Review Articles

Thyroid hormone deficiency and coronary artery disease

 

Saira Shan, B.Sc, MBBS1, Shumaila Aslam, MBBS2,
Nazish Saleem, BS (Hons), M.Phil, BS. Ed3,
Nayab Batool Rizvi, M.Sc, PhD4, Shan Elahi, M.Sc, PhD5

1House Officer; 2Woman Medical Officer
Government Lady Aitchison Hospital, Lahore, (Pakistan)
3Lecturer; 4Assistant Professor
Institute of Chemistry, New Campus, University of the Punjab, Lahore, (Pakistan)
5Principal Scientist, Centre for Nuclear Medicine (CENUM), Mayo Hospital, Lahore, (Pakistan)

Correspondence: Dr. Shan Elahi, Centre for Nuclear Medicine (CENUM), PO Box No.53, Mayo Hospital, Lahore, (Pakistan); Phone: 092-42-9214436-38 E-mail: shan.elahi@gmail.com

SUMMARY

The heart is sensitive to thyroid hormone action and thyroid dysfunctions. Thyroid hormone deficiency (hypothyroidism) either overt or subclinical has adverse cardiovascular consequences. They results from direct influences of hypothyroidism on heart function as well as due to secondary effects like atherogenic lipid profile, diastolic hypertension and impaired endothelial function leading to atherosclerosis. This review summarizes the basic and clinical studies on the role of hypothyroidism in development of atherosclerosis and traditional risk factors for coronary artery disease.
Key words: Thyroid hormone; Hypothyroidism; Coronary artery disease; Thyroid stimulating hormone; Hyperhomocysteinemia
Citation: Shan S, Aslam S, Saleem N, Rizvi NB, Elahi S. Thyroid hormone deficiency and coronary artery disease. Anaesth Pain & Intensive Care 2017;21(4):489-496
Received: 4 Oct 2017; Reviewed: 5 Nov 2017; Corrected & Accepted: 15 Nov 2017

INTRODUCTION

Thyroid hormones (TH; thyroxine, T4 & tri-iodothyronine T3) and thyroid stimulating hormone (TSH) have a number of profound effects on the cardiovascular system.1 Normal thyroid hormone level is essential for maintaining normal structure and function of heart. This is because of their important role in metabolism through alterations in oxygen consumption and changes in protein, lipid, carbohydrate, and vitamin metabolism.2 Thyroid hormone affects several genes encoding the expression of important structural and regulatory and proteins in the myocardium.3 Moreover, thyroid hormones play important role in maintaining cardiovascular homeostasis.
Hypothyroidism or thyroid hormone deficiency is a graded phenomenon characterized by low TH and high TSH in overt and only TSH elevation in subclinical hypothyroidism. Worldwide most common reason of hypothyroidism is iodine deficiency in areas where iodine intake is low and chronic autoimmune thyroiditis in iodine sufficient countries.4,5 The prevalence of overt hypothyroidism is in the range of 1–2% and that of subclinical hypothyroidism is 4.0-20% of general population. Its incidence is more common in female than male gender and increases with increasing age.5 Thyroxine supplementation is the only treatment of choice in overt hypothyroidism. However, thyroxine supplementation in subclinical hypothyroidism is controversial and is recommended only when TSH level is > 10 IU/L or TSH level above population normal range is accompanied by high titer of thyroid antibodies and/or presence of goiter.4,6
Hypothyroidism produces major derangements of human physiology.5 It causes a hypodynamic cardiovascular state like decreased left ventricular contraction and relaxation and decrease in cardiac output. Hypothyroidism is, either overt or subclinical may cause or accelerate heart diseases.1 It is because receptors for thyroid hormones are present in myocardial and vascular endothelial tissues and are responsive to changes in circulating thyroid hormone concentration.1,2 Although a relationship between overt hypothyroidism and cardiovascular diseases was appreciated about one and half century ago, but role of subclinical hypothyroidism in coronary heart disease was first suggested by Bastenie et al (1971).7 Over the past two decades, accumulating evidence supports the role of hypothyroidism in atherosclerosis development and derangement of traditional risk factors for coronary artery disease (CAD). A plethora of clinical and experimental data had consistently showed an association of hypothyroidism- overt, subclinical and low triiodothyronine syndrome with increased risk of atherosclerosis as well as ischemic heart disease.8-10 Recently expansion of this relationship is being extended to normal healthy population with slightly increased TSH level within normal population range.11-12 Some emerging risk factors for atherosclerosis like thyroid autoimmunity, increased C-reactive protein (CRP) level and hyperhomocysteinemia are also under intensive investigation to seek explanation of the relationship between hypothyroidism and heart disease.13,14 In addition, some recent studies have suggested an anti-atherosclerotic effect of thyroid hormone.15 The results of recent clinical trials elucidating effect of thyroid hormone supplementation to cardiovascular diseases are promising but results of all studies are not uniform17. Moreover, a causal association per se of low TH, high TSH, thyroid autoimmunity or additive effect of all components of hypothyroidism on coronary artery disease is still elusive.8,16 In this brief review role and effect of both overt and subclinical hypothyroidism on atherosclerosis and traditional risk factors for CAD is summarized.

HYPOTHYROIDISM AND DEVELOPMENT OF ATHEROSCLEROSIS

Atherosclerosis is the central event in CAD. It is a process of intimal deposition of lipid in coronary arteries and its progression into atherosclerotic plaques. Carotid intima-media thickness (CIMT) is a good marker of early atherosclerotic change and future cardiovascular event.18 CIMT is evaluated using high-resolution ultrasound technique and is a low cost non-invasive method. Nagasaki et al. found that in patients with overt hypothyroidism CIMT was larger as compared to euthyroid control (0.635 ± 0.08 mm vs. 0.559 ± 0.021 mm, p < 0.005) and it decreased (0.552 ± 0.015 mm) after one year levothyroxine replacement.19 The presence of atherosclerosis in overt hypothyroidism is probably secondary to associated hypertension, hypercholesterolemia and hyperhomocysteinemia. An alternative mechanism is proposed by Zhang et al.20 according to which enhanced CIMT in patients with hypothyroidism is because of increased serum level of a microRNA (miRNA) called miRNA21-5. This miRNA is already reported to enhance proliferation and migration of vascular smooth muscle cells.21
A number of epidemiological studies supported the direct association between subclinical hypothyroidism and atherosclerosis. In Rotterdam study cross-sectional analysis showed that women with subclinical hypothyroidism had a significantly more incidence of atherosclerosis than euthyroid women after adjustment for age, body mass index, high density lipoprotein (HDL), blood pressure and smoking status.22 Mya et al.23 and Monzani et al.24 reported the same findings which were confirmed by later studies.25,26 Valentina et al. reported that increased CIMT and presence of carotid plaques in subclinical hypothyroid patients was independent of classical risk factors for atherosclerosis.26 However, studies of Rodondi et al.27 and Cappola et al.28 reported contradictory results. First meta-analysis of such studies29 published in 2008 and reported significant association between subclinical hypothyroidism and coronary heart disease with relative risk (RR) of 1.533. Another meta-analysis30 reported the same conclusion with RR of 1.20. Moreover, in a reanalysis of the Wickham study, Ravzi et al. demonstrated a strong association between ischemic heart disease and subclinical hypothyroidism.31
Recently, association of TSH with cardiovascular diseases have been investigated among healthy subjects with normal thyroid status.32-35 Although findings of these studies are not same but majority of them showed that higher levels of serum TSH within reference range were positively associated with coronary artery disease.32,33,35 Thus even mild thyroid dysfunction may affect atherogenesis. The clinical utility of such findings remain to be determined. Only large prospective studies can prove whether reducing of TSH by thyroxine replacement therapy in such healthy subjects reduces the potential risk of coronary heart disease.
It has been suggested that patient age had significant impact on relationship between subclinical hypothyroidism and atherosclerosis. The positive association between TSH and atherosclerosis risk was increased in younger patients but not older subjects.35,36 So far two meta-analyses of such studies had reported that relationship between subclinical hypothyroidism and coronary artery disease only existed37 or stronger30 in subjects younger than 65 year old. In older patients higher TSH level is physiological and suggested to have protective effect on cardiac health.38

HYPOTHYROIDISM AND CARDIOVASCULAR RISK FACTORS

Hypothyroidism, overt or subclinical is associated with an increased prevalence of cardiovascular heart disease through its effect on each individual risk factor like hyperlipidemia, hypertension, endothelial dysfunction etc. for cardiovascular diseases. If these risk factors are not accounted for then hypothyroidism per se is not associated with an increased risk for carotid atherosclerosis as reported for example by Chiche et al in hyperlipidemic patients.39 In the past two decades a growing body of research about TH regulation of lipid metabolism, effects on blood pressure and modulation of atherosclerotic factors like endothelial function, oxidative stress, homocysteine and C-reactive protein (CRP) level had widen our understanding of how hypothyroidism predisposes patients to cardiovascular disease. A brief account of each derangement associated with hypothyroidism is provided below:

Lipid Profile

Thyroid hormone effects absorption, synthesis and degradation of lipids and thus regulates the intravascular metabolism of lipoproteins. In hypothyroidism lipid metabolism is impaired. Staub et al. reported that total cholesterol, low density lipoprotein (LDL) cholesterol and apo B levels are elevated in overt hypothyroidism.40 Among hypercholesterolemic patients about 14% are reported to have hypothyroidism.41 TH regulates LDL receptor in liver as promoter region of the gene coding for LDL receptor contains functional thyroid response elements. Animal studies have shown that expression of mRNA in liver is directly related to peripheral concentration of thyroid hormones. Induction of hypothyroidism decreases 50% expression of LDL receptor mRNA in rat liver.42 This reduced expression of LDL receptor results decreased LDL clearance and hence its increase concentration in blood. In a clinical study receptor-mediated LDL metabolism was significantly improved in a hypothyroid woman after T4 supplementation.43 The increased LDL cholesterol in hypothyroid patients is more prone to oxidation that enhances its atherogenicity.43,44 The HDL cholesterol is antiatherosclerotic but its profile is variable in hypothyroid patients. However, low levels of proteins related to HDL metabolism are reported in hypothyroidism.43 Another reason for dyslipidemia in overt hypothyroidism is its association with insulin resistance that worsens the atherogenic lipid profile and makes the LDL subfraction more prone to oxidation.45 In subclinical hypothyroidism inconsistent effects on lipid profile were reported in different studies. Vierhapper et al. reported no effect of subclinical hypothyroidism on serum total cholesterol, LDL and HDL cholesterol levels.46 Similarly, HUNT study revealed a positive association of serum TSH in euthyroid range (0.2 – 4.5 mIU/L) with LDL cholesterol and triglyceride levels.47 A meta-analysis of 16 observational studies in 2014 reported that in subclinical hypothyroid patients LDL cholesterol and triglyceride levels were significantly elevated but HDL cholesterol levels were unaffected.48 A number of clinical studies and trials have reported effect of thyroxine replacement therapy on serum lipid profile of subclinical patients.24,33 A meta-analysis of such studies revealed modest reduction in LDL but no change in HDL cholesterol after thyroid hormone replacement in such patients.49 Thus relationship of thyroid deficiency and atherogenic lipid profile is confirmed. However, in interpretation of this association patient age, gender and thyroid autoimmune status should be necessarily considered.12,35,37,50

Hypertension

Hypertension is one the major risk factor for cardiovascular diseases.51 Euthyroid state is important for the maintenance of appropriate blood pressure (BP). Both hyperthyroidism and hypothyroidism are associated with hypertension.15 In Japan, Saito et al. reported a higher prevalence of hypertension in overt hypothyroid patients as compared to euthyroid subjects (14.8% vs 5.5%).52 In an Indian study 44% hypothyroid patients were reported to have hypertension45. In most hypothyroid patients only increase in diastolic blood pressure is reported but it may also affect systolic blood pressure.15 A plausible mechanism for hypertension in hypothyroidism is the enhanced systemic vascular resistance and arterial stiffness53,54 or altered lipid profile. However, Purohit and Mathur showed that hypertension in hypothyroid patients is also associated with insulin resistance and C-peptide.45 A few studies also suggested subclinical hypothyroidism as a risk factor for hypertension but this association is still a matter of debate.55 Recently Canbolat et al showed that patients with subclinical hypothyroidism had significantly higher diastolic hypertension, though within normal BP limits, than the controls but had significantly higher prevalence of diastolic non-dipping.56 Among healthy subjects association of high levels of TSH within the reference range with hypertension was reported in children and adolescents57 as well as adults58 but a latest study did not confirm this relationship.55 However, influence of family history of blood pressure on serum TSH levels in healthy individuals is reported that points to existence of possible genetic variants affecting both hypertension and serum TSH levels.59
The effect of replacement with thyroxine in both overt and subclinical hypothyroid patient was evaluated in a number of studies.60-62 The beneficial response was significant in overt than subclinical hypothyroidism and in later group was limited to improvement in systolic component only.60 Another study reported improvement only in arterial stiffness with L-thyroxine in subclinical hypothyroidism without alteration in myocardial functional reserve.61 However, in these studies subclinical hypothyroid patients were not stratified on the basis of presence or absence of autoimmune thyroiditis, a leading cause of this subclinical hypothyroidism. Only a small study by Traub-Weidinger et al reported improvement in coronary microvascular function after supplementation with LT4 in asymptomatic subjects with subclinical hypothyroidism due to thyroid autoimmunity.62 Further large studies are warranted to evaluate and confirm this effect.

Endothelial Function

The endothelium plays an important role in vascular function by production of vasodilator and vasoconstrictor substances. The most important vasodilator is nitric oxide (NO).63 Endothelial dysfunction is characterized by low production of NO from endothelial cells and is one of the initial steps in atherosclerosis development.64 In both overt and subclinical hypothyroidism endothelium-dependent flow-mediated vasodilation is impaired.65,66 Association of high levels of TSH with impaired endothelial function67 and arterial stiffness68 is also reported. However, it is not clear whether this effect is because of thyroid hormone deficiency or hypothyroidism- associated hypercholesterolemia and hypertension that also cause endothelial dysfunction.64 The role of thyroid hormone deficiency is evident from the improvement of endothelial function after L-T4 therapy in hypothyroidism.69,70 However, some studies have suggested that hypothyroidism-mediated endothelial dysfunction is because of chronic inflammation caused by autoimmune thyroiditis.63 This low-grade inflammation also causes increased oxidative stress in hypothyroidism.63 This assertion is verified by an increase in serum levels of CRP in patients with overt and subclinical hypothyroidism.71 However, replacement of thyroid hormone in patients with subclinical hypothyroidism did not affect CRP levels.72 Moreover, molecular mechanism for the thyroid hormone regulation of CRP is still not elucidated. Therefore, further studies are required to clarify this mechanism.

Homocysteine

Serum homocysteine level in human is affected by genetic, nutritional and acquired factors. Vitamin B6, B12 and folate are important nutritional factors while smoking and renal function also affect homocysteine level.15 Presence of high concentration of serum homocysteine is an established and known cardiovascular risk factor promoting premature atherosclerosis.73 Presence of high level of serum homocysteine is suggested to increase oxidative stress, enhance endothelial dysfunction and induce thrombosis in atherosclerosis..74 An elevation in serum homocysteine concentration in overt hypothyroidism as compared to healthy subjects is reported,75,76 that was successfully reduced after thyroxin supplementation.71,77 In mild or subclinical hypothyroidism serum homocysteine levels is not significantly affected.77,78 Moreover, no association between euthyroid chronic autoimmune thyroiditis and homocysteine levels was found in women. However, decrease in homocysteine level after L-T4 replacement as compared with healthy controls is intriguing.79 A recent meta-analysis by Zhou et al., reported a significant association between degree of hypothyroidism and levels of serum homocysteine80. The plausible mechanism may be the role of thyroid hormone in modulating the expression of genes involved in the homocysteine metabolism.81 An alternative explanation is the change in folate levels in hypothyroidism that increased serum homocysteine level.81,82 Another suggested mechanism for increased homocysteine in hypothyroidism is the renal function impairment that reduce renal clearance of homocysteine.15,83

CONCLUSION AND FUTURE DIRECTION

Overt hypothyroidism is strongly associated with all components of coronary artery disease but relation of subclinical hypothyroidism is partially proved in different studies. The favorable effect of thyroxine supplementation on cardiac health in subclinical hypothyroid patients points to some missing confounder. In this regard thyroid autoimmunity is the best candidate. A few studies have elucidated the contribution of autoimmune thyroiditis in context of hypothyroidism and CAD. Recently involvement of euthyroid autoimmune thyroiditis in early atherosclerosis is reported in postmenopausal women and adolescent girls.14,84 As thyroid autoimmunity is associated with chronic inflammation which may cause endothelial dysfunction it is expected that it might have greater role in cardiovascular diseases. Thus role of thyroid autoimmunity still need further exploration. A second point is the consideration of patient age and gender. Both hypothyroidism and heart diseases have different profile in male and female with increasing age.12 Cross-sectional and longitudinal studies recruiting exclusively male or female subjects may elucidate relation of subclinical hypothyroidism with heart more clearly. Third consideration is the lack of oxidized low density lipid (ox-LDL) determination in most studies pertaining to lipid profile and cardiovascular risk in hypothyroidism.85 Ox-LDL is the chief culprit in atherosclerosis and its determination should be included in future studies.

Conflict of interest: Nil declared by the authors
Author contribution:
SS
– conceived idea, Literature search
SA – Literature study, review
NS – Editing, literature study, writing
NBR – Manuscript writing
SE – Manuscript writing, reviewing

REFERENCES

1) Grais IM, Sowers JR. Thyroid and the Heart. Am J Med. 2014 Aug;127(8):691–698.  doi: 10.1016/j.amjmed.2014.03.009 [PubMed] [Free full text]
2) Mishra P, Samanta L Oxidative stress and heart failure in altered thyroid states. ScientificWorldJournal. 2012;2012:741861. doi: 10.1100/2012/741861. [PubMed] [Free full text]
3) Klein I, Danzi S Thyroid disease and the heart. Circulation. 2007 Oct 9;116(15):1725-1735. [PubMed] [Free full text]
4) Abid M, Sharma KK, Ali SS, Chandra P, Verma A, Kishore K, et al. Complication and management of hypothyroidism: a review. Ind J Drugs. 2016;4(2):42-56. [Free full text]
5) Hussain Z, Elahi S. Undetected hypothyroidism and its anesthetic implications. Anaesth Pain Intens Care. 2012;16(2):205-210.  [Free full text]
6) Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association Endocr Pract. 2012 Nov-Dec;18(6):989-1028. [PubMed]
7) Bastenie PA, Vanhaelst L, Bonnyns M, Neve P, Staquet M. Preclinical hypothyroidism: a risk factor for coronary heart-disease. Lancet. 1971 Jan 30;1(7692):203-204. [PubMed]
8) Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid. 1996 Jun;6(3):155-160. [PubMed]
9) Rodondi N, Newman AB, Vittinghoff E, de Rekeneire E, Satterfield S, Haris TB, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005 Nov;165(21):2460-2466.[PubMed]
10) Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006 Mar 1;295(9):1033-1041.[PubMed] [Free full text]
11) Ittermann T, Lorbeer R, Dorr M, Schneider T, Hebalbarth L, Wenzel M, et al. High levels of thyroid-stimulating hormone are associated with aortic wall thickness in the general population. Eur Radiol. 2016 Dec;26(12):4490-4496. [PubMed]
12) Chon SJ, Heo JY, Yun BH, Jung YS, Seo SK Serum thyroid stimulating hormone levels are associated with the presence of coronary atherosclerosis in healthy postmenopausal women. J Menopausal Med. 2016 Dec;22(3):146-153. doi: 10.6118/jmm.2016.22.3.146 [PubMed] [Free full text]
13) Sara JD, Zhang M, Gharib H, Lerman LO, Lerman A Hypothyroidism is associated with coronary endothelial dysfunction in women. J Am Heart Assoc. 2015 Jul 9;4(8):e002225 (DOI: 10.1161/JAHA.115.002225) [PubMed] [Free full text]
14) McLeod SA Autoimmune thyroid disease: a novel risk factor for atherosclerosis? Endocrine. 2013 Aug;44(1):8-10. doi: 10.1007/s12020-013-9952-8. [PubMed] [Free full text]
15) Ichiki T Thyroid hormone and vascular remodeling. J Atheroscler Thromb. 2016;23(3):266-275.[PubMed]
16) Fiarresga AJ, Feliciano J, Fernandes R, Martins A, Pelicano N, Timoteo AT, et al. Relationship between coronary disease and subclinical hypothyroidism: an angiographic study.
Rev Port Cardiol. 2009 May;28(5):535-543. [PubMed] [Free full text]
17) Floriani C, Gencer B, Collet T, Rodondi N Subclinical thyroid dysfunction and cardiovascular diseases: 2016 update. Eur Heart J. 2017 Feb 27. (DOI: 10.1093/eurheartj/ehx050) [PubMed]
18) O’Leary DH, Polak JF: Intima-media thickness: a tool for atherosclerosis imaging and event prediction. Am J Cardiol. 2002 Nov 21;90(10C):18L-21L.[PubMed]
19) Nagasaki T, Inaba M, Henmi Y, Kumeda Y, Ueda M, Tahara H, et al. Decrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function. Clin Endocrinol (Oxf). 2003 Nov;59(5):607-612. [PubMed]
20) Zhang X, Shao S, Geng H, Yu Y, Wang C, Liu Z, et al. Expression profiles of six circulating microRNAs critical to atherosclerosis in patients with subclinical hypothyroidism: a clinical study. J Clin Endocrinol Metab. 2014 May;99(5):E766-E774. doi: 10.1210/jc.2013-1629. [PubMed] [Free full text]
21) Wang M, Li W, Chang GQ, Ye CS, Ou JS, Li XX, et al. MicroRNA-21 regulates vascular smooth muscle cell function via targeting tropomyosin 1 in arteriosclerosis obliterans of lower extremities. Arterioscler Thromb Vasc Biol. 2011 Sep;31(9):2044-2053. doi: 10.1161/ATVBAHA.111.229559. [PubMed] [Free full text]
22) Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman, Witteman JC: Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000 Feb 15;132(4):270-278. [PubMed]23) Mya MM, Aronow WS Subclinical hypothyroidism is associated with coronary artery disease in older persons. J Gerontol A Biol Sci Med Sci. 2002 Oct;57(10):M658-M659. [PubMed
24) Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double–blind, placebo-controlled study. J Clin Endocrinol Metab. 2004 May;89(5):2099-106. [PubMed] [Free full text]
25) Kim SK, Kim SH, Park KS, Park SW, Cho YW. Regression of the increased common carotid artery-intima media thickness in subclinical hypothyroidism after thyroid hormone replacement. Endocr J. 2009;56(6):753-758. [PubMed]
26) Valentina VN, Marijan B, Chedo D, Branka K Subclinical hypothyroidism and risk to carotid atherosclerosis Arq Bras Endocrinol Metabol. 2011 Oct;55(7):475-480. [PubMed] [Free full text]
27) Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005 Nov 28;165(21):2460-2466. [PubMed]
28) Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006 Mar 1;295(9):1033-1041. [PubMed] [Free full text]
29) Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a met-analysis. Int J Cardiol. 2008;125:41-48. [PubMed]
30) Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008 Jun 3;148(11):832-845. [PubMed] [Free full text]
31) Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin Endocrin Metab. 2010 Apr;95(4):1734–1740. [PubMed] [Free full text]
32) Asvold BO, Bjoro T, Nilsen TI, Gunnell D, Vatten LJ. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch Intern Med. 2008 Apr 28;168(8):855-860.[PubMed] [Free full text]
33) Coceani M, Iervasi G, Pingitore A, Carpeggiani C, L’Abbate A. Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications. Clin Cardiol. 2009 Jul;32(7):380-385. [PubMed] [Free full text]
34) Jung CH, Rhee EJ, Shin HS, Jo SK, Won JC, Park CY, et al. Higher serum free thyroxine levels are associated with coronary artery disease. Endocr J. 2008 Oct;55(5):819-826. [PubMed]
35) Yang L, Zou J, Zhang M, Xu H, Qi W, Gao L, et al. The relationship between thyroid stimulating hormone within the reference range and coronary artery disease: impact of age. Endocr J. 2013;60 (6):773-779.[PubMed]
36) Hyland KA, Arnold AM, Lee JS, Cappola AR. Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: The Cardiovascular Health Study. J Clin Endocrinol Metab. 2013 Feb;98(2):533-540. [PubMed] [Free full text]
37) Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a meta-analysis. J Clin Endocrinol Metab. 2008 Aug;93(8):2998-3007. [PubMed] [Free full text]
38) Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004 Dec 1;292(21):2591-2599. [PubMed] [Free full text]
39) Chiche F, Jublanc C, Coudert M, Carreau V, Kahn JF, Bruckert E Hypothyroidism is not associated with increased carotid atherosclerosis when cardiovascular risk factors are accounted for in hyperlipidemic patients. Atherosclerosis. 2009 Mar;203(1):269-276.[PubMed] [Free full text]
40) Staub JJ, Althaus BU, Engler H, Ryff AS, Trabucco P, Marquardt K, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med. 1992 Jun;92(6):631-642. [PubMed]
41) Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995 Jul 24;155(14):1490-1495. [PubMed]
42) Staels B, Van Tol A, Chan L, Will H, Verhoeven G, Auwerx J. Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase, and low density lipoprotein receptor in rats. Endocrinology. 1990 Sep;127(3):1144–1152. [PubMed]
43) Franco M, Chavez E, Perez-Mendez O Pleiotropic Effects of thyroid hormones: learning from hypothyroidism. J Thyroid Res. 2011;2011:321030. doi: 10.4061/2011/321030. [PubMed] [Free full text]
44) Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM. Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab. 1997 Oct;82(10):3421-3424.[PubMed] [Free full text]
45) Purohit P, Mathur R Hypertension association with serum lipoproteins, insulin, insulin resistance and C-peptide: unexplored forte of cardiovascular risk in hypothyroidism. North Am J Med Sci. 2013 Mar;5(3):195-201. doi: 10.4103/1947-2714.109187.[PubMed] [Free full text]
46) Vierhapper H, Nardi A, Grosser P, Raber W, Gessl A. Low-density lipoprotein cholesterol in subclinical hypothyroidism. Thyroid. 2000 Nov;10(11):981-984. [PubMed]
47) Asvold BO, Vatten LJ, Nilsen TI, Bjoro T The association between TSH within the reference range and serum lipid concentrations in a population-based study: The HUNT Study. Eur J Endocrinol. 2007 Feb;156(2):181-186. [PubMed] [Free full text]
48) Liu XL, He S, Zhang SF, Wang J, Sun XF, Gong CM, et al. Alteration of lipid profile in subclinical hypothyroidism: a meta-analysis. Med Sci Monit. 2014 Aug 14;20:1432-1441. [PubMed] [Free full text]
49) Danese MD, Ladenson PW, Meinert CL, Powe NR effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000 Sep;85(9):2993-3001. [PubMed] [Free full text]
50) Topaloglu O, Gokay F, Kucukler K, Burnik FS, Mete T, Yavuz HC, et al, Is autoimmune thyroiditis a risk factor for early atherosclerosis in premenopausal women even if in euthyroid status? Endocrine. 2013 Aug;44(1):145-151.[PubMed]
51) Lacruz ME, Kluttig A, Hartwig S, Loer M, Tiller D, Greiser KH, Werdan K, Haerting J Prevalence and incidence of hypertension in the general adult population: Results of the Carla-Cohort Study. Medicine(Baltimore). 2015 Jun;94(22):e952. doi: 10.1097/MD.0000000000000952. [PubMed] [Free full text]
52) Saito I, Saruta T. Hypertension in thyroid disorders. Endocrinol Metab Clin North Am. 1994 Jun;23(2):379-386. [PubMed]
53) Obuobie K, Smith J, Evans LM, John R, Davies JS and Lazarus JH: Increased central arterial stiffness in hypothyroidism. J Clin Endocrinol Metab. 2002 Oct;87(10):4662-4666. [PubMed] [Free full text]
54) Nagasaki T, Inaba M, Kumeda Y, Hiura Y, Shirakawa K, Yamada S, et al. Increased pulse wave velocity in subclinical hypothyroidism. J Clin Endocrinol Metab. 2006 Jan;91(1):154-158. [PubMed] [Free full text]
55) Amouzegar A, Heidari M, Gharibzadeh S, Mehran L, Tohidi M, Azizi F. The association between blood pressure and normal range thyroid function tests in a population based Tehran Thyroid Study. Horm Metab Res. 2016 Mar;48(3):151–156. [PubMed]
56) Polat Canbolat I, Belen E, Bayyigit A, Helvaci A, Kilickesmez K. Evaluation of daily blood pressure alteration in subclinical hypothyroidism. Acta Cardiol Sin. 2017 Sep;33(5):489-494. [PubMed] [Free full text]
57) Ittermann T, Thamm M, Wallaschofski H, Rettig R, Volzke H Serum thyroid stimulating hormone levels are associated with blood pressure in children and adolescents. J Clin Endocrinol Metab. 2012 Mar;97(3):828-834. doi: 10.1210/jc.2011-2768 [PubMed] [Free full text]
58) Asvold BO, Bjoro T, Nilsen TIL, Vatten LJ. Association between blood pressure and serum thyroid- stimulating hormone concentration within the reference range: a population-based study. J Clin Endocrinol Metab. 2007 Mar;92(3):841–845. [PubMed] [Free full text]
59) Gumieniak O, Hurwitz S, Perlstein TS, Ngumezi UC, Hopkins PN, Jeunemaitre X, et al. Aggregation of high-normal thyroid-stimulating hormone in hypertensive families. J Clin Endocrinol Metab. 2005 Nov;90(11):5985–5990. [PubMed] [Free full text].
60) Agarwal G, Mehra D, Kumar A. Hypertension in hypothyroidism, a response to replacement therapy with l-thyroxine. PARIPEX – Indian Journal Research. 2016;5(10):55-57.
61) Owen PJD, Rajiv C, Vinereanu D, Mathew T, Fraser AG, Lazarus JH Subclinical hypothyroidism, arterial stiffness, and myocardial reserve. J Clin Endocrinol Metab. 2006 Jun;91(6):2126–2132. [PubMed] [Free full text]
62) Traub-Weidinger T, Graf S, Beheshti M, Ofluoglu S, Zettinig G, Khorsand A, Nekolla SG, Kletter K, Dudczak R, Pirich C Coronary vasoreactivity in subjects with thyroid autoimmunity and subclinical hypothyroidism before and after supplementation with thyroxine. Thyroid. 2012 Mar;22(3):245-251. doi: 10.1089/thy.2011.0183 [PubMed]
63) Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al. Low-Grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2006 Dec;91(12):5076–5082.[PubMed] [Free full text]
64) Giannotti G, Landmesser U. Endothelial dysfunction as an early sign of atherosclerosis. Herz. 2007 Oct;32(7):568-72.[PubMed]
65) 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 Jun;7(3):411-414. [PubMed]
66) Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism:beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003 Aug;88(8):3731-3737. [PubMed] [Free full text]
67) Volzke H, Robinson DM, Spielhagen T, Nauck M, Obst A, Ewert R, et al. Are serum thyrotropin levels within the reference range associated with endothelial function? Eur Heart J 2009 Jan;30(2):217-224. doi: 10.1093/eurheartj/ehn508 [PubMed] [Free full text]
68) Lambrinoudaki I, Armeni E, Rizos D, Georgiopoulos G, Kazani M, Alexandrou A, et al. High normal thyroid-stimulating hormone is associated with arterial stiffness in healthy postmenopausal women. J Hypertens. 2012 Mar;30(3):592-599. doi: 10.1097/HJH.0b013e32834f5076. [PubMed]
69) Papaioannou GI, Lagasse M, Mather JF and Thompson PD Treatinghypothyroidism improves endothelial function. Metabolism. 2004 Mar;53(3):278-279. [PubMed]
70) Alibaz Oner F, Yurdakul S, Oner E, Kubat Uzum A, Erguney M. Evaluation of the effect of L-thyroxin therapy on endothelial functions in patients with subclinical hypothyroidism. Endocrine. 2011 Oct;40(2):280-284 [PubMed]
71) Christ-Crain M, Meier C, Guglielmetti M, Huber PR, Riesen W, Staub JJ, et al. Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross sectional and a double blind, placebo controlled trial. Atherosclerosis. 2003 Feb;166(2):379-386. [PubMed] [Free full text]
72) Luboshitzky R, Herer P Cardiovascular risk factors in middle aged women with subclinical hypothyroidism. Neuro Endocrinol Lett. 2004 Aug;25(4):262-266. [PubMed]
73) Welch GN, Loscalzo J. Homocysteine and atherothrombosis N Engl J Med. 1998 Apr 9;338(15):1042-1050. [PubMed]
74) Guthikonda S, Haynes WG. Homocysteine: role and implications in atherosclerosis. Curr Atheroscler Rep. 2006 Mar;8(2):100-106. [PubMed]
75) Morris MS, Bostom AG, Jacques PF, Selhub J, Rosenberg IH Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. Atherosclerosis. 2001 Mar;155(1):195-200. [PubMed] [Free full text]
76) Sengul E, Cetinarslan B, Tarkun I, Canturk Z, Turemen E Homocysteine concentrations in subclinical hypothyroidism. Endocr Res. 2004 Aug;30(3):351-359. [PubMed]
77) Orzechowska-Pawilojc A, Sworczak K, Lewczuk A, Babinska A Homocysteine, folate and cobalamin levels in hypothyroid women before and after treatment. Endocr J. 2007 Jun;54(3):471-476. [PubMed]
78) Hueston WJ, King DE, Geesey ME Serum biomarkers for cardiovascular inflammation in subclinical hypothyroidism. Clin Endocrinol (Oxf). 2005 Nov;63(5):582-587. [PubMed]
79) Owecki M, Dorszewska J, Sawicka-Gutaj N, Oczkowska A, Owecki MK, Michalak M. Serum homocysteine levels are decreased in levothyroxine treated women with autoimmune thyroiditis. BMC Endocrine Disord. 2014 Mar 1;14:18. [PubMed] [Free full text]
80) Zhou Y, Chen Y, Cao X, Liu C, Xie Y Association between plasma homocysteine status and hypothyroidism: a meta-analysis. Int J Clin Exp Med. 2014 Nov 15;7(11):4544-4553.[PubMed] [Free full text]
81) Nair CP, Viswanathan G, Noronha JM. Folate mediated incorporation of ring-2-carbon of histidine into nucleic acids: influence of thyroid hormone. Metabolism. 1994 Dec;43(12):1575-1578.[PubMed]
82) Lien EA, Nedrebo BG, Varhaug JE, Nygard O, Aakvaag A, Ueland PM Plasma total homocysteine levels during short term iatrogenic hypothyroidism. J Clin Endocrinol Metab. 2000 Mar;85(3):1049-1053.[PubMed] [Free full text].
83) Barbe F, Klein M, Chango A, Fremont S, Gerard P, Weryha G, et al. Homocysteine, folate, vitamin B12, and transcobalamins in patients undergoing successive hypo- and hyperthyroid states. J Clin Endocrinol Metab. 2001 Apr;86(1):1845-1846. [PubMed] [Free full text]
84) Isguven P, Gunduz Y, Kilic M. Effects of thyroid autoimmunity on early atherosclerosis in euthyroid girls with Hashimoto’s thyroiditis. J Clin Res Pediatr Endocrinol. 2016;8(2):150-156. doi: 10.4274/jcrpe.2145 [PubMed] [Free full text]
85) Bansal SK, Yadav R. A Study of Extended Lipid Profile Including Oxidized LDL, Small Dense LDL, Lipoproteins (a) and Apolipoproteins in the Assessment of Cardiovascular Risk in Hypothyroidism Patients. J Clin Diagn Res. 2016;10(6):BC04-BC08. doi: 10.7860/JCDR/2016/19775.8067. [PubMed] [Free full text]