Hypertension and hypothyroidism:
results from an ambulatory blood pressure monitoring study
Hypertension and hypothyroidism:
results from an ambulatory blood pressure monitoring study
Objective: To examine differences between hypothyroid patients and healthy volunteers in 24-h ambulatory blood pressure parameters.
Methods: The study population consisted of 100 individuals who were recently diagnosed for hypothyroidism. These patients had never been treated before with antihypertensive treatment or received drugs for hypothyroidism. All participants underwent 24-h ambulatory blood pressure monitoring. The control group consisted of 100 healthy volunteers matched one to one for gender and age with the hypothyroid participants.
Results: Clinic systolic and diastolic blood pressures were significantly higher in patients with hypothyroidism compared with volunteers. The mean 24-h systolic blood pressure and 24-h pulse pressure were significantly higher in patients with hypothyroidism compared with volunteers. The 24-h systolic blood pressure variability was also significantly higher in patients with hypothyroidism. Fasting serum cholesterol tended to be higher in patients with hypothyroidism compared with volunteers but the difference was not statistically significant, while fasting serum triglycerides were significantly higher. Body mass index was also significantly higher in patients with hypothyroidism.
Conclusions: These findings indicate that hypothyroidism may be an important predictor of higher mean 24-h systolic blood pressure, 24-h pulse pressure and 24-h systolic blood pressure variability, parameters of ambulatory blood pressure monitoring that have been previously associated with higher cardiovascular target organ damage.
Hypothyroidism is considered a disease that may alter blood pressure. Thyroid hormone is known to increase cardiac output and decrease systemic vascular resistance [1]. Some studies have indicated a high prevalence of systolic and diastolic hypertension in hypothyroidism [2–8], while others reported no association of diastolic hypertension with hypothyroidism in geriatric patients in a primary care setting [9].
We therefore re-examined the relationship between hypothyroidism and blood pressure in patients who had recently been diagnosed with hypothyroidism. Previous studies had not used 24-h ambulatory blood pressure monitoring, while we used 24-h measurements in order to evaluate blood pressure parameters. The 24-h blood pressure parameters are reproducible [10] and correlate better with target organ damage than those of clinic blood pressure [11,12]. Evidence is also available that the same ambulatory values are more predictive of cardiovascular risk than office values [13–17] and that treatment-induced regression of left ventricular hypertrophy is more closely related to changes in average ambulatory blood pressure than office blood pressures [18]. Combined office and ambulatory blood pressure measurements have also been used to identify white-coat hypertension [19–21] and masked hypertension [21]. Using ambulatory blood pressure monitoring also enables one to study blood pressure and heart rate variabilities and, finally, the circadian 24-h blood pressure profile of the patients [22–26].
In the present study we explored possible correlations between hypothyroidism, thyroid-stimulating hormone (TSH) and parameters of 24-h ambulatory blood pressure monitoring. To our knowledge, there are no previous studies of the impact of hypothyroidism on ambulatory blood pressure monitoring parameters and the 24-h circadian rhythm.
The hypothyroid patients were referred to the Hypertension Center of the Department of Clinical Therapeutics from the outpatient Hypothyroidism Clinic of Alexandra Hospital from 2000 to 2004. To be considered for further analysis, criteria included no past or concurrent antihypertensive or hypothyroidism medication (individuals never treated before), no concurrent medication with the potential to raise blood pressure (e.g. prednisone), and no clinical signs or laboratory evidence of other secondary causes of hypertension. Finally, the study population consisted of 100 consecutive outpatient individuals with hypothyroidism (TSH >= 5 µU/ml) (82% women). The etiology of hypothyroidism was autoimmune (atrophic), which includes Hashimoto's thyroiditis and silent thyroiditis in 80% of the cases. Other causes of hypothyroidism were postablative ([131I]thyroidectomy, head and neck irradiation), goitrus, Riedel's thyroiditis and hypothyroid nontransient stage of subacute thyroiditis. The control group consisted of 100 healthy volunteers matched one to one for gender and age with the hypothyroid patients. The matching process was performed by attributing to each hypothyroid patient one corresponding healthy volunteer to obtain the same gender and closest value of age (± 3 years).
All patients gave their informed consent to participate in the study. The institutional review board approved the human research protocol. Body weight was measured with the participants in light clothing without shoes. The body mass index (BMI) was calculated as weight (kg)/height (m2). According to National Institutes of Health criteria, patients were underweight if their BMI was lower than 18.49 kg/m2, were normal weight if their BMI was between 18.5 and 24.9 kg/m2, were overweight if their BMI was between 25 and 29.9 kg/m2, and were obese if their BMI was higher than 30 kg/m2 [27]. Fasting serum glucose, fasting serum total cholesterol and triglycerides were measured in all individuals. The glomerular filtration rate was calculated according to a previously validated method [28].
Clinic blood pressures were measured three times in each participant using a mercury sphygmomanometer (appropriate-size cuff applied around the nondominant arm and systolic and diastolic values identified from the first and fifth phase of Korotkoff sounds). During the measurements the participant remained seated with the arm comfortably placed at heart level.
All participants underwent 24-h ambulatory blood pressure monitoring on a usual working day. They were instructed to act and work normally. The Spacelabs 90217 ambulatory blood pressure monitor (Spacelabs Inc., Redmond, Washington, USA) was used. The appropriate-size cuff was placed around the nondominant arm and three blood pressure determinations were made, along with sphygmomanometric measurements to verify that the average of the two sets of values did not differ by more than 5 mmHg. Readings were obtained automatically at 15-min intervals throughout the 24-h study period. All individuals included in the study had at least three valid readings per hour. The resulting 72–96 pairs of systolic and diastolic blood pressure readings per recording with the corresponding time of measurements were used to calculate 24-h ambulatory blood pressure parameters including the mean 24-h, daytime and night-time systolic and diastolic blood pressures, and the mean 24-h, daytime and night-time heart rates. All participants were instructed to rest or sleep between 2200 and 0600 h (night-time) and to maintain their usual activities between 0600 and 2200 h (daytime) [11,18]. Shift workers were excluded from our population. The patients that did not rest or sleep at night (n = 2) were also excluded from the analysis. Dippers were defined as individuals whose night-time blood pressures dropped more than 10% compared with their daytime blood pressures [29]. Participants with both office and ambulatory normotension or hypertension were characterized as confirmed normotensive individuals or hypertensive individuals, respectively. White-coat hypertension was defined as office hypertension with ambulatory normotension [19], and masked hypertension defined as office normotension and ambulatory hypertension [21].
Serum TSH was measured in all study participants within 1 week from the ambulatory blood pressure monitoring study. Serum TSH was assayed by the IRMA, Amerlex hs TSH-coated Tube assay (Johnson and Johnson Clinical Diagnostics intra-assay and inter-assay coefficients of variation, 3.2 and 5.7%, respectively; Ortho-Clinical Diagnostics, Amersham, UK). Assays were performed centrally at the Alexandra University Hospital core laboratory. The reference range for hypothyroid patients for serum TSH was at least 5.0 µU/ml.
The SPSS (SPSS Inc., Chicago, Illinois, USA) statistical package was used to analyze the data. Standard descriptive statistics, a two-tailed Student's t-test and a chi-squared test were used where appropriate to compare characteristics of the groups. Results are expressed as percentages or as means ± standard deviations. Linear regression analysis was used to study the relationship of the mean 24-h systolic blood pressure with TSH. Multiple comparisons between subgroups were performed using one-way analysis of variance, post-hoc multiple comparisons, Tukey's analysis and the nonparametric Kruskal–Wallis test. Multivariate linear regression analysis (stepwise criteria: probability of F to enter, <= 0.050; probability of F to remove, >= 0.100). The collinearity statistics tolerance (tolerance = 1-Ri2, where Ri is the square multiple correlation of that variable with the other independent variables) was used for collinearity diagnostics. The default value for tolerance was 0.0001. All variables must pass this criterion in order to be included in an equation, regardless of the selection method used (SPSS Base Applications Guide; SPSS Inc.) The receiver operating characteristic plot (curve analysis) was also used. P values less than 0.05 were considered statistically significant.
Demographic data of the two groups are presented in Table 1. Clinic systolic and diastolic blood pressures were significantly higher in patients with hypothyroidism compared with volunteers. Fasting serum cholesterol tended to be higher in patients with hypothyroidism compared with volunteers but the difference was not statistically significant, while fasting serum triglycerides were significantly higher in the patients with hypothyroidism. The BMI was also significantly higher in patients with hypothyroidism. According to World Health Organization criteria for obesity, 50% of the control group had normal weight, 39.7% were overweight and 10.3% were obese, while in the hypothyroid group 31.7% had normal weight, 42.7% were overweight and 25.6% were obese, differences that were statistically significant (P < 0.05, Pearson chi-squared test).
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Table 1 Demographic data of the study population and parameters of 24-h ambulatory blood pressure monitoring |
The mean 24-h systolic blood pressure and 24-h pulse pressure were significantly higher in patients with hypothyroidism compared with volunteers. The 24-h systolic blood pressure variability and daytime and night-time systolic blood pressure variabilities were also significantly higher in patients with hypothyroidism. The 24-h circadian systolic blood pressure profiles in control individuals and hypothyroid participants are shown in Fig. 1. The mean 24-h diastolic blood pressure, daytime and night-time diastolic blood pressures, and the 24-h and daytime diastolic blood pressure variabilities did not differ significantly. The mean 24-h heart rates of the hypothyroid patients were lower than normal control individuals’ heart rates but the differences were not statistically significant. The 24-h, daytime and night-time heart rate variability was significantly lower in hypothyroid participants than in control individuals (Table 1).
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Fig. 1. . |
In the subgroup of patients with hypothyroidism, multivariate regression analysis revealed that TSH was negatively related to the mean 24-h systolic blood pressure (P < 0.001 and F = 7.2). Parameters that were included in the model were the mean 24-h systolic blood pressure as the dependent variable, and age, hematocrit, fasting serum glucose, fasting total cholesterol, triglycerides, BMI and creatinine as independent variables (Fig. 2). When the mean 24-h diastolic blood pressure was tested in the model as the dependent variable with the same independent variables, no relationship was found between TSH and mean 24-h diastolic blood pressure values in the hypothyroid subgroup.
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Fig. 2. . |
Confirmed normotensive participants were 93.9% of our control group and 48.5% of the patients with hypothyroidism. Isolated office (white-coat) hypertension was increased in patients with hypothyroidism. The incidence of white coat hypertension was 23.2% in hypothyroid patients and 4.2% in control individuals. On the other hand, masked hypertension was present in 5.1% of our control participants and 8.1% of the hypothyroid patients. Of the patients with hypothyroidism, 20.2% were confirmed hypertensive with both clinic and ambulatory blood pressure values. The mean 24-h systolic blood pressure was 112.3 ± 8.8 mmHg in confirmed normotensive hypothyroid individuals, 120.0 ± 6.9 mmHg in white-coat hypothyroid participants, 138.0 ± 9.7 mmHg in masked hypertensive hypothyroid participants and 139.2 ± 11.1 mmHg in confirmed hypertensive hypothyroid individuals. The same statistically significant results for mean 24-h systolic blood pressure, 24-h pulse pressure and 24-h systolic blood pressure variability were found when we compared hypothyroid participants ‘without white-coat hypertension’ with the control individuals. Forty-five percent of the control participants and 43% of the hypothyroid participants were dippers, a difference that was not statistically significant. Hypothyroid patients did not exhibit statistically significant differences in dipping/nondipping status compared with the healthy volunteers.
The receiver operating characteristic plot (curve analysis) for the use of the mean 24-h systolic blood pressure and the mean 24-h diastolic blood pressure to predict the presence of significant hypothyroidism has shown that only the mean 24-h systolic blood pressure has at least one tie between the positive actual state group and the negative actual state group (area under the curve = 0.592, P < 0.05), which demonstrates both high (> 70%) sensitivity and specificity, suggesting that the mean 24-h systolic blood pressure and not the mean 24-h diastolic blood pressure values predict the presence of significant hypothyroidism in our population.
Finally, we divided the hypothyroid group of patients into two subgroups: individuals with mild hypothyroidism (TSH <= 25 µU/ml; 75% percentile of our hypothyroid patients' TSH, n = 78) and individuals with severe hypothyroidism (TSH > 25 µU/ml, n = 22). The mean 24-h systolic blood pressure was 122.5 ± 15.2 mmHg in mild hypothyroid patients versus 116.3 ± 9.6 mmHg in control individuals (P < 0.01) and 108.8 ± 11 mmHg in severe hypothyroid patients, a value that was lower than, but was not statistically significant, the control group mean 24-h blood pressure. The glomerular filtration rate was 86.2 ±18 ml/min per 1.73 m2 in the control group, 82.5 ± 19.5 ml/min per 1.73 m2 in patients with mild hypothyroidism and significantly lower (69.2 ± 21.5 ml/min per 1.73 m2) in patients with severe hypothyroidism (P < 0.05).
In the present study we investigated the possible association between hypothyroidism, TSH and parameters of 24-h ambulatory blood pressure monitoring. We found that patients with hypothyroidism had significantly higher mean 24-h systolic blood pressure values, 24-h pulse pressure values and 24-h systolic blood pressure variability compared with healthy volunteers. Fasting serum cholesterol tended to be higher and fasting serum triglycerides were significantly higher. The BMI was also significantly higher in patients with hypothyroidism.
The majority of the studies in the literature have pointed out a high prevalence of hypertension in hypothyroidism, in particular diastolic values. In a study of 169 women with overt hypothyroidism [2], the prevalence of hypertension was significantly higher than in a euthyroid control group (14.8 versus 5.5%). Euthyroid normotensive patients had an increase in diastolic blood pressure after thyroidectomy-induced hypothyroidism. The elevation in blood pressure levels was reversible with thyroid hormone replacement therapy [30]. In a survey of consecutive hypertensive outpatients [31], 3.6% were found to be hypothyroid, and in this subset the diastolic blood pressure fell significantly after adequate thyroid replacement therapy. Regarding subclinical hypothyroidism and hypertension, two case–control studies [32,33] reported that systolic and diastolic blood pressure values were higher in 57 and 44 women with subclinical hypothyroidism than in euthyroid control individuals. Epidemiological studies have also linked hypothyroidism and atherosclerosis [34]. Coronary artery atherosclerosis is twice as common in patients with hypothyroidism compared with sex-matched and age-matched control individuals, and adequate thyroid hormone replacement therapy may protect against progression [35]. The increased cardiovascular morbidity in hypothyroid patients has been attributed to the cardiovascular risk factors: elevated low-density lipoprotein-cholesterol levels [36,37] and diastolic hypertension. The findings of our study are in accordance with these studies. The hypothyroid participants of our study exhibited increased blood pressure levels and a possible elevated cardiovascular risk.
Potential mechanisms for the hypertension in hypothyroidism include increases in peripheral vascular resistance [38] and arterial stiffness [39,40]. Vasoconstriction may reflect the absence of demonstrated vasodilatory T3 effects on vascular smooth muscle [41] or may be the result of a higher circulating noradrenaline level and a decrease in the number of vascular [beta]-adrenergic receptors [2]. More than one-half of hypothyroid hypertensive patients display low plasma renin activity [42]. Low angiotensin levels have also been reported in hypothyroidism [43], and vasopressin plasma levels are mildly increased and improve after replacement therapy [44]. On the other hand, thyroid hormone deficiency may be associated with a reduction of the glomerular filtration rate and renal blood flow [45,46]. Finally, another possible mechanism by which hypothyroid individuals exhibit an increase in blood pressure may be associated with obesity. We found that hypothyroid individuals were significantly more overweight and obese than normal healthy volunteers. Previous studies had reported that obesity is associated with increased 24-h ambulatory blood pressure values in children and adults [24,26,47]. The statistically significant differences diminished after correcting mean 24-h systolic blood pressure values, 24-h pulse pressure values and 24-h systolic blood pressure variability for BMI, suggesting that obesity, which is a major clinical characteristic of the hypothyroid syndrome, plays an important role in the observed higher blood pressure values of the hypothyroid individuals.
The novel findings of our study were that patients with hypothyroidism had significantly higher mean 24-h systolic blood pressure values, 24-h pulse pressure values and 24-h systolic blood pressure variability compared with healthy volunteers. The mean 24-h diastolic blood pressure levels, however, did not differ from healthy volunteer levels. Also, only the mean 24-h systolic blood pressure levels could predict the presence of the hypothyroidism. These findings emphasize that patients with hypothyroidism are at increased cardiovascular risk than healthy volunteers because 24-h systolic blood pressure values, 24-h pulse pressure values [48,49] and 24-h systolic blood pressure variability [50,51] have been previously independently associated with increased target organ damage and cardiovascular morbidity and mortality.
Another interesting finding of our study is that the 24-h heart rate levels of the patients with hypothyroidism were not significantly lower than the values of the healthy individuals. On the other hand, the 24-h, daytime and night-time heart rate variabilities were significantly lower, a finding that suggests small variation of the heart rate during 24-h, daytime and night-time. Only the patients with severe hypothyroidism (highest quartile of TSH) had a significantly lower mean 24-h heart rate than control individuals.
Finally, we found that there was a negative relationship of the mean 24-h systolic blood pressure with TSH. This negative relationship means that patients with severe hypothyroidism exhibited lower mean 24-h blood pressures than individuals with mild hypothyroidism. Furthermore, when we subdivided the hypothyroid group into patients with mild hypothyroidism and severe hypothyroidism, the previously described statistically significant difference in mean 24-h systolic blood pressure was found only in the mild hypothyroidism group. It is possible that other mechanisms are involved in severe hypothyroidism that reverses the effects of low thyroid hormone levels and obesity in the blood pressure homeostasis. Possible explanations for this finding could be a decreased sympathetic nervous system activity in the severe hypothyroid patients associated with the observed significantly lower heart rates, a significant decrease in the glomerular filtration rate from the remove of the fluids from the intra-arterial space to the subcutaneous tissues (myxedema) and a reduced sodium reabsorption. These decreasing blood pressure mechanisms in the severe hypothyroid patients should overlap, increasing mechanisms such as vasoconstriction from reduced T3 and obesity.
A limitation of this study is that the design was observational and could not study extensively the possible mechanisms. Further studies need to confirm this finding in patients with severe hypothyroidism, elucidating the mechanisms of the blood pressure homeostasis in mild and severe hypothyroidism before and after hormone replacement treatment. Other possible limitations of the study may include bias as a result of participant selection and limits in generalizing the findings to other populations. We found that patients with hypothyroidism had significantly higher mean 24-h systolic blood pressure, 24-h pulse pressure and 24-h systolic blood pressure variability compared with healthy volunteers. This finding was more pronounced in patients with mild hypothyroidism.
Kotsis, Vasiliosa,b;
Alevizaki, Mariaa; Stabouli, Stellac;
Pitiriga, Vassilikia; Rizos, Zoed;
Sion, Michaelb; Zakopoulos, Nikosa
Journal of Hypertension
Marzo 2007
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1 Klein I. Thyroid hormone and the cardiovascular system. Am J Med 1990; 88:631–637. Bibliographic Links [Context Link]
2 Saito I, Saruta T. Hypertension in thyroid disorders. Endocrinol Metab Clin North Am 1994; 23:379–386. Bibliographic Links [Context Link]
3 Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the heart. Circulation 1993; 87:1435–1441. Ovid Full Text Bibliographic Links [Context Link]
4 Endo T, Komiya I, Tsukui T, Yamada T, Izumiyama T, Nagata H, et al. Re-evaluation of a possible high incidence of hypertension in hypothyroid patients. Am Heart J 1979; 98:684–688. Bibliographic Links [Context Link]
5 Saito I, Ito K, Saruta T. Hypothyroidism as a cause of hypertension. Hypertension 1983; 5:112–115. Bibliographic Links [Context Link]
6 Streeten DH, Anderson GH Jr, Howland T, Chiang R, Smulyan H. Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension. Hypertension 1988; 11:78–83. Bibliographic Links [Context Link]
7 Danzi S, Klein I. Thyroid hormone and blood pressure regulation. Curr Hypertens Rep 2003; 5:513–520. Bibliographic Links [Context Link]
8 Fletcher AK, Weetman AP. Hypertension and hypothyroidism. J Hum Hypertens 1998; 12:79–82. Bibliographic Links [Context Link]
9 Bergus GR, Mold JW, Barton ED, Randall GS. The lack of association between hypertension and hypothyroidism in a primary care setting. J Hum Hypertens 1999; 13:231–235. Bibliographic Links [Context Link]
10 Zakopoulos NA, Nanas SN, Lekakis JP, Vemmos KN, Kotsis VT, Pitiriga VC, et al. Reproducibility of ambulatory blood pressure measurements in essential hypertension. Blood Press Monit 2001; 6:41–45. Bibliographic Links [Context Link]
11 Mancia G, Parati G. Ambulatory blood pressure monitoring and organ damage. Hypertension 2000; 36:394–399. [Context Link]
12 Imai Y, Ohkubo T, Sakuma M, Tsuji I, Satoh H, Nagai K, et al. Predictive power of screening blood pressure, ambulatory blood pressure and blood pressure measured at home for overall and cardiovascular mortality: a prospective observation in a cohort from Ohasama, northern Japan. Blood Press Monit 1996; 1:251–254. Bibliographic Links [Context Link]
13 Stepson JA, Thijs L, Fagard R, O'Brien ET, Clement D, De Leeuw PW, et al. Predicting cardio-vascular risk using conventional vs. ambulatory blood pressure in older patients with systolic hypertension. JAMA 1999; 282:539–546. [Context Link]
14 Khattar RS, Swales JD, Banfield A, Dore C, Senior R, Lahiri A. Prediction of coronary and cerebrovascular morbidity and mortality by direct continuous arterial blood pressure monitoring in essential hypertension. Circulation 1999; 100:1071–1076. Ovid Full Text Bibliographic Links [Context Link]
15 Robinson TG, Dawson SL, Ahmed U, Manktelow B, Fotherby MD, Potter JF. Twenty-four hour systolic blood pressure predicts long-term mortality following acute stroke. J Hypertens 2001; 19:2127–2134. Ovid Full Text Bibliographic Links [Context Link]
16 Mancia G, Sega R, Bravi C, De Vito G, Valagussa F, Cesana G, Zanchetti A. Ambulatory blood pressure normality: results from the PAMELA study. J Hypertens 1995; 13:1377–1390. Bibliographic Links [Context Link]
17 Guidelines Sub-Committee. 1999 World Health Organization/International Society of Hypertension Guidelines for the management of hypertension. J Hypertens 1999; 17:151–183. Ovid Full Text Bibliographic Links [Context Link]
18 Mancia G, Zanchetti A, Agabiti-Rosei E, Benemio G, De Cesaris R, Fogari R, et al. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment induced regression of left ventricular hypertrophy. Circulation 1997; 95:1464–1470. [Context Link]
19 Pickering TG. White-coat hypertension. Curr Opin Nephrol Hypertens 1996; 5:192–198. Bibliographic Links [Context Link]
20 Zakopoulos NA, Kotsis VT, Pitiriga VC, Toumanidis ST, Lekakis JP, Nanas SN, et al. White coat effect in normotension and hypertension. Blood Press Monit 2002; 7:1–6. [Context Link]
21 Stabouli S, Kotsis V, Toumanidis S, Papamichael C, Constantopoulos A, Zakopoulos N. White coat and masked hypertension in children: association with target organ damage. Pediatr Nephrol 2005; 20:1151–1155. Bibliographic Links [Context Link]
22 Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target organ damage. J Hypertens 1987; 5:93–98. Bibliographic Links [Context Link]
23 Parati G. Blood pressure variability: its measurement and significance in hypertension. J Hypertens 2005; 23:S19–S25. Ovid Full Text Bibliographic Links [Context Link]
24 Kotsis V, Stabouli S, Bouldin M, Low A, Toumanidis S, Zakopoulos N. Impact of obesity on 24-hour ambulatory blood pressure and hypertension. Hypertension 2005; 45:602–607. Bibliographic Links [Context Link]
25 Kotsis VT, Pitiriga VCh, Stabouli SV, Papamichael CM, Toumanidis ST, Rokas SG, Zakopoulos NA. Carotid artery intima media thickness could predict the presence of coronary artery lesions. Am J Hypertens 2005; 18:601–606. Bibliographic Links [Context Link]
26 Stabouli S, Kotsis V, Papamichael C, Constantopoulos A, Zakopoulos N. Adolescent obesity is associated with high ambulatory blood pressure and increased carotid intimal medial thickness. J Pediatr 2005; 147:651–656. Bibliographic Links [Context Link]
27 National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. NIH Publication no. 98-4083. Bethesda, MD: National Heart, Lung, and Blood Institute in cooperation with The National Institute of Diabetes and Digestive and Kidney Diseases; 1998. [Context Link]
28 Levey A, Bosch J, Lewis J, Greene T, Rogers N, Roth D, for the Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130:461–470. Bibliographic Links [Context Link]
29 Cuspidi C, Meani S, Salerno M, Valerio C, Fusi V, Severgnini B, et al. Cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure. J Hypertens 2004; 22:273–280. Ovid Full Text Bibliographic Links [Context Link]
30 Fommei E, Iervasi G. The role of thyroid hormone in blood pressure homeostasis: evidence from short-term hypothyroidism in humans. J Clin Endocrinol Metab 2002; 87:1996–2000. Bibliographic Links [Context Link]
31 Bing RF, Briggs RSJ, Burden AC, Russell GI, Swales JD, Thurston H. Reversible hypertension and hypothyroidism. Clin Endocrinol 1980; 13:339–342. Bibliographic Links [Context Link]
32 Luboshitzky R, Aviv A, Herer P, Lavie L. Risk factors for cardiovascular disease in women with subclinical hypothyroidism. Thyroid 2002; 12:421–425. Bibliographic Links [Context Link]
33 Luboshitzky R, Herer P. Cardiovascular risk factors in middle-aged women with subclinical hypothyroidism. Neuro Endocrinol Lett 2004; 25:262–266. [Context Link]
34 Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab 2003:2438–2444. [Context Link]
35 Vanhaelst L, Neve P, Chailly P, Bastenie PA. Coronary artery disease in hypothyroidism. Observations in clinical myxoedema. Lancet 1967; II:800–802. Bibliographic Links [Context Link]
36 Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, Koutras DA. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol 1998; 138:141–145. Bibliographic Links [Context Link]
37 Pallas D, Koutras DA, Adamopoulos P, Marafelia P, Souvatzoglou A, Piperingos G, Moulopoulos SD. Increased mean serum thyrotropin in apparently euthyroid hypercholesterolemic patients: does it mean occult hypothyroidism? J Endocrinol Invest 1991; 14:743–746. Bibliographic Links [Context Link]
38 Graettinger JS, Muenster JJ, Checchia CS, Grisson RL, Campbell JA. A correlation of clinical and hemodymanic studies in patients with hypothyroidism. J Clin Invest 1958; 9:502–510. Bibliographic Links [Context Link]
39 Papaioannou GI, Lagasse M, Mather JF, Thompson PD. Treating hypothyroidism improves endothelial function. Metabolism 2004; 53:278–279. Bibliographic Links [Context Link]
40 Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, et al. Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid 1997; 7:411–414. Bibliographic Links [Context Link]
41 Ojamaa K, Klember JD, Klein I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid 1996; 6:505–512. Bibliographic Links [Context Link]
42 Satura T, Kajima W, Hayashi M, Kato E, Matsuki S. Renin and aldosterone in hypothyroidism: relation to excretion of sodium and potassium. Clin Endocrinol 1980; 12:483–489. Bibliographic Links [Context Link]
43 Dzau VJ, Hermann HC. Hormonal control of angiotensinogen production. Life Sci 1982; 30:648–652. [Context Link]
44 Skowsky RW, Kikuchi TA. The role of vassopresin in the impaired water excretion of myxedema. Am J Med 1978; 64:613–621. Bibliographic Links [Context Link]
45 Allon M, Harrow A, Pasque CB, Rodriguez M. Renal sodium and water handling in hypothyroid patient: the role of renal insufficiency. J Am Soc Nephrol 1990; 1:205–210. Bibliographic Links [Context Link]
46 Montenegro J, Gonzalez O, Saracho R, Aguirre R, Gonzalez O, Martinez I. Changes in renal function in primary hypothyroidism. Am J Kidney Dis 1996; 27:195–198. Bibliographic Links [Context Link]
47 Hall JE, Brands W, Dixon WN, Smith MJ. Obesity-induced hypertension. Renal function and systemic hemodynamics. Hypertension 1993; 22:292–299. Bibliographic Links [Context Link]
48 Benetos A. Pulse pressure and arterial stiffness in type 1 diabetic patients. J Hypertens 2003; 21:2005–2007. Ovid Full Text Bibliographic Links [Context Link]
49 Benetos A. Pulse pressure and cardiovascular risk. J Hypertens Suppl 1999; 17:S21–S24. [Context Link]
50 Parati G, Mancia G, Rienzo MD, Castiglioni P, Taylor JA, Studinger P. Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 2006; 101:690–691. Bibliographic Links [Context Link]
51 Parati G, Valentini M. Prognostic relevance of blood pressure variability. Hypertension 2006; 47:137–138. Bibliographic Links [Context Link]
