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The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease
Atherosclerosis xxx (2012) 1e6
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Review
The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease Erhan Tatar*, Fatih Kircelli, Ercan Ok Ege University School of Medicine, Division on Nephrology, 35100 Bornova, Izmir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 May 2012 Received in revised form 31 October 2012 Accepted 31 October 2012 Available online xxx
Accelerated atherosclerosis and arterial stiffness are the two leading causes of increased cardiovascular disease in patients with chronic kidney disease. Dysfunctional thyroid hormone metabolism has been suggested to play a role in atherosclerosis and arterial stiffness. Changes in cardiac contractility and output, myocardial oxygen demand, systemic and peripheral vascular resistance, blood pressure and lipid profile, increased inflammatory burden and endothelial dysfunction may be responsible for thyroid hormone-related cardiovascular disease. This article focuses on the mechanistic insights of this association and provides a concise review of the current literature. Ó 2012 Published by Elsevier Ireland Ltd.
Keywords: Thyroid hormones Triiodothyronine Atherosclerosis Arterial stiffness Chronic kidney disease
Contents 1. 2. 3.
4. 5.
Thyroid hormone and the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone and endothelial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone and atherosclerosis in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Endothelial functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone and arterial stiffness in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone replacement and cardiovascular outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Despite ongoing efforts to reduce the high cardiovascular disease burden in patients with chronic kidney disease (CKD), cardiovascular (CV) morbidity and mortality still remain unacceptably higher compared to the general population. In addition to the traditional CV risk factors, uraemia itself may be a risk factor for CV disease [1,2]. Accelerated atherosclerosis and arterial stiffness (AS) are the two major causes of increased CV disease in CKD patients [3,4]. While the underlying pathophysiological mechanisms of
* Corresponding author. Tel.: þ90 232 3904254. E-mail address: [email protected] (E. Tatar).
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these two diseases are mostly similar (advanced age, diabetes, hypertension mainly due to chronic volume excess, inflammation and dyslipidaemia), they are considered to be two distinct problems [5,6]. In addition to these similarities, arterial calcification and overactivity of the sympathetic nervous and renine angiotensinogenealdosterone systems have been shown to be risk factors for the development and progression of AS; obesity, hyperhomocysteinaemia and hyperuricaemia have been shown to be risk factors for atherosclerosis [6e9]. As a potential novel mechanism, our group has recently reported that dysfunctional carbohydrate and thyroid hormone metabolism may also be responsible for the occurrence and progression of both atherosclerosis and AS [10e12].
0021-9150/$ e see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.068
Please cite this article in press as: Tatar E, et al., The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease, Atherosclerosis (2012), http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.068
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E. Tatar et al. / Atherosclerosis xxx (2012) 1e6
CKD patients have a higher rate of thyroid dysfunction compared to the general population [13e15]. This rate excludes hyperthyroid disorders. The prevalence of hyperthyroidism in the CKD population is similar to the general population [16,17]. Dysfunctional thyroid hormone metabolism becomes more prevalent with CKD progression, ranging from 5% to 25% as the stage of kidney disease worsens [13]. Similarly, the presence of low T3 syndrome in CKD patients varies from 20 to 80% (8.2% in CKD1, 10.9% in CKD2, 20.8% in CKD3, 60.6% in CKD4; 78.6% in CKD5) [17e 20]. A study by our group has shown that 71.7% of CKD5 patients have low T3 syndrome [20]. The causes of thyroid dysfunction in CKD patients have not been fully elucidated; however, decreased renal clearance of TRH, TSH and iodine, an increased frequency of autoimmune disorders such as thyroiditis, systemic lupus erythematosus, and type 1 diabetes, metabolic acidosis, retention of organic acids and guanido compounds and inflammation have been suggested to contribute to primary thyroid disorders. Older age, HCV positivity, interferon therapy, exposure to disinfectants containing povidineeiodine and certain drugs (amiodarone, steroids, b-blockers) have also been implicated [17,21,22]. In the non-uraemic population, the effect of thyroid disturbances on the cardiovascular system have been suggested to occur via changes in cardiac contractility and output, myocardial oxygen demand, systemic and peripheral vascular resistance, blood pressure and lipid profile [23]. The data are scarce for uraemic patients, but several lines of evidence indicate a role for increased inflammatory burden and endothelial dysfunction in thyroid hormonerelated cardiovascular disease in this population [24e27]. In this manuscript, we will review the current literature on the effects of thyroid hormones on the cardiovascular system, focussing mainly on the CKD population but also highlighting the data generated from the general population. 1. Thyroid hormone and the heart The effects of dysfunctional thyroid hormone (TH) metabolism on the cardiovascular system have been reviewed elsewhere [23]. Briefly, several mechanisms have been proposed. First of all, the lack of deiodinase activity in cardiac myocytes has been associated with inhibition of the conversion of thyroxine (T4) to triiodothyronine (T3) [28]. T3 is the biologically active form of TH in myocytes. T3 can directly or indirectly affect the heart depending on its binding to nuclear receptors. In the direct pathway, after entering cells, T3 binds to its nuclear receptors (TR-a1, TR-a2, TR-b1 and TRb2) located in the atria and ventricles and exert its effects [29]. T3 also regulates the transcription of some specific cardiac genes (genomic effect) in the cardiac myocytes. Alpha myosin heavy chain, sarcoplasmic reticulum Caþþ-ATPase, Naþ/Kþ ATPase, voltage-gated potassium channels, atrial and brain natriuretic peptide, a-1 adrenergic receptor, and adenine nucleotide transporter 1 are positively regulated by thyroid hormones, and amyosin heavy chain, phospholamban, the Naþ/Caþþ exchanger, thyroid hormone receptor a1, adenyl cyclase V and VI, and guanine nucleotide-binding protein Gi are negatively regulated [30e32]. While TR-a receptors predominantly have contractile (basal heart rate) and electrophysiological functions (ventricular repolarisation) in the heart, TR-b mediates a hormone-induced change in heart rate [29e34]. The indirect effects, or non-genomic effects, of T3 involve extranuclear binding. An example is the effect of T3 on the transport of amino acids, glucose, calcium and other ions [33,35]. These genomic and non-genomic effects are important for TH metabolism in the heart.
T3 also can directly regulate systolic and diastolic function at the receptor level in cardiac myocytes. This regulation is accompanied by an indirect decrease in peripheral vascular resistance, decreased effective arterial filling volume leading to the activation of the renineangiotensinogenealdosterone system, increased renal sodium absorption and eventually increased blood volume. These changes result in increased inotropy, chronotropy, and cardiac output. Additionally, T3 can directly increase cardiac output at the receptor level in cardiac myocytes [33,36,37]. 2. Thyroid hormone and endothelial function The major effects of T3 on the peripheral vascular system are via regulation of vascular resistance and inhibition of atherosclerotic precursors. Vascular smooth muscle cells (VSMCs) play a key role in regulating vascular tonicity and are the direct target of T3, leading to vascular relaxation [38e40]. In experiments, VSMCs have been shown to contain binding regions in the plasma membrane that together with type II iodothyronine deiodinase maintain the intracellular concentration of T3 [39,40]. T3 via its direct effect on secretion of adrenomedullin, a potent vasodilating agent, has been shown to decrease vascular resistance in animal models [41]. Another mode of non-genomic action for T3 is the regulation of levels of ATP, ADP and adenosine, which is a potent vasodilator and antiaggregation molecule, controlled by ecto-50 -nucleotidase [42]. In a study by Bruno et al., T3 has been shown to interact with ATP diphosphohydrolase, affecting the physiological maintenance of ADP, and 50 -nucleotidase to induce adenosine-dependant vasodilation [43]. Similarly, T3 has been reported to regulate cyclic ADP-ribose, leading to Caþþ release from ryanodine-sensitive channels [44] and stimulation of intracellular cAMP production [42,44]. In addition, the effects of T3 on nitric oxide (NO) metabolism have been implicated in several experimental and clinical studies [26,45,46]. Activation of the phosphatidylinositol 3-kinase/protein kinase b (PI3K/Akt) signalling pathway has been proposed to lead to NO synthesis in the endothelium and VSMCs [45,46]. 3. Thyroid hormone and atherosclerosis in CKD Hyperlipidaemia, endothelial dysfunction, low-grade inflammation, hypertension and uraemic itself (uraemic toxins, anaemia, renal dystrophy) are associated with advanced atherosclerosis leading to increased cardiovascular morbidity and mortality in CKD patients [3,5,9]. 3.1. Lipid metabolism Abnormalities in lipid metabolism are common in CKD and, in part, can be affected by dysfunctional thyroid hormone metabolism [47e50]. As CKD progresses, these changes become more pronounced. CKD-induced dyslipidaemia is characterised by hypertriglyceridaemia, elevated very-low density lipoprotein (VLDL), a high plasma concentration of lipoprotein remnants, accumulation of oxidised lipids and lipoproteins, a low plasma high-density lipoprotein cholesterol (HDL-C) concentration, and impaired HDL-C maturation and function. Low-density lipoprotein cholesterol (LDL-C) is usually normal or lower than normal but consists of highly atherogenic, small, dense particles [47e50]. Different than the general population, alterations in apolipoprotein metabolism accompany the changes in lipoprotein levels in CKD patients. In renal dyslipidemia, triglyceride-rich apoB-containing lipoprotein levels are frequently increased; often accompanied by increased apoC and E levels. VLDL and IDL are found to have lipoprotein particle B, C and lipoprotein particle- AII, B, C, D, E
Please cite this article in press as: Tatar E, et al., The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease, Atherosclerosis (2012), http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.068
E. Tatar et al. / Atherosclerosis xxx (2012) 1e6
accumulation, respectively. On the other hand, apoA-containing lipoprotein levels, especially AI, are decreased. This leads to the typical apolipoprotein pattern of decreased apoA-I/apoC-III ratio observed in renal patients [50]. As a conclusion, disturbed lipoprotein lipase, hepatic lipase and lecithin cholesterol acyl transferase enzyme metabolism, decreased catabolism and cellular uptake of lipoproteins (due to increased ApoCIII/ApoE ratio) and increased lipoprotein synthesis due to hyperinsulinemia and nutritional changes are held responsible in CKD-induced dyslipidaemia [49,50]. Hyperlipidaemia per se contributes not only to the progression of CKD but also accelerates atherosclerosis [48]. Dysfunctional thyroid hormone metabolism is responsible for a worsening lipid profile in the non-uraemic population [51e53]. This effect is important because abnormal lipid metabolism is an established risk factor for cardiovascular disease [53]. In patients with hypothyroidism, several mechanisms for the effect of thyroid disease on these changes have been proposed but alterations in lipid synthesis and metabolism lie at the core of these mechanisms. Total cholesterol, LDL-C, apolipoprotein B, lipoprotein (a) and triglyceride levels are increased, and HDL-C is decreased. In addition, induction of hepatic hydroxymethylglutaryl coenzyme A reductase expression by thyroid hormones leads to increased cholesterol synthesis. Additionally, a reduced number of LDL cell surface receptors, decreased LDL secretion into the bile and increased cholesterol absorption cause LDL-C accumulation and eventually increased LDL-C oxidation. Furthermore, cholesterol-ester transferase, which is responsible for the transfer of cholesterol from HDL-C to LDL-C and VLDL, decreases. Similarly, the decreased lipoprotein lipase activity observed in hypothyroidic patients causes hypertriglyceridaemia [51,52]. While there is data in the general population on the effects of thyroid hormones, there is scarce data regarding uraemic patients. Liu et al. [54] investigated haemodialysis patients and reported a positive correlation between fT3 and HDL and a negative correlation between fT3 and TG, LDL-C and ApoB, emphasising the importance of the association between thyroid hormones and hyperlipidaemia, hypoalbuminaemia, and hyposelenaemia. A similar finding was observed in a study by our group, in which in a subgroup analysis of 57 peritoneal dialysis (PD) patients, an increase in TSH despite still being in the normal range was associated with an increased triglyceride level and cardiac dysfunction [12].
3
hormones likely play an important role in regulating blood pressure in this population. In the subgroup analysis of one study, Enia et al. reported a negative correlation between fT3 and diastolic blood pressure in PD patients (r ¼ 0.50, p ¼ 0.001) [25]. 3.3. Endothelial functions Secondary endothelial dysfunction has been observed in hypothyroid patients [64,65]. Similarly, secondary risk factors for endothelial dysfunction, such as hyperlipidaemia, hypertension, hypercoagulability (decreased fibrinolytic activity, low D-dimer and high plasminogen activator inhibitor-1), have been reported in these patients [66e69]. In addition to these factors, hyperhomocysteinaemia and increased osteoprotegerin were found to be significantly higher in hypothyroid patients than normal controls [70e73]. Hyperhomocysteinaemia has atherogenic and prothrombic effects caused by the induction of smooth muscle proliferation, enhancement of collagen synthesis, increased LDL aggregation, altered binding of tissue plasminogen activator to endothelial tissue and thrombomodulin functions [74e76]. In contrast, osteoprotegerin prolongs VSMC and endothelial cell survival, stimulates proinflammatory cytokines and thus creates an atherosclerotic environment. Additionally, osteoprotegerin causes cardiovascular disease by inducing vascular calcification by mechanisms still to be identified [77e79]. In a cohort of non-diabetic, stage 3e4 CKD patients, Yilmaz et al. reported an association between low T3 and endothelial dysfunction [26]. They suggested that the association between free T3 (fT3) and asymmetric dimethylarginine (ADMA) (an endogenous NO synthase inhibitor) levels might be responsible for the effects of fT3 on vascular beds. ADMA has been shown to be an important contributor to cardiovascular diseases in several studies [80,81]. In a study by our group, we found a strong association between atherosclerosis (determined by carotid arteryeintima media thickness) and fT3 level, suggesting an adaptive mechanism to minimise the energy consumption generated by malnutrition, inflammation, and atherosclerosis (reflected by the close association among fT3 level, CRP and leptin). T3 was an independent predictor of atherosclerosis, suggesting a direct effect on vascular beds [11,54,82]. A list of factors responsible for atherosclerosis in CKD patients and general population with thyroid disturbances are depicted in the Fig. 1. 4. Thyroid hormone and arterial stiffness in CKD
3.2. Blood pressure Thyroid hormones play an important role in regulating blood pressure [55]. Hypothyroidism can cause secondary hypertension in some patients [56]. An increase in diastolic blood pressure is distinctive, but systolic blood pressure may also be increased [57,58]. T3 deficiency may change vascular function and dilation at the cellular level. T3 deficiency leads to increased peripheral vascular resistance, which may be another cause of hypertension [38e40]. The second important mechanism is a decrease in cardiac contractility and output causing decreased glomerular filtration and impaired sodium and water secretion and leading to hypervolaemia [23,59]. Another atherosclerotic effect on vascular beds is due to the renineangiotensinogenealdosterone system [60e63]. The effect of thyroid hormones on the RAAS is via induction of renin synthesis and secretion [60], regulation of angiotensinogen mRNA gene expression in the liver, increased plasma angiotensin II [61,62], decreased AT1R expression and stimulation of AT2R in VSMCs [63]. Despite the lack of a study that directly examined the effect of thyroid hormones on blood pressure in CKD patients, thyroid
Similar to atherosclerosis in most ways, arterial stiffness develops as a result of hypertension, hypervolaemia, arterial
Fig. 1. Atherosclerotic mechanisms in hypothyroidic patients with and without chronic kidney disease.
Please cite this article in press as: Tatar E, et al., The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease, Atherosclerosis (2012), http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.068
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calcification, increased oxidative stress, inflammation, overactive sympathetic nervous and renineangiotensinogenealdosterone systems, insulin resistance, and increased lipid oxidation. AS further worsens the cardiovascular profile of these patients and thus is an independent predictor for increased cardiovascular and all-cause mortality [4,83]. Many studies have revealed an association between AS and hypothyroidism in non-uraemic patients [84e86]. In a study by Dagre et al., AS was detected not only in clinically hypothyroid patients but also in those with subclinical findings [82]. They suggested that left ventricular dysfunction and impaired coronary perfusion may be responsible for this outcome. Later, two other studies reported the reversal of AS by T4 replacement therapy due to lowering systolic blood pressure in this patient population [85,86]. Furthermore, Nagasaki et al. proposed that inflammation [C-reactive protein, (CRP)] may be responsible for the association between hypothyroidism and AS and suggested monitoring the CRP level to track improvements in AS [87]. In a study by our group, a low T3 level was associated with increased AS in 113 non-diabetic haemodialysis patients [11]. A similar result was also found in euthyroid PD patients [12]. Although a causal link was not provided in these studies, impaired vascular and cardiac regulation are likely responsible. In this study, an increase in TSH despite being in the normal range was also associated with decreased subendocardial viability (SEVR), which is a validated method for determining oxygen consumption in the subendocardial myocardium. Supporting these deleterious effects, Kang et al. have shown that a high TSH level causes a lower left ventricular ejection fraction, suggesting impaired systolic function in PD patients [88]. Zoccalli et al. confirmed this finding in ESRD patients with a low triiodothyronine level [27]. A list of the studies that investigated the association between low T3 and cardiovascular disease in CKD disease are presented in the Table 1. 5. Thyroid hormone replacement and cardiovascular outcomes In healthy individuals and those with CKD, the thyroid hormones have very important roles on not only the cardiovascular system but also on lipid, carbohydrate, protein, mineral and oxygen-energy metabolism [23,48]. Thus, treatment of thyroid dysfunction using replacement therapy may help to overcome the deleterious effects of thyroid disease [85,86]. Thyroid replacement therapy leads to an improved lipid profile and decreased body fat mass but also causes positive cardiac chronotropy as an unwanted outcome [89]. Thyroid hormone mimetics (thyromimetics) are synthetic analogues of thyroid hormones with tissue-specific
Table 1 Associations of low T3 with cardiovascular disease in CKD patients. Study
Patients (n)
Determinant
Potential mechanistic factors
Tatar et al. [11]
HD (137)
CA-IMT c-f PWV
Tatar et al. [12]
PD (57)
Yilmaz et al. [26]
CKD stage 3e4 (217) HD (190) PD (44)
Augmentation index SEVR Flow-mediated vasodilation LV systolic function LV mass LV systolic function
Inflammation (CRP) Endothelial dysfunction Inflammation (CRP) Endothelial dysfunction Endothelial dysfunction (nitric oxide system) Inflammation (CRP, interleukin-6)
Zocali et al. [27]
Kang et al. [88]
PD (51)
No
CKD: chronic kidney disease; CA-IMT: carotid arteryeintima media thickness; c-f PWV: carotid-femoral, HD: haemodialysis; PD: peritoneal dialysis; PWV: pulsewave velocity; LV: left ventricular; SEVR: subendocardial viability ratio.
thyroid hormone actions [89,90]. They selectively bind to TR-
b receptors and decrease LDL-C and lipoprotein (a) levels without adversely affecting cardiac chronotropy [90]. However, there are no data on the effect of thyromimetics in the CKD population. Thyromimetics may be beneficial in this patient population considering the high prevalence of thyroid dysfunction and hyperlipidaemia. However, to determine the exact mechanism and potential benefits of hormone replacement therapy, future studies are warranted. In conclusion, abnormal thyroid hormone metabolism is commonly observed in CKD patients and has been shown to increase cardiovascular and overall morbidity and mortality. Studies have indicated a role for thyroid dysfunction in atherosclerosis and AS in the CKD population. Most likely, thyroid hormone has direct and indirect mechanistic effects on the cardiovascular system, contributing to these disorders. Future studies providing further insight into thyroid hormone-related cardiovascular disease may provide more data. Additionally, the outcome data from interventional studies that correct thyroid dysfunction seem promising but still remain limited. Conflict of interest All authors confirm that this work is original and all authors meet the criteria for authorship, including acceptance of responsibility for the scientific content of the manuscript. The authors declare no conflict of interest. References [1] Vanholder R, Massy Z, Argiles A, et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 2005;20: 1048e56. [2] Van der Zee S, Baber U, Elmariah S, et al. Cardiovascular risk factors in patients with chronic kidney disease. Nat Rev Cardiol 2009;6:580e9. [3] Kato A, Takita T, Maruyama Y, et al. Impact of carotid atherosclerosis on longterm mortality in chronic hemodialysis patients. Kidney Int 2003;64:1472e9. [4] Blacher J, Pannier B, Guerin AP, et al. Carotid arterial stiffness as a predictor of cardiovascular and all cause mortality in end-stage renal disease. Hypertension 1998;32:570e4. [5] Drüeke TB, Massy ZA. Atherosclerosis in CKD: differences from the general population. Nat Rev Nephrol 2010;6:723e35. [6] Covic A, Gusbeth-tatomir P, Goldsmith DJ. Arterial stiffness in renal patients: an update. Am J Kidney Dis 2005;45:965e77. [7] Gusbeth-Tatomir P, Covic A. Causes and consequences of increased arterial stiffness in chronic kidney disease patients. Kidney Blood Press Res 2007;30: 97e107. [8] Fassett RG, Driver R, Healy H, et al. Comparison of markers of oxidative stress, inflammation and arterial stiffness between incident hemodialysis and peritoneal dialysis patientsean observational study. BMC Nephrol 2009;10:8. [9] Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697e701. [10] Tatar E, Demirci MS, Kircelli F, et al. Association of insulin resistance with arterial stiffness in nondiabetic peritoneal dialysis patients. Int Urol Nephrol 2012;44:255e62. [11] Tatar E, Kircelli F, Asci G, et al. Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients. Clin J Am Soc Nephrol 2011;6:2240e6. [12] Tatar E, Sezis Demirci M, Kircelli F, et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. Int Urol Nephrol 2012;44:601e6. [13] Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005;67:1047e52. [14] Chonchol M, Lippi G, Salvagno G, et al. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008; 3:1296e300. [15] Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489e99. [16] Kaptein EM, Wilcox RB, Nelson JC. Assessing thyroid hormone status in a patient with thyroid disease and renal failure: from theory to practice. Thyroid 2004;14:397e400. [17] Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996;17:45e63.
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Review
The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease Erhan Tatar*, Fatih Kircelli, Ercan Ok Ege University School of Medicine, Division on Nephrology, 35100 Bornova, Izmir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 May 2012 Received in revised form 31 October 2012 Accepted 31 October 2012 Available online xxx
Accelerated atherosclerosis and arterial stiffness are the two leading causes of increased cardiovascular disease in patients with chronic kidney disease. Dysfunctional thyroid hormone metabolism has been suggested to play a role in atherosclerosis and arterial stiffness. Changes in cardiac contractility and output, myocardial oxygen demand, systemic and peripheral vascular resistance, blood pressure and lipid profile, increased inflammatory burden and endothelial dysfunction may be responsible for thyroid hormone-related cardiovascular disease. This article focuses on the mechanistic insights of this association and provides a concise review of the current literature. Ó 2012 Published by Elsevier Ireland Ltd.
Keywords: Thyroid hormones Triiodothyronine Atherosclerosis Arterial stiffness Chronic kidney disease
Contents 1. 2. 3.
4. 5.
Thyroid hormone and the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone and endothelial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone and atherosclerosis in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Endothelial functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone and arterial stiffness in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone replacement and cardiovascular outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Despite ongoing efforts to reduce the high cardiovascular disease burden in patients with chronic kidney disease (CKD), cardiovascular (CV) morbidity and mortality still remain unacceptably higher compared to the general population. In addition to the traditional CV risk factors, uraemia itself may be a risk factor for CV disease [1,2]. Accelerated atherosclerosis and arterial stiffness (AS) are the two major causes of increased CV disease in CKD patients [3,4]. While the underlying pathophysiological mechanisms of
* Corresponding author. Tel.: þ90 232 3904254. E-mail address: [email protected] (E. Tatar).
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these two diseases are mostly similar (advanced age, diabetes, hypertension mainly due to chronic volume excess, inflammation and dyslipidaemia), they are considered to be two distinct problems [5,6]. In addition to these similarities, arterial calcification and overactivity of the sympathetic nervous and renine angiotensinogenealdosterone systems have been shown to be risk factors for the development and progression of AS; obesity, hyperhomocysteinaemia and hyperuricaemia have been shown to be risk factors for atherosclerosis [6e9]. As a potential novel mechanism, our group has recently reported that dysfunctional carbohydrate and thyroid hormone metabolism may also be responsible for the occurrence and progression of both atherosclerosis and AS [10e12].
0021-9150/$ e see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.068
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CKD patients have a higher rate of thyroid dysfunction compared to the general population [13e15]. This rate excludes hyperthyroid disorders. The prevalence of hyperthyroidism in the CKD population is similar to the general population [16,17]. Dysfunctional thyroid hormone metabolism becomes more prevalent with CKD progression, ranging from 5% to 25% as the stage of kidney disease worsens [13]. Similarly, the presence of low T3 syndrome in CKD patients varies from 20 to 80% (8.2% in CKD1, 10.9% in CKD2, 20.8% in CKD3, 60.6% in CKD4; 78.6% in CKD5) [17e 20]. A study by our group has shown that 71.7% of CKD5 patients have low T3 syndrome [20]. The causes of thyroid dysfunction in CKD patients have not been fully elucidated; however, decreased renal clearance of TRH, TSH and iodine, an increased frequency of autoimmune disorders such as thyroiditis, systemic lupus erythematosus, and type 1 diabetes, metabolic acidosis, retention of organic acids and guanido compounds and inflammation have been suggested to contribute to primary thyroid disorders. Older age, HCV positivity, interferon therapy, exposure to disinfectants containing povidineeiodine and certain drugs (amiodarone, steroids, b-blockers) have also been implicated [17,21,22]. In the non-uraemic population, the effect of thyroid disturbances on the cardiovascular system have been suggested to occur via changes in cardiac contractility and output, myocardial oxygen demand, systemic and peripheral vascular resistance, blood pressure and lipid profile [23]. The data are scarce for uraemic patients, but several lines of evidence indicate a role for increased inflammatory burden and endothelial dysfunction in thyroid hormonerelated cardiovascular disease in this population [24e27]. In this manuscript, we will review the current literature on the effects of thyroid hormones on the cardiovascular system, focussing mainly on the CKD population but also highlighting the data generated from the general population. 1. Thyroid hormone and the heart The effects of dysfunctional thyroid hormone (TH) metabolism on the cardiovascular system have been reviewed elsewhere [23]. Briefly, several mechanisms have been proposed. First of all, the lack of deiodinase activity in cardiac myocytes has been associated with inhibition of the conversion of thyroxine (T4) to triiodothyronine (T3) [28]. T3 is the biologically active form of TH in myocytes. T3 can directly or indirectly affect the heart depending on its binding to nuclear receptors. In the direct pathway, after entering cells, T3 binds to its nuclear receptors (TR-a1, TR-a2, TR-b1 and TRb2) located in the atria and ventricles and exert its effects [29]. T3 also regulates the transcription of some specific cardiac genes (genomic effect) in the cardiac myocytes. Alpha myosin heavy chain, sarcoplasmic reticulum Caþþ-ATPase, Naþ/Kþ ATPase, voltage-gated potassium channels, atrial and brain natriuretic peptide, a-1 adrenergic receptor, and adenine nucleotide transporter 1 are positively regulated by thyroid hormones, and amyosin heavy chain, phospholamban, the Naþ/Caþþ exchanger, thyroid hormone receptor a1, adenyl cyclase V and VI, and guanine nucleotide-binding protein Gi are negatively regulated [30e32]. While TR-a receptors predominantly have contractile (basal heart rate) and electrophysiological functions (ventricular repolarisation) in the heart, TR-b mediates a hormone-induced change in heart rate [29e34]. The indirect effects, or non-genomic effects, of T3 involve extranuclear binding. An example is the effect of T3 on the transport of amino acids, glucose, calcium and other ions [33,35]. These genomic and non-genomic effects are important for TH metabolism in the heart.
T3 also can directly regulate systolic and diastolic function at the receptor level in cardiac myocytes. This regulation is accompanied by an indirect decrease in peripheral vascular resistance, decreased effective arterial filling volume leading to the activation of the renineangiotensinogenealdosterone system, increased renal sodium absorption and eventually increased blood volume. These changes result in increased inotropy, chronotropy, and cardiac output. Additionally, T3 can directly increase cardiac output at the receptor level in cardiac myocytes [33,36,37]. 2. Thyroid hormone and endothelial function The major effects of T3 on the peripheral vascular system are via regulation of vascular resistance and inhibition of atherosclerotic precursors. Vascular smooth muscle cells (VSMCs) play a key role in regulating vascular tonicity and are the direct target of T3, leading to vascular relaxation [38e40]. In experiments, VSMCs have been shown to contain binding regions in the plasma membrane that together with type II iodothyronine deiodinase maintain the intracellular concentration of T3 [39,40]. T3 via its direct effect on secretion of adrenomedullin, a potent vasodilating agent, has been shown to decrease vascular resistance in animal models [41]. Another mode of non-genomic action for T3 is the regulation of levels of ATP, ADP and adenosine, which is a potent vasodilator and antiaggregation molecule, controlled by ecto-50 -nucleotidase [42]. In a study by Bruno et al., T3 has been shown to interact with ATP diphosphohydrolase, affecting the physiological maintenance of ADP, and 50 -nucleotidase to induce adenosine-dependant vasodilation [43]. Similarly, T3 has been reported to regulate cyclic ADP-ribose, leading to Caþþ release from ryanodine-sensitive channels [44] and stimulation of intracellular cAMP production [42,44]. In addition, the effects of T3 on nitric oxide (NO) metabolism have been implicated in several experimental and clinical studies [26,45,46]. Activation of the phosphatidylinositol 3-kinase/protein kinase b (PI3K/Akt) signalling pathway has been proposed to lead to NO synthesis in the endothelium and VSMCs [45,46]. 3. Thyroid hormone and atherosclerosis in CKD Hyperlipidaemia, endothelial dysfunction, low-grade inflammation, hypertension and uraemic itself (uraemic toxins, anaemia, renal dystrophy) are associated with advanced atherosclerosis leading to increased cardiovascular morbidity and mortality in CKD patients [3,5,9]. 3.1. Lipid metabolism Abnormalities in lipid metabolism are common in CKD and, in part, can be affected by dysfunctional thyroid hormone metabolism [47e50]. As CKD progresses, these changes become more pronounced. CKD-induced dyslipidaemia is characterised by hypertriglyceridaemia, elevated very-low density lipoprotein (VLDL), a high plasma concentration of lipoprotein remnants, accumulation of oxidised lipids and lipoproteins, a low plasma high-density lipoprotein cholesterol (HDL-C) concentration, and impaired HDL-C maturation and function. Low-density lipoprotein cholesterol (LDL-C) is usually normal or lower than normal but consists of highly atherogenic, small, dense particles [47e50]. Different than the general population, alterations in apolipoprotein metabolism accompany the changes in lipoprotein levels in CKD patients. In renal dyslipidemia, triglyceride-rich apoB-containing lipoprotein levels are frequently increased; often accompanied by increased apoC and E levels. VLDL and IDL are found to have lipoprotein particle B, C and lipoprotein particle- AII, B, C, D, E
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accumulation, respectively. On the other hand, apoA-containing lipoprotein levels, especially AI, are decreased. This leads to the typical apolipoprotein pattern of decreased apoA-I/apoC-III ratio observed in renal patients [50]. As a conclusion, disturbed lipoprotein lipase, hepatic lipase and lecithin cholesterol acyl transferase enzyme metabolism, decreased catabolism and cellular uptake of lipoproteins (due to increased ApoCIII/ApoE ratio) and increased lipoprotein synthesis due to hyperinsulinemia and nutritional changes are held responsible in CKD-induced dyslipidaemia [49,50]. Hyperlipidaemia per se contributes not only to the progression of CKD but also accelerates atherosclerosis [48]. Dysfunctional thyroid hormone metabolism is responsible for a worsening lipid profile in the non-uraemic population [51e53]. This effect is important because abnormal lipid metabolism is an established risk factor for cardiovascular disease [53]. In patients with hypothyroidism, several mechanisms for the effect of thyroid disease on these changes have been proposed but alterations in lipid synthesis and metabolism lie at the core of these mechanisms. Total cholesterol, LDL-C, apolipoprotein B, lipoprotein (a) and triglyceride levels are increased, and HDL-C is decreased. In addition, induction of hepatic hydroxymethylglutaryl coenzyme A reductase expression by thyroid hormones leads to increased cholesterol synthesis. Additionally, a reduced number of LDL cell surface receptors, decreased LDL secretion into the bile and increased cholesterol absorption cause LDL-C accumulation and eventually increased LDL-C oxidation. Furthermore, cholesterol-ester transferase, which is responsible for the transfer of cholesterol from HDL-C to LDL-C and VLDL, decreases. Similarly, the decreased lipoprotein lipase activity observed in hypothyroidic patients causes hypertriglyceridaemia [51,52]. While there is data in the general population on the effects of thyroid hormones, there is scarce data regarding uraemic patients. Liu et al. [54] investigated haemodialysis patients and reported a positive correlation between fT3 and HDL and a negative correlation between fT3 and TG, LDL-C and ApoB, emphasising the importance of the association between thyroid hormones and hyperlipidaemia, hypoalbuminaemia, and hyposelenaemia. A similar finding was observed in a study by our group, in which in a subgroup analysis of 57 peritoneal dialysis (PD) patients, an increase in TSH despite still being in the normal range was associated with an increased triglyceride level and cardiac dysfunction [12].
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hormones likely play an important role in regulating blood pressure in this population. In the subgroup analysis of one study, Enia et al. reported a negative correlation between fT3 and diastolic blood pressure in PD patients (r ¼ 0.50, p ¼ 0.001) [25]. 3.3. Endothelial functions Secondary endothelial dysfunction has been observed in hypothyroid patients [64,65]. Similarly, secondary risk factors for endothelial dysfunction, such as hyperlipidaemia, hypertension, hypercoagulability (decreased fibrinolytic activity, low D-dimer and high plasminogen activator inhibitor-1), have been reported in these patients [66e69]. In addition to these factors, hyperhomocysteinaemia and increased osteoprotegerin were found to be significantly higher in hypothyroid patients than normal controls [70e73]. Hyperhomocysteinaemia has atherogenic and prothrombic effects caused by the induction of smooth muscle proliferation, enhancement of collagen synthesis, increased LDL aggregation, altered binding of tissue plasminogen activator to endothelial tissue and thrombomodulin functions [74e76]. In contrast, osteoprotegerin prolongs VSMC and endothelial cell survival, stimulates proinflammatory cytokines and thus creates an atherosclerotic environment. Additionally, osteoprotegerin causes cardiovascular disease by inducing vascular calcification by mechanisms still to be identified [77e79]. In a cohort of non-diabetic, stage 3e4 CKD patients, Yilmaz et al. reported an association between low T3 and endothelial dysfunction [26]. They suggested that the association between free T3 (fT3) and asymmetric dimethylarginine (ADMA) (an endogenous NO synthase inhibitor) levels might be responsible for the effects of fT3 on vascular beds. ADMA has been shown to be an important contributor to cardiovascular diseases in several studies [80,81]. In a study by our group, we found a strong association between atherosclerosis (determined by carotid arteryeintima media thickness) and fT3 level, suggesting an adaptive mechanism to minimise the energy consumption generated by malnutrition, inflammation, and atherosclerosis (reflected by the close association among fT3 level, CRP and leptin). T3 was an independent predictor of atherosclerosis, suggesting a direct effect on vascular beds [11,54,82]. A list of factors responsible for atherosclerosis in CKD patients and general population with thyroid disturbances are depicted in the Fig. 1. 4. Thyroid hormone and arterial stiffness in CKD
3.2. Blood pressure Thyroid hormones play an important role in regulating blood pressure [55]. Hypothyroidism can cause secondary hypertension in some patients [56]. An increase in diastolic blood pressure is distinctive, but systolic blood pressure may also be increased [57,58]. T3 deficiency may change vascular function and dilation at the cellular level. T3 deficiency leads to increased peripheral vascular resistance, which may be another cause of hypertension [38e40]. The second important mechanism is a decrease in cardiac contractility and output causing decreased glomerular filtration and impaired sodium and water secretion and leading to hypervolaemia [23,59]. Another atherosclerotic effect on vascular beds is due to the renineangiotensinogenealdosterone system [60e63]. The effect of thyroid hormones on the RAAS is via induction of renin synthesis and secretion [60], regulation of angiotensinogen mRNA gene expression in the liver, increased plasma angiotensin II [61,62], decreased AT1R expression and stimulation of AT2R in VSMCs [63]. Despite the lack of a study that directly examined the effect of thyroid hormones on blood pressure in CKD patients, thyroid
Similar to atherosclerosis in most ways, arterial stiffness develops as a result of hypertension, hypervolaemia, arterial
Fig. 1. Atherosclerotic mechanisms in hypothyroidic patients with and without chronic kidney disease.
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calcification, increased oxidative stress, inflammation, overactive sympathetic nervous and renineangiotensinogenealdosterone systems, insulin resistance, and increased lipid oxidation. AS further worsens the cardiovascular profile of these patients and thus is an independent predictor for increased cardiovascular and all-cause mortality [4,83]. Many studies have revealed an association between AS and hypothyroidism in non-uraemic patients [84e86]. In a study by Dagre et al., AS was detected not only in clinically hypothyroid patients but also in those with subclinical findings [82]. They suggested that left ventricular dysfunction and impaired coronary perfusion may be responsible for this outcome. Later, two other studies reported the reversal of AS by T4 replacement therapy due to lowering systolic blood pressure in this patient population [85,86]. Furthermore, Nagasaki et al. proposed that inflammation [C-reactive protein, (CRP)] may be responsible for the association between hypothyroidism and AS and suggested monitoring the CRP level to track improvements in AS [87]. In a study by our group, a low T3 level was associated with increased AS in 113 non-diabetic haemodialysis patients [11]. A similar result was also found in euthyroid PD patients [12]. Although a causal link was not provided in these studies, impaired vascular and cardiac regulation are likely responsible. In this study, an increase in TSH despite being in the normal range was also associated with decreased subendocardial viability (SEVR), which is a validated method for determining oxygen consumption in the subendocardial myocardium. Supporting these deleterious effects, Kang et al. have shown that a high TSH level causes a lower left ventricular ejection fraction, suggesting impaired systolic function in PD patients [88]. Zoccalli et al. confirmed this finding in ESRD patients with a low triiodothyronine level [27]. A list of the studies that investigated the association between low T3 and cardiovascular disease in CKD disease are presented in the Table 1. 5. Thyroid hormone replacement and cardiovascular outcomes In healthy individuals and those with CKD, the thyroid hormones have very important roles on not only the cardiovascular system but also on lipid, carbohydrate, protein, mineral and oxygen-energy metabolism [23,48]. Thus, treatment of thyroid dysfunction using replacement therapy may help to overcome the deleterious effects of thyroid disease [85,86]. Thyroid replacement therapy leads to an improved lipid profile and decreased body fat mass but also causes positive cardiac chronotropy as an unwanted outcome [89]. Thyroid hormone mimetics (thyromimetics) are synthetic analogues of thyroid hormones with tissue-specific
Table 1 Associations of low T3 with cardiovascular disease in CKD patients. Study
Patients (n)
Determinant
Potential mechanistic factors
Tatar et al. [11]
HD (137)
CA-IMT c-f PWV
Tatar et al. [12]
PD (57)
Yilmaz et al. [26]
CKD stage 3e4 (217) HD (190) PD (44)
Augmentation index SEVR Flow-mediated vasodilation LV systolic function LV mass LV systolic function
Inflammation (CRP) Endothelial dysfunction Inflammation (CRP) Endothelial dysfunction Endothelial dysfunction (nitric oxide system) Inflammation (CRP, interleukin-6)
Zocali et al. [27]
Kang et al. [88]
PD (51)
No
CKD: chronic kidney disease; CA-IMT: carotid arteryeintima media thickness; c-f PWV: carotid-femoral, HD: haemodialysis; PD: peritoneal dialysis; PWV: pulsewave velocity; LV: left ventricular; SEVR: subendocardial viability ratio.
thyroid hormone actions [89,90]. They selectively bind to TR-
b receptors and decrease LDL-C and lipoprotein (a) levels without adversely affecting cardiac chronotropy [90]. However, there are no data on the effect of thyromimetics in the CKD population. Thyromimetics may be beneficial in this patient population considering the high prevalence of thyroid dysfunction and hyperlipidaemia. However, to determine the exact mechanism and potential benefits of hormone replacement therapy, future studies are warranted. In conclusion, abnormal thyroid hormone metabolism is commonly observed in CKD patients and has been shown to increase cardiovascular and overall morbidity and mortality. Studies have indicated a role for thyroid dysfunction in atherosclerosis and AS in the CKD population. Most likely, thyroid hormone has direct and indirect mechanistic effects on the cardiovascular system, contributing to these disorders. Future studies providing further insight into thyroid hormone-related cardiovascular disease may provide more data. Additionally, the outcome data from interventional studies that correct thyroid dysfunction seem promising but still remain limited. Conflict of interest All authors confirm that this work is original and all authors meet the criteria for authorship, including acceptance of responsibility for the scientific content of the manuscript. The authors declare no conflict of interest. References [1] Vanholder R, Massy Z, Argiles A, et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 2005;20: 1048e56. [2] Van der Zee S, Baber U, Elmariah S, et al. Cardiovascular risk factors in patients with chronic kidney disease. Nat Rev Cardiol 2009;6:580e9. [3] Kato A, Takita T, Maruyama Y, et al. Impact of carotid atherosclerosis on longterm mortality in chronic hemodialysis patients. Kidney Int 2003;64:1472e9. [4] Blacher J, Pannier B, Guerin AP, et al. Carotid arterial stiffness as a predictor of cardiovascular and all cause mortality in end-stage renal disease. Hypertension 1998;32:570e4. [5] Drüeke TB, Massy ZA. Atherosclerosis in CKD: differences from the general population. Nat Rev Nephrol 2010;6:723e35. [6] Covic A, Gusbeth-tatomir P, Goldsmith DJ. Arterial stiffness in renal patients: an update. Am J Kidney Dis 2005;45:965e77. [7] Gusbeth-Tatomir P, Covic A. Causes and consequences of increased arterial stiffness in chronic kidney disease patients. Kidney Blood Press Res 2007;30: 97e107. [8] Fassett RG, Driver R, Healy H, et al. Comparison of markers of oxidative stress, inflammation and arterial stiffness between incident hemodialysis and peritoneal dialysis patientsean observational study. BMC Nephrol 2009;10:8. [9] Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697e701. [10] Tatar E, Demirci MS, Kircelli F, et al. Association of insulin resistance with arterial stiffness in nondiabetic peritoneal dialysis patients. Int Urol Nephrol 2012;44:255e62. [11] Tatar E, Kircelli F, Asci G, et al. Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients. Clin J Am Soc Nephrol 2011;6:2240e6. [12] Tatar E, Sezis Demirci M, Kircelli F, et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. Int Urol Nephrol 2012;44:601e6. [13] Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005;67:1047e52. [14] Chonchol M, Lippi G, Salvagno G, et al. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008; 3:1296e300. [15] Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489e99. [16] Kaptein EM, Wilcox RB, Nelson JC. Assessing thyroid hormone status in a patient with thyroid disease and renal failure: from theory to practice. Thyroid 2004;14:397e400. [17] Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev 1996;17:45e63.
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Please cite this article in press as: Tatar E, et al., The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease, Atherosclerosis (2012), http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.068