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Impaired Endothelium-Dependent Vasodilatation in Subclinical Hypothyroidism: Beneficial Effect of Levothyroxine Therapy
Abstract
Subclinical hypothyroidism (sHT) is associated with enhanced cardiovascular risk. To test the hypothesis that patients with sHT are characterized by endothelial dysfunction and impaired nitric oxide (NO) availability, in 14 patients [serum cholesterol, 218 +/- 41 mg/dl (5.6 +/- 0.9 mM)] and 28 euthyroid subjects, subdivided into groups A and B [serum cholesterol, 170 +/- 19 mg/dl (4.4 +/- 0.5 mM) and 217 +/- 21 mg/dl (5.6 +/- 0.5 mM), respectively], we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine, an endothelium-dependent vasodilator, at baseline and during infusion of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor. Response to sodium nitroprusside and minimal forearm vascular resistances were also evaluated. In sHT patients, vasodilation to acetylcholine was reduced, compared with group B (+358 +/- 29% vs. +503 +/- 19%, P = 0.0003) and group A (663 +/- 65%, P = 0.02 vs. group B and P = 0.0002 vs. sHT). L-NMMA blunted the vasodilation to acetylcholine in groups A and B (49.1 +/- 6.3% and 42.7 +/- 5.5% maximal forearm blood flow reduction, respectively, P < 0.0001 vs. acetylcholine), whereas it was ineffective in sHT patients (12.8 +/- 2.5%). Response to sodium nitroprusside and minimal vascular resistances were similar. In sHT (n = 9) patients, 6 months of euthyroidism by levothyroxine replacement increased acetylcholine-vasodilation and restored L-NMMA inhibition. Patients with sHT are characterized by endothelial dysfunction resulting from a reduction in NO availability, an alteration partially independent of dyslipidemia and reversed by levothyroxine supplementation.
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“Both hyperlipidemia and thyroid antibodies are thought to reduce expression of endothelial nitric oxide synthase, thereby impairing vasodilation (15).”
From Thyroid Hormones and Cardiovascular Function and Diseases (2018) · cites this paper as [15]
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“It has also been described that endothelial function, which has a pivotal role in the maintenance of vascular integrity, is impaired in SCH resulting from reduced reserves of nitric oxide (NO), the most important vasodilator substance that induces relaxation of vascular smooth muscle (93).”
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Effects of 18 months of l‐T4 replacement in women with subclinical hypothyroidism
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“Some studies have suggested that the vasodilatory effect of TH may be mediated through activation of eNOS increasing nitric oxide levels and reducing total peripheral resistance [18,19].”
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Mechanism of subclinical hypothyroidism accelerating endothelial dysfunction (Review)
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Effects of TSH on the function of human umbilical vein endothelial cells
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Association of Lipids with Oxidative Stress Biomarkers in Subclinical Hypothyroidism
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“TSH was also associated with deleterious changes in serum lipids, particularly HDLC, LDL-C, and the ratio of LDL-C to HDL-C as suggested by recent investigations [36–38].”
ResultThyroid Hormone and Vascular Remodeling
Ichiki, T. (2015) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.32755 · Cited by 62
Weltman, N. Y., Ojamaa, K., Schlenker, E. H., Chen, Y., Zucchi, R., Saba, A., Colligiani, D., Rajagopalan, V., Pol, C. J., & Gerdes, A. M. (2014) · Molecular Medicine · doi:10.2119/molmed.2013.00040 · Cited by 60
Tatar, E., Kırçelli, F., Aşçı, G., Carrero, J. J., Güngör, Ö., Demirci, M. S., Özbek, S. S., Ceylan, N., Özkahya, M., Töz, H., et al. (2011) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.02540311 · Cited by 60
Hypothyroidism Is Associated With Coronary Endothelial Dysfunction in Women
Sara, J. D. S., Zhang, M., Gharib, H., Lerman, L. O., & Lerman, A. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.115.002225 · Cited by 60
“Other studies have shown an improvement in noninvasively measured flowmediated dilatation in hypothyroid patients treated with thyroxine.(33,39,40) In 2 of these studies, the sample size was very small (14 and 8 patients, respectively) while in the third, the observed difference in flow-mediated dilatation of 1.”
ResultTherapeutic Approach in the Improvement of Endothelial Dysfunction: The Current State of the Art
Radenković, M., Stojanović, M., Potpara, T., & Prostran, M. S. (2013) · BioMed Research International · doi:10.1155/2013/252158 · Cited by 59
“thyroid hormone replacement therapy improves endothelial function in patients with hypothyroidism [53], the potential”
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Low Triiodothyronine Alters Flow-Mediated Vasodilatation in Advanced Nondiabetic Kidney Disease
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“and coherent observations in patients with subclinical [”
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Subclinical hypothyroidism and cardiovascular risk factors
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Hypothyroidism in coronary heart disease and its relation to selected risk factors
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Acute Effects of Triiodothyronine on Endothelial Function in Human Subjects
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Abnormal endothelial function in female patients with hypothyroidism and borderline thyroid function
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“Meanwhile, a recent paper found that SCH can cause endothelial dysfunction because of a decrease in NO availability, which is partly independent of dyslipidaemia, and L-T4 supplementation can reverse endothelial dysfunction.(31) Thus, we found that SCH not only results in endothelial dysfunction but is also an indepen…”
Xiaohui, Q., Ji, Y., Zhang, C., Guo, X., Zhang, Y., Jia, S., Ma, W., Fan, Y., & Wang, C. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000486769 · Cited by 52
Elevated Arterial Stiffness and Diastolic Dysfunction in Subclinical Hypothyroidism
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Thyroid Disease in the Oldest Old
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Hypothyroidism and Risk of Cardiovascular Disease
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Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency
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Subclinical thyroid disorders: significance and clinical impact
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Regulation of nitric oxide production in hypothyroidism
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“Decreased bioavailability of NO is one of several probable causes of ED [72], and it features in hyperthyroid [73], and both subclinical [74] and clinical hypothyroid Table 1”
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“partially restore endothelial functions [11].”
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“[5] Taddei S, Caraccio N, Virdis A, Dardane A, Versari D, Ghiadoni L, et al.”
Background
Metadata
- Authors
- Taddei, S., Caraccio, N., Virdis, A., Dardano, A., Versari, D., Ghiadoni, L., Salvetti, A., Ferrannini, E., & Monzani, F.
- Affiliations
- University of Pisa (IT)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-08-01
- Volume
- 88
- Issue
- 8
- Pages
- 3731-3737
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2060930755
- Cited by
- 431
- References
- 43
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 14 · 2023: 15 · 2022: 24 · 2021: 14 · 2020: 27 · 2019: 19 · 2018: 19 · 2017: 12 · 2016: 24 · 2015: 17 · 2014: 34 · 2013: 26 · 2012: 26
- FWCI
- 9.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- subclinical hypothyroidism, endothelial dysfunction, endothelium-dependent vasodilation, nitric oxide bioavailability, levothyroxine, acetylcholine, L-NMMA, forearm blood flow, dyslipidemia, cardiovascular risk, sodium nitroprusside
- MeSH terms
- Acetylcholine, Adult, Endothelium, Vascular, Enzyme Inhibitors, Female, Humans, Hypothyroidism, Iodide Peroxidase, Lipids, Lipoproteins, LDL, Male, Nitric Oxide, Nitroprusside, Regional Blood Flow, Thyroglobulin, Thyroid Hormones, Thyroiditis, Autoimmune, Thyroxine, Vascular Resistance, Vasodilation, Vasodilator Agents, Nitric Oxide Synthase, omega-N-Methylarginine, Nitric Oxide Donors, Nitric Oxide Synthase Type III
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