| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Internal Medicine, University of Pisa, 56100 Pisa, Italy
Address all correspondence and requests for reprints to: Stefano Taddei, M.D., Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. E-mail: s.taddei{at}med.unipi.it.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Previous studies have suggested an association between sHT and coronary heart disease (7, 8). Whether this association is related to sHT-induced changes in serum lipid levels is still debated (9, 10, 11). In a recent population-based survey, sHT emerged as a significant risk factor for aortic atherosclerosis and myocardial infarction in elderly women, independently of serum cholesterol levels (12). Therefore, the association between sHT and atherosclerosis may not be entirely explained by dyslipidemia, and further mechanisms must be taken into consideration (13, 14, 15).
The endothelium plays a major role in the maintenance of vascular function and integrity through the production of vasodilator and vasoconstrictor substances (16, 17). The most important vasodilator substance produced by the endothelium is nitric oxide (NO) (18, 19), derived from the conversion of L-arginine into citrulline via the activity of the enzyme NO-synthase (20). In the presence of major cardiovascular risk factors, including hypercholesterolemia, the endothelium can generate oxidative stress, which, in turn, causes NO breakdown (16, 21). It is now well established that endothelial dysfunction, a condition characterized by decreased NO availability, acts as a promoter of atherosclerosis and is associated with an increased risk of cardiovascular events (22, 23, 24).
The aim of this study was to assess vascular reactivity in sHT patients and its relation to the serum lipid profile. The effect of restored euthyroidism was also evaluated.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The study population included 14 sHT patients with Hashimoto’s thyroiditis, who were positive for both antithyroid peroxidase (TPO-Ab) and antithyroglobulin (Tg-Ab) antibodies (Table 1
). To be enrolled, patients had to have documented sHT (TSH > 3.6 µIU/ml) for at least 6 months before the study. As controls, 28 euthyroid subjects, matched to the patient group for sex, age, and body mass index (BMI), were recruited among staff and relatives of patients. According to the lipid profile, they were divided into group A [n = 14; serum cholesterol less than 200 mg/dl (5.2 mM)] and group B (n = 14; lipid profile matched to sHT patients). Women were premenopausal, with regular menses, and none were pregnant. Obese (BMI > 30 kg/m2) subjects, smokers, and those with hypertension, diabetes mellitus, or other systemic diseases were excluded from the study. No individual was taking any drug. All study subjects gave their signed informed consent to the study, which was approved by the Institutional Ethics Committee.
|
Vascular reactivity was assessed by the perfused forearm technique, as already described (21). Briefly, the brachial artery was cannulated for drug infusion at systemically ineffective rates, and intraarterial blood pressure and heart rate were monitored. Forearm blood flow (FBF) was measured in both forearms by strain-gauge venous occlusion plethysmography (25). Circulation to the hand was excluded 1 min before FBF measurement by inflating a pediatric cuff around the wrist at suprasystolic blood pressure. Forearm volume was measured by the water displacement method.
NO contribution to endothelium-dependent vasodilatation was estimated by performing a dose-response curve to acetylcholine (at infusion rates of 0.15, 0.45, 1.5, and 4.5 µg·min-1·dl-1; 5 min at each dose), in the absence and presence of NG-monomethyl-L-arginine (L-NMMA; 100 µg·min-1·dl-1), to block NO synthase (26). To avoid L-NMMA-induced basal flow modification, the NO-clamp (which allows assessment of endothelial agonists in the presence of NO-synthase blockade without changes in basal flow) was applied (27). Thus, after 10 min of L-NMMA infusion, sodium nitroprusside was coinfused (0.3 µg·min-1·dl-1 for 5 min) to neutralize the L-NMMA-induced vasoconstriction and restore baseline FBF.
Endothelium-independent vasodilatation was assessed with a dose-response curve to sodium nitroprusside (1, 2, and 4 µg·min-1·dl-1; 5 min at each dose) (28). These rates were selected to induce vasodilatation comparable with that obtained with acetylcholine. A 30-min washout was allowed between dose-response curves.
Finally, minimal forearm vascular resistances (MFVRs), an index of structural vascular alteration (29), were evaluated by calculating the ratio between mean intraarterial blood pressure and maximal forearm vasodilation induced by 13 min of forearm ischemia (obtained by inflating the plethysmographic cuff at 300 mm Hg) plus 1 min of hand exercise (30).
Patients were then given levothyroxine (L-T4) replacement therapy. Treatment always started with 25 µg, the dose being then gradually increased. To confirm patient compliance and to adjust the L-T4 dose, serum TSH was measured every 3 months. The L-T4 dose required for restoring euthyroidism averaged 67.5 µg/d. Nine sHT patients were reevaluated after 6-months of stable euthyroidism [achieved by an average of 11 months of treatment (range, 6–15)], whereas five patients dropped out because of poor compliance.
Analytical measurements
Serum FT3 and FT4 levels were measured by specific RIA (Techno-Genetics Recordati, Milan, Italy). TSH was determined with an ultrasensitive immunoradiometric assay method (Cis Diagnostici, Tronzano Vercellese, Italy). Tg-Ab was measured by specific immunoradiometric assay (Biocode, Sclessin, Belgium); TPO-Ab was measured by specific RIA (Sorin Biomedica, Saluggia, Italy). Total serum cholesterol, triglycerides, and high-density lipoprotein (HDL)-cholesterol were assayed by enzymatic methods (Roche, Diagnostic, Mannheim, Germany). Low-density lipoprotein (LDL)-cholesterol level was calculated by Friedewald’s equation. Apolipoprotein B (ApoB) and lipoprotein (a) [Lp(a)] were assayed by nephelometry (Behring Diagnostics, Marburg, Germany). Normal ranges in our laboratory are as follows: FT4 = 6.8–20 pM; FT3 = 4.3–8.6 pM, TSH = 0.30–3.6 µIU/ml, Tg-Ab less than 50 U/ml, and TPO-Ab less than 10 U/ml; ApoB = 0.55–1.65 g/liter; and Lp(a) less than 0.3 g/liter.
Statistical analysis
Data were analyzed in terms of FBF increase or decrease, taken as evidence of local vasodilation and vasoconstriction, respectively. Student’s unpaired or paired t test, 
2 test, and ANOVA for repeated measures were used as appropriate. Because of the highly skewed distribution of Lp(a) values, the nonparametric Mann-Whitney U test was applied to assess differences between groups. Linear regression analysis was carried out by standard techniques. Unless otherwise stated, results were expressed as mean ± SEM.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
At baseline, serum TSH levels were significantly higher in sHT patients than in controls (P < 0.0001), whereas serum FT3 and FT4 levels, though still within the normal range, were lower (P = 0.001 and P < 0.05, respectively). With regard to the serum lipid profile, sHT patients had serum total and LDL-cholesterol and ApoB levels that were higher than group A subjects (P < 0.0001, P < 0.001, and P < 0.01, respectively) but were comparable with those of group B subjects (Table 1
). Mean Lp(a) values proved similar in the three subgroups, although four sHT patients and one group B subject had elevated Lp(a) values. A positive relationship between serum TSH and LDL-cholesterol levels (r = 0.66, P = 0.05) was observed. Finally, sHT patients showed a significantly higher erythrocyte sedimentation rate (ESR) than both control groups (P < 0.01), whereas fibrinogen was similar in the three study groups (Table 1).
Vascular parameters
Throughout all experimental steps, blood pressure and contralateral FBF remained stable (data not shown). MFVRs were similar in sHT patients and control subjects (2.3 ± 0.1, 2.6 ± 0.2, and 2.5 ± 0.2 mm Hg.min.ml-1.dl-1 in sHT patients, group A, and group B, respectively).
Response to acetylcholine and sodium nitroprusside
The FBF increase induced by acetylcholine was significantly smaller in sHT patients (from 2.5 ± 0.1 to a maximum of 11.4 ± 0.8 ml·min-1·dl-1, 358 ± 29% increase above baseline), compared with group B (from 3.0 ± 0.1 to a maximum of 19.9 ± 1.0 ml·min-1·dl-1; 503 ± 19% increase, P = 0.0003 vs. sHT). Moreover, both sHT patients and group B subjects had a lower response to acetylcholine, in comparison with group A (from 3.0 ± 0.2 to a maximum of 22.6 ± 2.0 ml·min-1·dl-1; 663 ± 65% increase, P = 0.02 vs. group B and P = 0.0002 vs. sHT). In contrast, vasodilatation to sodium nitroprusside was not significantly different between sHT patients (396 ± 38% increase) and group A (472 ± 33%) or group B subjects (424 ± 41%) (Fig. 1).
|
) and LDL-cholesterol levels (r = 0.68, P < 0.01).
|
L-NMMA significantly blunted the maximum vasodilating effect of acetylcholine in group A (saline, 22.6 ± 2.0 ml·min-1·dl-1; L-NMMA, 11.5 ± 1.4; 49.1 ± 6.3% maximal FBF reduction, P < 0.0001 vs. acetylcholine alone) and, to a lesser extent, in group B subjects (saline, 19.9 ± 1.0 ml·min-1·dl-1; L-NMMA, 11.4 ± 0.6; 42.7 ± 5.5% maximal FBF reduction; P < 0.02 vs. group A). In contrast, in sHT patients L-NMMA coinfusion only slightly attenuated the response to acetylcholine (saline, 11.4 ± 0.8 ml·min-1·dl-1; L-NMMA, 9.9 ± 0.8; 12.8 ± 2.5% maximal FBF reduction; P = 0.053 vs. acetylcholine alone) (Fig. 3).
|
Moreover, in the sHT group, 9 out of 14 patients were characterized by LDL levels lower than 160 mg/dl (4 mM). In these individuals, the vasodilating effect to acetylcholine (from 2.6 ± 0.1 to a maximum of 12.3 ± 0.8 ml·min-1·dl-1; 383.8 ± 33.6% increase above baseline) and the blunting effect of L-NMMA (10.2 ± 0.9 ml·min-1·dl-1; 16.9 ± 2.8% maximal FBF reduction; P = 0.066 vs. acetylcholine alone) still proved to be significantly reduced, compared with groups A (P = 0.002) and B (P = 0.001).
Finally, even excluding patients with elevated Lp(a), the results do not substantially change (data not shown).
Effect of L-T4 replacement therapy
Serum TSH levels decreased significantly (P < 0.0005 vs. baseline) and returned within the normal range; FT3 and FT4 values remained within the normal range throughout the entire treatment period, although FT4 rose significantly (P = 0.01 vs. baseline) (Table 2). Though remaining not significantly different from group B, sHT patients showed a slight decrease in both total and LDL-cholesterol (P = 0.04 and P = 0.05, respectively), whereas ApoB did not change. Moreover, the Lp(a) value was unchanged both as a mean and in patients with elevated baseline values. A significant relationship between baseline serum TSH level and LDL-cholesterol reduction was detected (r = 0.69, P < 0.05). Interestingly, the inflammatory status was not modified, because ESR and autoantibody titer did not change (Table 2).
|
). Moreover, the inhibitory effect of L-NMMA on the response to acetylcholine was restored (saline, 13.4 ± 0.8 ml·min-1·dl-1; L-NMMA, 7.3 ± 0.8; P < 0.001 vs. saline), so that the degree of inhibition exerted by the NO-synthase inhibitor was now similar to that obtained in group B subjects (45.3 ± 4.3 vs. 42.7 ± 5.5% reduction of maximal FBF response, respectively). The maximal response to acetylcholine was positively associated with both baseline serum TSH levels (r = 0.82, P < 0.01) and treatment-induced changes in TSH (r = 0.80, P < 0.01). A significant correlation between maximal response to acetylcholine and change in LDL-cholesterol (r = 0.84, P < 0.01) was also observed.
|
In six of nine treated patients characterized by pretreatment LDL levels lower than 160 mg/dl (4 nM), after L-T4 administration, the vasodilating effect to acetylcholine increased slightly and nonsignificantly (baseline: from 2.7 ± 0.1 to a maximum of 12.6 ± 1.1 ml·min-1·dl-1, 375.0 ± 35.8% increase above baseline; after L-T4: from 2.7 ± 0.2 to a maximum of 13.3 ± 0.8 ml·min-1·dl-1, 410.7 ± 30.1% increase above baseline). However, the blunting effect of L-NMMA (6.9 ± 1.1 ml·min-1·dl-1; 47.8 ± 5.3% maximal FBF reduction) was found to be significantly potentiated, compared with baseline (10.3 ± 1.3 ml·min-1·dl-1; 18.1 ± 2.9% maximal FBF reduction; P = 0.04).
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The present results indicate that the vasodilating effect of acetylcholine was significantly reduced in sHT patients, compared with healthy subjects, an effect which was evident even in those patients with TSH lower than 10 µIU/ml. Because the response to sodium nitroprusside (which specifically acts on smooth muscle cells) (28) and calculated MFVRs (an index of vascular structural alterations) (29) were similar in the two study groups, the present results indicate that sHT is characterized by the presence of endothelial dysfunction. This alteration cannot be accounted for exclusively by the alteration in lipid profile, because the response to acetylcholine in group B control subjects was found to be impaired, compared with normocholesterolemic controls (group A), but significantly better than that of sHT patients. Moreover, in sHT patients with normal Lp(a) values or LDL cholesterol lower than 160 mg/dl (4 mM), vasodilation to acetylcholine proved to be impaired, compared with control groups. Thus, it is conceivable that sHT per se causes an impairment of endothelium-dependent vasodilation. On the other hand, though a significant relationship between the maximal response to acetylcholine and serum LDL-cholesterol level was observed in both patients and controls, in sHT patients a significant correlation between the maximal response to acetylcholine and baseline serum TSH value was also obtained.
In the euthyroid subjects, the vasodilator response to acetylcholine was blunted by L-NMMA, confirming earlier observations (21, 26). This finding indicates that the relaxing activity of this agonist must be predominantly mediated by activation of the L-arginine-NO pathway. In contrast, in sHT patients, both the entire population and the subgroup with TSH lower than 10 µIU/ml, the vasodilation to acetylcholine was almost fully resistant to L-NMMA, indicating the presence of an alteration in the L-arginine-NO pathway, leading to impaired NO availability. Again, this alteration is probably, in part, related to sHT per se because, in group B subjects, the degree of inhibition exerted by L-NMMA on vasodilation to acetylcholine was reduced, compared with group A subjects, but greater than that observed in sHT patients. Moreover, in sHT patients with normal Lp(a) values or LDL cholesterol lower than 160 mg/dl (4 mM), the blunting effect of L-NMMA on the vasodilation to acetylcholine proved to be reduced.
A causal relationship between the presence of sHT and endothelial dysfunction is also supported by the effect of hormone replacement. Thus, after 6 months of stable euthyroidism, a significant improvement in acetylcholine-induced vasodilatation (along with an unchanged response to sodium nitroprusside) was observed. Moreover, the most relevant issue is probably the finding that the slight increased response to acetylcholine was associated with a restoration of the inhibitory activity of L-NMMA, indicating that L-T4 treatment improves endothelium-dependent vasodilation by restoring NO availability. A tendency to improvement after L-T4 treatment was also observed in those patients with TSH lower than 10 µIU/ml. However, the low numerosity of this subgroup (n = 6) does not allow a definite conclusion to be reached. It is important to note that, after treatment, the degree of inhibition exerted by L-NMMA on acetylcholine-dependent vasodilation was similar to that observed in group B subjects. This beneficial effect of L-T4 administration was associated with a reduction of serum LDL-cholesterol levels, which were shown to be not significantly different from the corresponding values of group B. On the other hand, it is of interest that L-T4 treatment increased the L-NMMA-induced inhibition on vasodilation to acetylcholine, even in patients with LDL cholesterol plasma level lower than 160 mg/dl (4 mM). Finally, significant relationships between the maximal response to acetylcholine and both serum TSH and LDL-cholesterol reduction were found.
However, it is important to consider that the effect of L-T4 treatment would have been more appropriately addressed by a placebo-controlled design. In the present investigation, this issue was assessed as a secondary end-point, when several patients were already on L-T4 administration We therefore decided to perform an open study. Although this represents a study limitation, the good reproducibility of the forearm technique and lack of time-dependent effects on endothelial responses confer substantial plausibility on the results obtained with L-T4 treatment.
Overall, these findings suggest the presence of an early, reversible impairment of endothelium-dependent vasodilatation in sHT patients (possibly because of reduced NO availability), which is, only in part, explained by the mild dyslipidemia. This finding, together with the evidence of a relationship between maximal vasodilation to acetylcholine and serum TSH levels, supports the hypothesis that sHT per se may conspire with dyslipidemia to promote endothelial dysfunction. It can be argued that, by definition, sHT patients have thyroid hormone levels within the normal range. However, given the narrow limit of individual thyroid hormone level variations, about half of laboratory reference ranges, a test result within the laboratory reference limits is not necessarily normal for that subject (33).
These results extend the previous evidence demonstrating the presence of impaired flow-mediated endothelium-dependent vasodilation in the conduit arteries of patients with sHT (34) and provide new information on NO availability alteration and the effect of L-T4 replacement therapy.
In addition to a direct effect of thyroid hormones, other mechanisms could lead to endothelial dysfunction in sHT patients. In this regard, all the patients had thyroiditis; and therefore, a possible concomitant effect of inflammation and autoimmunity should be not overlooked, because inflammatory states are associated with endothelial dysfunction (35). Although in the present study, the presence of increased ESR values in sHT patients seems to confirm this hypothesis, the lack of measurements of more specific inflammation parameters, including interleukins and C-reactive protein, may represent a major methodological limitation restricting the substantiation of this likely interpretation. Furthermore, four sHT patients showed increased Lp(a) levels, in contrast to only one subject in group B. Because elevated Lp(a) values are associated with endothelial dysfunction in human coronary circulation (36), this alteration could, in part, participate in the impaired endothelium-dependent vasodilation. It is therefore conceivable that these factors (direct effect of thyroid hormone, inflammatory status, and lipid profile) can jointly contribute to impairing endothelium-dependent vasodilation in sHT patients. The finding that after 6 months of stable euthyroidism, inflammatory status did not change (as supported by the lack of ESR and autoantibody titer modifications) and lipid profile improved only slightly, with no change in Lp(a) values, is in keeping with only partial restoration of endothelium-dependent vasodilation.
In conclusion, endothelial dysfunction may represent early development of cardiovascular damage in sHT patients. Therefore, early L-T4 replacement therapy may be advised not only to prevent progression to frank hypothyroidism but also to slow down atherogenesis.
|
Footnotes |
|---|
Received January 8, 2003.
Accepted April 13, 2003.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  R. Napoli, B. Biondi, V. Guardasole, C. D'Anna, A. De Sena, C. Pirozzi, D. Terracciano, C. Mazzarella, M. Matarazzo, and L. Sacca Enhancement of Vascular Endothelial Function by Recombinant Human Thyrotropin J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1959 - 1963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. O. Asvold, T. Bjoro, T. I. L. Nilsen, D. Gunnell, and L. J. Vatten Thyrotropin Levels and Risk of Fatal Coronary Heart Disease: The HUNT Study Arch Intern Med, April 28, 2008; 168(8): 855 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Biondi and D. S. Cooper The Clinical Significance of Subclinical Thyroid Dysfunction Endocr. Rev., February 1, 2008; 29(1): 76 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H G Raterman, V P van Halm, A E Voskuyl, S Simsek, B A C Dijkmans, and M T Nurmohamed Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk Ann Rheum Dis, February 1, 2008; 67(2): 229 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Klein and S. Danzi Thyroid Disease and the Heart Circulation, October 9, 2007; 116(15): 1725 - 1735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Razvi, L. Ingoe, G. Keeka, C. Oates, C. McMillan, and J. U. Weaver The Beneficial Effect of L-Thyroxine on Cardiovascular Risk Factors, Endothelial Function, and Quality of Life in Subclinical Hypothyroidism: Randomized, Crossover Trial J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1715 - 1723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. O. Asvold, T. Bjoro, T. I. L. Nilsen, and L. J. Vatten Association between Blood Pressure and Serum Thyroid-Stimulating Hormone Concentration within the Reference Range: A Population-Based Study J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 841 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Napoli, V. Guardasole, V. Angelini, E. Zarra, D. Terracciano, C. D'Anna, M. Matarazzo, U. Oliviero, V. Macchia, and L. Sacca Acute Effects of Triiodothyronine on Endothelial Function in Human Subjects J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 250 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Taddei, N. Caraccio, A. Virdis, A. Dardano, D. Versari, L. Ghiadoni, E. Ferrannini, A. Salvetti, and F. Monzani Low-Grade Systemic Inflammation Causes Endothelial Dysfunction in Patients with Hashimoto's Thyroiditis J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5076 - 5082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Fernandez-Real, A. Lopez-Bermejo, A. Castro, R. Casamitjana, and W. Ricart Thyroid Function Is Intrinsically Linked to Insulin Sensitivity and Endothelium-Dependent Vasodilation in Healthy Euthyroid Subjects J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3337 - 3343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. D. Owen, C. Rajiv, D. Vinereanu, T. Mathew, A. G. Fraser, and J. H. Lazarus Subclinical Hypothyroidism, Arterial Stiffness, and Myocardial Reserve J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2126 - 2132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Brabant, P Beck-Peccoz, B Jarzab, P Laurberg, J Orgiazzi, I Szabolcs, A P Weetman, and W M Wiersinga Is there a need to redefine the upper normal limit of TSH? Eur. J. Endocrinol., May 1, 2006; 154(5): 633 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagasaki, M. Inaba, Y. Kumeda, Y. Hiura, K. Shirakawa, S. Yamada, Y. Henmi, E. Ishimura, and Y. Nishizawa Increased Pulse Wave Velocity in Subclinical Hypothyroidism J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 154 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Walsh, A. P. Bremner, M. K. Bulsara, P. O'Leary, P. J. Leedman, P. Feddema, and V. Michelangeli Subclinical Thyroid Dysfunction as a Risk Factor for Cardiovascular Disease Arch Intern Med, November 28, 2005; 165(21): 2467 - 2472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-D. Tang, J. A. Kuzman, S. Said, B. E. Anderson, X. Wang, and A. M. Gerdes Low Thyroid Function Leads to Cardiac Atrophy With Chamber Dilatation, Impaired Myocardial Blood Flow, Loss of Arterioles, and Severe Systolic Dysfunction Circulation, November 15, 2005; 112(20): 3122 - 3130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Mohn, S Di Michele, R Faricelli, S Martinotti, and F Chiarelli Increased frequency of subclinical hypothyroidism and thyroid-associated antibodies in siblings of children and adolescents with type 1 diabetes mellitus Eur. J. Endocrinol., November 1, 2005; 153(5): 717 - 718. [Full Text] [PDF]
|
|
|
|
|
|
O. Gumieniak, S. Hurwitz, T. S. Perlstein, U. C. Ngumezi, P. N. Hopkins, X. Jeunemaitre, and G. H. Williams Aggregation of High-Normal Thyroid-Stimulating Hormone in Hypertensive Families J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5985 - 5990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Guang-da, S. Hui-ling, C. Zhi-song, and Z. Lin-shuang Changes in Plasma Concentrations of Osteoprotegerin before and after Levothyroxine Replacement Therapy in Hypothyroid Patients J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5765 - 5768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Squizzato, V.E.A. Gerdes, D.P.M. Brandjes, H.R. Buller, and J. Stam Thyroid Diseases and Cerebrovascular Disease Stroke, October 1, 2005; 36(10): 2302 - 2310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wartofsky and R. A Dickey The Evidence for a Narrower Thyrotropin Reference Range Is Compelling J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5483 - 5488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Surks, G. Goswami, and G. H. Daniels The Thyrotropin Reference Range Should Remain Unchanged J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5489 - 5496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Kahaly and W. H. Dillmann Thyroid Hormone Action in the Heart Endocr. Rev., August 1, 2005; 26(5): 704 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Colantuoni, P. L. Marchiafava, D. Lapi, F. S. Forini, and G. Iervasi Effects of tetraiodothyronine and triiodothyronine on hamster cheek pouch microcirculation Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1931 - H1936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Cooper Thyroid Disease in the Oldest Old: The Exception to the Rule JAMA, December 1, 2004; 292(21): 2651 - 2654. [Full Text] [PDF]
|
|
|
|
|
|
O. Gumieniak, T. S. Perlstein, P. N. Hopkins, N. J. Brown, L. J. Murphey, X. Jeunemaitre, N. K. Hollenberg, and G. H. Williams Thyroid Function and Blood Pressure Homeostasis in Euthyroid Subjects J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3455 - 3461. [Abstract] [Full Text] [PDF]
|
|
