alone. von Willebrand factor antigen levels declined significantly under the influence of pegvisomant alone (1.1 +/- 0.07 vs. 0.8 +/- 0.06 U/ml). In conclusion, in different metabolic conditions the GH receptor antagonist pegvisomant induces no significant acute changes in the major risk markers for cardiovascular disease. These data suggest that the secondary metabolic changes, e.g. abdominal obesity or inflammatory factors, that develop as a result of long-standing GHD are of primary importance in the pathogenesis of atherosclerosis in patients with GHD.