The Pro 12 Ala PPAR gamma gene polymorphism: possible modifier of the activity and severity of thyroid-associated orbitopathy (TAO).

OBJECTIVE: The PPAR gamma transcription factor, is involved in both adipogenesis and inflammation, which have been implicated in the pathogenesis of thyroid-associated orbitopathy (TAO). The aim of this study was to explore the possibility that the Pro(12)Ala polymorphism of the PPAR gamma gene, associated with a modified transcriptional activity, might be affecting the severity of TAO. SUBJECTS AND DESIGN: We studied two cohorts of patients with Graves' disease (GD): Group 1 comprised 172 patients of Dutch ethnic origin with TAO, who attended the outpatients' clinic, Department of Endocrinology and Orbital Centre of the Academic Medical Centre, Amsterdam. Group 2 comprised 93 consecutive patients with GD of Greek ethnic origin, who did not have TAO. In group 1, exophthalmometry measurements, lid oedema, diplopia (n = 172) and clinical activity score (CAS) (n = 110), always assessed by the same group of three investigators, were recorded. Autoantibody levels were measured. RESULTS: Allele frequency was 11.5%. There was no difference in the distribution of the polymorphism between GD patients with and without TAO. Among group 1 patients proptosis was significantly lower in Pro(12)Ala carriers (20.1 +/- 3.3 vs. 22.1 +/- 3.1, P = 0.003, t-test). PPAR gamma polymorphism carriers had lower TSH-Rab levels (mean rank 61.8 vs. 83.2, P = 0.015) and lower CAS (available in 110 patients) (mean rank 38.9 vs. 55.4, P = 0.022, M-W-test). The frequency of the polymorphism decreased with increasing CAS (P = 0.023 linear by linear association). Multivariate analysis (step) showed that the association of either proptosis or CAS with the PPAR gamma gene variant remained significant when age, smoking and TSH-Rab levels were taken into account (P < 0.01). CONCLUSIONS: The distribution of the Pro(12)Ala PPAR gamma gene polymorphism is equally present in patients with GD with or without TAO. Among patients with TAO this polymorphism is associated with less-severe and less-active disease.

The importance of the (TAAAA)n alleles at the SHBG gene promoter for the severity of coronary artery disease in postmenopausal women.

OBJECTIVE: Androgen may be detrimental in the development of coronary artery disease (CAD) in women. We investigated possible associations between the (TAAAA)n polymorphism of sex hormone-binding globulin (SHBG) gene promoter, which influences transcriptional efficiency of the SHBG gene and the severity of CAD in women. DESIGN: In this prospective clinical study, 146 postmenopausal women (46-88 y) undergoing coronary angiography were studied. CAD severity, history of angina and myocardial infarction, and reproductive history were recorded and hormonal parameters measured. According to the number of SHBG gene promoter repeat polymorphisms, participants were classified into short (seven or fewer), medium length (eight), and long repeat (nine or more) allele groups. RESULTS: Significant CAD was more prevalent in the long repeat allele carrier group: 65% of the participants with three vessels with severe stenosis belonged to the long repeat allele group, whereas only 37% of participants with mild CAD belonged to this group (P=0.01). A history of angina and prevalence of hyperlipidemia was more frequent in the long repeat allele group (P<0.05). Calculated free testosterone levels were higher in the long repeat allele groups (P<0.05), whereas SHBG levels tended to be lower (P=0.06). SHBG levels correlated inversely with body mass index and waist circumference (P<0.05). CONCLUSIONS: Longer (TAAAA)n repeats in the SHBG gene promoter are associated with more severe CAD in women undergoing coronary angiography, a finding not previously reported. This association may reflect the lifelong tissue exposure to higher free androgens and supports the adverse cardiovascular effect of androgenic exposure in this highly selected group of women.

High anticipatory stress plasma cortisol levels and sensitivity to glucocorticoids predict severity of coronary artery disease in subjects undergoing coronary angiography.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and/or increased sensitivity of peripheral tissues to glucocorticoids may be associated with the dysmetabolic syndrome and its cardiovascular sequelae. In this prospective pilot clinical study, we examined possible associations between HPA axis activity and severity of cardiovascular disease. We measured morning serum cortisol and intima media thickness (IMT) of carotid and femoral arteries in 105 subjects before undergoing coronary angiography for suspected coronary artery disease (CAD). In a randomly selected 46 of these subjects, we obtained late afternoon and morning cortisol levels (after ultralow-dose dexamethasone [0.25 mg] treatment) and determined their genotype for the Bcl1 polymorphism of the glucocorticoid receptor gene, which has been associated with increased sensitivity to glucocorticoids. There was significant association between morning preangiography cortisol levels and the number of vessels with severe stenosis in the angiography, independently of age or sex (P = .002), and a trend for a positive correlation between morning cortisol and the IMT of the femoral artery (P = .057). Bcl1 G allele homozygotes had a significantly higher carotid IMT (P = .005) and a nonsignificant tendency for higher waist-hip ratio (P = .059). Hyperactivity of the HPA axis in anticipation of a stressful procedure, such as angiography, may be an index of CAD severity. Chronic HPA axis hyperreactivity combined with tissue hypersensitivity to glucocorticoids may contribute to more severe atherosclerosis and CAD.

Rapid effect of pravastatin on endothelial function and lipid peroxidation in unstable angina.

BACKGROUND: Oxidative stress contributes to endothelial dysfunction, an important step to the pathogenesis of atherosclerosis and coronary events. Latest studies revealed the existence of pleiotropic and especially antioxidant properties of statins. We sought to examine the effects of pravastatin on lipid peroxidation and endothelial function, independently from lipid-lowering, in patients with unstable angina (UA). METHODS: Thirty-seven patients (males), 64.46+/-9.09 years, suffering from UA enrolled in the study. Patients were not on statin medication before admission and they received after randomization either 40 mg pravastatin daily (group A, n = 20), or placebo (group B, n = 17). Malondialdehyde (MDA) concentration, an index of lipid peroxidation and plaque instability, flow-mediated dilatation (FMD) of the brachial artery and blood lipids were measured on the second day of hospitalization and 10 days later. RESULTS: MDA decreased significantly in both groups (A, p = 0.008; B, p = 0.003). FMD increased significantly in group A (p = 0.007), whereas in group B it did not change. Serum lipids remained unaltered in all three groups. CONCLUSIONS: Pravastatin administration improved FMD within 10 days and this favorable effect occurred before any significant reduction in blood lipids, revealing its pleiotropic effects during the early phase of an acute coronary syndrome. Circulating lipid peroxidation products in patients with UA decreased significantly during the same period independently of endothelial function and pravastatin therapy.

TSH may not be a good marker for adequate thyroid hormone replacement therapy.

The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria. Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH < 2.5 microgU/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group: thus, for the same TSH levels, T3 levels were lower in the hypothyroid group. We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.

Molecular analysis of the estrogen receptor alpha gene in men with coronary artery disease: association with disease status.

BACKGROUND: The vasoprotective effects of estrogens are known to be mediated by their respective estrogen receptors (ER) alpha (ERalpha) and beta (ERbeta), which are present on the vascular wall. The amino-terminal part of the ERalpha appears to be important; genetic alterations in this region have been associated with arterial hypertension. This region has not been studied in atherosclerotic disease. In the present study, we examined the association between coronary artery disease (CAD) and alterations of the NH(2)-terminal part of ERalpha coding region. METHODS: Genomic DNA was isolated from 50 healthy men and 40 men with CAD confirmed by coronary angiography. The coding sequences of exons 1 and 2 were amplified by polymerase chain reaction (PCR) and analyzed by either denaturing gradient gel electrophoresis (DGGE) or single stranded conformational polymorphism (SSCP), or both, sequencing and restriction fragment length polymorphism (RFLP), as appropriate. In the same subjects, biochemical and vascular parameters were also determined by using the appropriate methodology. RESULTS: In exon 1, the codon 10 polymorphism was detected in both patients and healthy men either in heterozygous or homozygous form. The codon 87 polymorphism was detected mainly in homozygous form and only five individuals were heterozygotes. No mutations were found in exon 2. Statistical analysis of the allele distribution for either codon 10 or 87 between patients and healthy men showed no significant difference. In patients, the biochemical parameters were not statistically significantly different between ERalpha codon 10 genotypes or alleles. However, there was a clear effect of the TCT/TCT genotype and TCT allele on the vascular parameters whereas the right internal carotid artery (RICA) intima-media thickness was significantly associated with TCT/TCT genotype and TCT allele. CONCLUSIONS: We conclude that ERalpha genotypes play no role in the incidence of CAD disease, however, ERalpha codon 10 may be a genetic factor controlling some vessels' angiographic complications.

Severity of coronary artery disease in postmenopausal women: association with the androgen receptor gene (CAG)n repeat polymorphism.

OBJECTIVE: Androgen may adversely affect vascular health in women. We investigated the associations between the androgen receptor gene (CAG)n repeat polymorphism, which affects androgen receptor transcriptional activity, and the severity of coronary artery disease (CAD) in women undergoing coronary angiography. METHODS: We examined 131 postmenopausal women (46-82 y). CAD severity was assessed by the number of vessels with greater than 50% stenosis. The history of angina, myocardial infarctions, and biochemical parameters were recorded. CAG repeats ranged between 13 and 24 in the shorter allele and 16 and 28 in the longer allele. The mean lowest quartile corresponded to 19, and the highest, to 22 repeats. RESULTS: Carriers of 19 repeats or less in their shorter allele had severe disease (≥2 vessels affected) and a history of angina more frequently than those carrying 22 or more (39.2% vs 9.5%, P = 0.009 and 80.8% vs 55%, P = 0.037, respectively, using the Fisher exact test). A higher percentage of women carrying 19 repeats or less had one and two myocardial infarctions (28.6% and 10.7%, respectively) compared with women with more than 19 repeats (18.2% and 1.45%, respectively, P = 0.019). Women homozygous for two longer alleles (≥22 repeats) had less severe CAD, significantly higher sex hormone-binding globulin levels, and less frequent antilipid drug therapy compared with those homozygous for shorter alleles (P < 0.05). Total cholesterol and low-density lipoprotein cholesterol levels were negatively correlated with the number of repeats in the shorter allele (P < 0.04). CONCLUSIONS: Shorter polyglutamine stretch in the androgen receptor correlates with more severe CAD and worse predisposing factors in postmenopausal women undergoing coronary angiography. This association may support the adverse cardiovascular effect of lifelong androgenic exposure in this selected group of women.

Intima-media thickness score from carotid and femoral arteries predicts the extent of coronary artery disease: intima-media thickness and CAD.

OBJECTIVES: In the present study we measured carotid and femoral intima-media thickness (IMT) by B-Mode ultrasonography, as well as angiographic extent and severity of coronary artery disease in patients referred for coronary arteriography, to assess the relation between individual IMT, scores incorporating IMT from the carotid and femoral arteries and the extent and severity of coronary artery disease. METHODS: Two hundred and two patients referred for elective coronary angiography underwent ultrasound imaging of both carotid and femoral arteries for IMT measurements. An IMT score was developed as the number of sites with abnormal IMT (range 0-8). Multiple regression analysis indicated that IMT score was independently related to Gensini score, age and glucose levels. A high risk IMT score predicted an extended coronary artery disease although a low or medium risk IMT score cannot exclude the possibility of multivessel disease. Also, a high risk group could predict the performance of revascularization procedures and all cardiovascular events during a follow-up of 14.5 +/- 2.4 months. CONCLUSIONS: IMT incorporating data from common and internal carotid artery, carotid bifurcation and femoral artery are well correlated with the extent of coronary atherosclerosis, much better than individual IMT. Patients with high IMT score usually have multivessel coronary artery disease and are at increased risk for subsequent cardiovascular events.