Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid patients during normalization of thyroid function: a double-blind, placebo-controlled study.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population, is especially prevalent in females, and may be associated with increased morbidity from cardiovascular disease, although it remains controversial. We recently reported a significant increase in the brachial-ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor of cardiovascular events, in subclinical hypothyroidism without thyroiditis. The current study was performed to assess changes in baPWV in female subclinical hypothyroidism with autoimmune chronic thyroiditis (Hashimoto's disease) after restoration of normal thyroid function. METHODS: In a randomized placebo-controlled study, 95 female subclinical hypothyroid patients were monitored for changes in baPWV before and after levothyroxine (l-T(4)) replacement therapy. Changes in baPWV were also measured in 42 age-matched normal female subjects. RESULTS: The baseline baPWV values in patients with subclinical hypothyroidism were significantly higher than in normal subjects. With attainment of euthyroidism, baPWV showed a significant decrease from 1776.7+/-86.0 to 1674.3+/-79.2 cm/s (P=0.006) in patients treated with l-T(4), but the changes in baPWV and TSH were not correlated. The change in baPWV was significantly and negatively correlated with age and baseline pulse pressure, but multiple regression analysis revealed that these parameters failed to be associated with the change in baPWV. CONCLUSIONS: Sustained normalization of thyroid function during l-T(4) replacement therapy significantly decreases baPWV in female subclinical hypothyroid patients with autoimmune chronic thyroiditis, suggesting the improvement of arterial stiffening and, consequently, possible prevention of cardiovascular disease.

Increased levels of C-reactive protein in hypothyroid patients and its correlation with arterial stiffness in the common carotid artery.

OBJECTIVE: Hypothyroidism is associated with increased morbidity from cardiovascular disease. The arterial stiffness index beta (stiffness beta) in the common carotid artery (CCA), which is a parameter of arterial stiffening, is known to increase in hypothyroid patients, while normalization of thyroid function for 1 year by levothyroxine (L-T(4)) replacement therapy significantly decreases CCA stiffness beta. Since serum C-reactive protein (CRP) has recently emerged as an independent factor for cardiovascular risk, the present study was designed to examine whether hypothyroidism causes an increase in CRP and whether the serum CRP level is correlated with CCA stiffness beta in hypothyroid patients. PATIENTS AND METHODS: Serum CRP levels and CCA stiffness beta were determined in 46 patients with hypothyroidism and in 46 age- and sex-matched normal control subjects. Thirty-five patients were further monitored for change in CCA stiffness beta during 1 year in the euthyroid state induced by L-T(4) therapy. RESULTS: Baseline CRP and CCA stiffness beta were both significantly higher in hypothyroid patients than in normal controls [1064.6+/-224.3 vs. 602.1+/-43.3 ng/ml (mean+/-SE), p<0.0001; and 9.25+/-0.84 vs. 8.21+/-0.85, p<0.05, respectively]. Baseline CRP was significantly correlated in a positive manner with baseline values of CCA stiffness beta (r=0.683, p<0.0001). In multivariate analysis, baseline CCA stiffness beta was significantly associated with baseline levels of serum CRP (r=0.740, p<0.0001). During 1 year of L-T(4) replacement therapy, significant decrease in stiffness beta (from 9.25+/-0.84 to 8.57+/-0.58, p<0.0001) to the normal levels was found. Moreover, the change in CCA stiffness beta during L-T(4) replacement therapy was significantly and independently associated in a negative fashion with baseline levels of serum CRP (r=-0.696, p=0.0002). CONCLUSIONS: This study suggests that increased serum CRP might have an important independent role in increased arterial stiffening and the measurement of serum CRP is a useful predictor for the degree of improvement of arterial stiffening in hypothyroid patients.

Central pulse wave velocity is responsible for increased brachial-ankle pulse wave velocity in subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population, and is associated with increased morbidity from cardiovascular disease. We recently reported a significant increase in brachial-ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor for the presence of cardiovascular disease, in subclinical hypothyroidism. The current study was performed to assess which arterial segment is responsible for enhanced baPWV in subclinical hypothyroidism. PATIENTS AND METHODS: Central PWV (PWV in heart-femoral segments), peripheral PWV (PWV in femoral-ankle segments), and baPWV were measured in subclinical hypothyroid patients and normal subjects. RESULTS: Central PWV, baPWV, and peripheral PWV were significantly higher in subclinical hypothyroid patients than in normal subjects. BaPWV was significantly and positively correlated with central and peripheral PWV in both groups. However, a significant and positive correlation between central and peripheral PWV in normal subjects was not found in subclinical hypothyroid patients. Moreover, stepwise regression analysis showed that the association of central PWV with baPWV was stronger than that of peripheral PWV, whereas in normal subjects central PWV was not associated with baPWV. CONCLUSIONS: Our results demonstrate that central and peripheral PWV are significantly higher in subclinical hypothyroid patients, and that the increase in baPWV depends more strongly on central PWV than on peripheral PWV in these patients. This suggests that increased elastic arterial stiffening of the aorta, rather than of peripheral muscular arteries, might be more responsible for increased general arterial stiffening in subclinical hypothyroid patients.

Increased pulse wave velocity in subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the general population and is associated with increased morbidity from cardiovascular disease. Brachial-ankle pulse wave velocity (baPWV) is a parameter of arterial stiffening and a good independent predictor for the presence of coronary artery disease. This study was performed to assess whether subclinical hypothyroidism might cause enhanced baPWV. PATIENTS AND METHODS: baPWV was examined in subclinical hypothyroid patients (n = 50) and normal control subjects (n = 50). RESULTS: Diastolic blood pressure (DBP), a main risk factor for cardiovascular disease, and baPWV were both significantly higher in subclinical hypothyroid patients than normal subjects. baPWV was significantly positively correlated with age and systolic, diastolic, and pulse pressure and significantly negatively correlated with pulse rate in both subclinical hypothyroid patients and normal subjects. In contrast, there was no significant correlation of baPWV with free T3, free T4, TSH, total, high-density lipoprotein- and low-density lipoprotein-cholesterol, and the preejection time to ejection time ratio. A comparison of individual values of baPWV and DBP and regression slopes in two groups revealed that baPWV values increase to a larger extent than the increase in DBP in subclinical hypothyroid patients. In both groups, stepwise regression analysis showed a significant and independent association of DBP with baPWV. CONCLUSIONS: The present study demonstrated significant increases of baPWV and DBP in subclinical hypothyroid patients. Furthermore, the results suggest that increased DBP might be one of the main factors responsible for increased arterial stiffening in subclinical hypothyroid patients.

Plasma levels of adiponectin and soluble thrombomodulin in hypothyroid patients with normal thyroid function following levothyroxine replacement therapy.

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and adiponectin (ApN) is a newly-identified adipocytokine, which is expressed in human adipose cells and may have a protective effect against the development of coronary artery disease. The aim of the study was to evaluate the involvement of ApN secretion in hypothyroid patients with normal thyroid function following levothyroxine (L-T(4)) replacement therapy, and to associate plasma ApN levels with intima-media thickness (IMT) in the common carotid artery (CCA), an indicator of early atherosclerosis, and cardiovascular parameters including soluble thrombomodulin (sTM), a plasma endothelial injury marker. The CCA IMT and plasma levels of ApN and sTM were measured in 52 hypothyroid patients and in age-, sex- and body mass index (BMI)-matched normal control subjects. Thirty-six of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T(4) replacement therapy. Although the basal CCA IMT was significantly higher in hypothyroid patients [0.633 +/- 0.018 mm (mean +/- S.E.)] than in control subjects (0.552 +/- 0.022 mm, P < 0.005), both groups had similar baseline ApN and sTM levels [10.23 +/- 0.76 vs. 10.10 +/- 0.93 microg/ml: NS; and 2.58 +/- 0.14 vs. 2.68 +/- 0.20 ng/ml: NS, respectively]. Simple regression analysis revealed that plasma ApN was significantly correlated in a positive manner with age (r = 0.339, P = 0.015), HDL-cholesterol (r = 0.295, P = 0.048), and sTM (r = 0.490, P = 0.0005), but not with CCA IMT (r = 0.059, P = 0.742). In multivariate analysis, the plasma ApN level was significantly associated with that of sTM (r = 0.546, P = 0.0001) and with serum high-density lipoprotein (HDL)-cholesterol levels (r = 0.291, P = 0.029) in hypothyroid patients. During 1 year of L-T(4) replacement therapy, hypothyroid patients showed a significant decrease in CCA IMT, to 0.553 +/- 0.016 mm (P < 0.0001), a level comparable to normal controls, but no significant change in ApN (from 10.79 +/- 1.07 to 10.6 9+/- 1.14 microg/ml, NS) or sTM (from 2.59 +/- 0.15 to 2.74 +/- 0.18 ng/ml, NS). Hence, we provide evidence that ApN and sTM might not contribute to enhanced atherosclerosis, as reflected by increased CCA IMT in hypothyroid patients. However, this is the first report to demonstrate a positive and significant association of sTM with ApN. These data support the hypothesis that sTM is one of the determinant of ApN and thus suggest the presence of an sTM-associated regulatory mechanism for ApN secretion in hypothyroid patients.

Increased levels of serum osteoprotegerin in hypothyroid patients and its normalization with restoration of normal thyroid function.

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and an increase in serum osteoprotegerin (OPG) has recently been reported to be associated with the severity of coronary heart disease and cardiovascular mortality. The present study was designed to examine whether hypothyroidism causes an increase in serum OPG, and to determine whether levothyroxine (L-T4) replacement therapy might suppress serum OPG levels in hypothyroid patients. Fifty-three hypothyroid patients with chronic thyroiditis and age- and sex-matched normal control subjects were examined for the levels of serum OPG and plasma von Willebrand factor (vWF), a vascular injury marker. Thirty-seven of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T4 replacement therapy. Baseline OPG was significantly higher in hypothyroid patients than in normal controls (4.51 +/- 0.50 vs 3.72 +/- 0.23 pmol/l (mean +/- S.E.); P = 0.0182). In multivariate analysis, baseline OPG was significantly associated with baseline levels of TSH (r = 0.280, P = 0.0162) and vWF (r = 0.626, P < 0.0001). During one year of L-T4 replacement therapy, hypothyroid patients showed a significant decrease in OPG levels from 4.35 +/- 0.51 to 3.48 +/- 0.26 pmol/l (P = 0.0166), a level comparable to normal controls. The change in serum OPG levels during L-T4 replacement therapy was significantly and independently associated in a negative fashion with baseline vWF (r = -0.503, P = 0.0014). This study suggested that the severity of hypothyroidism and vascular injury might have important independent roles in increasing the serum OPG level in hypothyroid patients. Furthermore, it was demonstrated that a sustained euthyroid state might have the potential to decrease the serum OPG level in hypothyroid patients and that the degree of vascular injury in the hypothyroid state is independently associated with a decrease in serum OPG during a 1-year normalization of thyroid function.