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The Journal of Clinical Endocrinology & Metabolism 88(6):2438 –2444 Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-030398

Hypothyroidism and Atherosclerosis
ANNE R. CAPPOLA
AND

PAUL W. LADENSON

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Division of Epidemiology, Center for Clinical Epidemiology and Biostatistics (A.R.C.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and Division of Endocrinology and Metabolism, Department of Medicine (P.W.L.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

“There was edema of the skin. . . much serous effusion in the pericardium. . . the heart was large. . . the arteries were everywhere thickened, the larger ones atheromatous.” (1) [Dr. William Smith Greenfield, 1878] This autopsy finding of diffuse atherosclerosis in a 58-yrold woman was published as an appendix to William Ord’s classical description of the syndrome of myxedema. Soon thereafter, the hypothesis of a causal relationship between hypothyroidism and atherosclerosis was first raised in 1883 by E. Theodor Kocher (2), who noted that arteriosclerosis commonly occurred after thyroid extirpation. Since the time of the first associations between these two common disorders, hypothyroidism and atherosclerosis have subsequently been linked by a body of clinical case reports, epidemiological studies, and biochemical observations. The hypothesis of a relationship has subsequently been tested in case-control and cohort studies. Important associations have been identified among hypercholesterolemia, hypertension, and certain newer risk factors for atherosclerosis in individuals with overt hypothyroidism and, in some cases, subclinical hypothyroidism. There have also been clinical observations and trials describing the consequences of treating hypothyroidism in patients with ischemic heart disease and of revascularizing patients with ischemic heart disease who are hypothyroid. These studies are the subject of this commentary.
Case-control and cohort studies

In 1967 the first case-control study by Vanhaelst et al. (3) compared autopsy findings in 25 patients with myxedema with 50 age-matched controls and found a greater prevalence and severity of coronary atherosclerosis in the hypothyroid group. In a subsequent case-control study performed by Steinberg in 1968 (4), women with myxedema had more severe coronary artery disease on autopsy than did agematched women without myxedema. However, this difference was present only between hypertensive cases and controls, with similar degrees of atherosclerosis between normotensive hypothyroid women and normotensive controls. Another autopsy study (5) took the converse approach, examining the thyroid glands of 55 patients who had died of atherosclerotic disease. All of the thyroids were found to have some abnormality, in size or cellular structure, comAbbreviations: CI, Confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); PTCA, percutaneous transluminal coronary angioplasty.

pared with no abnormalities in four controls without atherosclerosis. Although these studies were conducted before the era of TSH testing to confirm the diagnosis of hypothyroidism, they suggested that the relationship between hypothyroidism and atherosclerotic disease exceeded the statistical coincidence of these two common processes (6). Several small case-control studies in living patients have also demonstrated an association between hypothyroidism and atherosclerosis. In a hospital-based study, men and women with a TSH level of 4.0 mU/liter or greater had higher prevalences of coronary artery disease than agematched controls (48% vs. 38% for men and 37% vs. 20% for women), although this was statistically significant only for women (7). In a report of nursing home residents, 56% of 18 patients with subclinical hypothyroidism and 44% of 18 patients with treated hypothyroidism had histories consistent with coronary artery disease, compared with 16% of the 231 euthyroid residents (8). A study of patients undergoing coronary angiography demonstrated that those who had inadequate therapy for hypothyroidism were more likely to have angiographic progression of coronary artery disease than those with adequate replacement (9). However, this study should be interpreted with caution because it is based on only 10 individuals and potentially subject to bias from the practices of referring physicians, who may have been reluctant to increase the dose of T4 in patients with more symptomatic or severe atherosclerotic disease. Several cohort studies have examined the linkage between hypothyroidism and various indicators of atherosclerotic disease in living persons, but all of these have either included or focused exclusively on individuals with subclinical hypothyroidism, which has markedly higher prevalence than overt hypothyroidism. The Whickham Survey, an English population-based cohort study of 2779 men and women, was the first large-scale examination of the relationship between thyroid status and cardiovascular outcomes (10). After five individuals with overt hypothyroidism were excluded, 132 persons with subclinical hypothyroidism were available for analysis. At baseline evaluation, there was no association between subclinical hypothyroidism and a history of ischemic heart disease or major electrocardiogram changes in males or females, but a weak association was present with minor electrocardiogram changes in females in adjusted analyses. In a 20-yr follow-up of the original Whickham Survey, there was no relationship between autoimmune thyroid disease at baseline (defined as hypothyroidism on replacement therapy, presence of circulating antithyroid anti-

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hypertension. high-density lipoprotein (HDL). 2. 1. June 2003. using isotopically labeled LDL.5 (95% CI. Because the magnitude of the expected effect from treatment of subclinical hypothyroidism is smaller than that from overt hypothyroidism. and odds ratio. 19).3– 4.5.7–9. Molecular mapping has revealed functional thyroid response elements in the promoter region of the LDL receptor. 95% CI. 3. Furthermore. particularly in this community in which awareness of thyroid dysfunction had been heightened. controversy exists regarding the indications for therapy in subclinical hypothyroidism. the true direction of causality is uncertain. Furthermore.2–3. smoking. fail to account for the practices of the treating physicians. 95% confidence interval (CI). 2.2) than euthyroid women. These studies support a biologically plausible role for hypothyroidism increasing the risk of atherosclerotic cardiovascular diseases. 95% CI. The most compelling data suggesting a greater cardiovascular risk in patients with subclinical hypothyroidism come from the Rotterdam Study (12). 1. in that hypothyroid individuals were often treated. One rationale for treating subclinical hypothyroidism is to lower levels of LDL cholesterol and thereby decrease atherosclerotic risk. giving a statistically insignificant adjusted relative risk of 2. Each of these odds ratio estimates was even greater in women with the combination of subclinical hypothyroidism and antibodies to thyroid peroxidase (odds ratio. an effect that was reversible with T4 therapy (15). Serological evidence of autoimmune thyroiditis may have reflected longer duration of preceding hypothyroidism. transient ischemic attack. both case control and cohort.org by on July 3. suggesting that the increased atherosclerosis was mediated by relative T4 deficiency rather than immune dysfunction.7–7. and smoking status. 1. and/or TSH greater than 6 mU/liter) and incident ischemic heart disease or mortality in men or women (11). Additional data in human fibroblasts verified that the T3-induced increase in LDL degradation was mediated through an increase in LDL receptor number. Although T4 therapy in overt hypothyroidism is standard practice. via increases in circulating levels of highly atherogenic low-density lipoprotein (LDL) cholesterol particles. induction of diastolic hypertension. autopsy data suggest that those with overt hypothyroidism have more atherosclerotic disease. However. Attributable risk calculations based on this relative risk estimate suggested that the risk conferred by subclinical hypothyroidism was comparable with other known risk factors for coronary artery disease. Further studies in rats with propylthiouracil-induced hypothyroidism showed a reduction in LDL receptor mRNA levels by 50% (18. Larger cohort studies addressing the impact of subclinical hypothyroidism have yielded conflicting results. Elevated levels of total cholesterol. Significant progress has been made in clarifying the mechanisms leading to these adverse changes in circulating lipid concentrations. body mass index. Several case-control studies have also shown higher prevalences of atherosclerotic disorders in small sets of overtly and subclinically hypothyroid patients.4 for myocardial infarction). 1.3 for aortic atherosclerosis. Hypothyroidism and traditional cardiovascular risk factors There is substantial evidence that overt hypothyroidism alters several of the traditional risk factors for cardiovascular disease. When the LDL receptor promoter was linked to a reporter gene and cotransfected with the 1 isoform of the thyroid hormone receptor into a hepatic cell line. women with subclinical hypothyroidism had a higher prevalence of aortic atherosclerosis on chest radiographs [odds ratio. some evidence suggests that hypothyroidism may exacerbate the cardiovascular risks associated with cigarette smoking and insulin resistance. however. there was no significant difference in ischemic heart disease or mortality in a nested case-control study comparing 126 women with antithyroid antibodies and/or TSH concentrations greater than 6 mU/liter with 126 euthyroid controls. altered coagulability. including hypercholesterolemia. without any change in the affinity of LDL for its receptor. 0.9. Furthermore. demonstrated a prolonged half-life of LDL cholesterol because of decreased catabolism. In the absence of data about the physicians’ thyroid testing and T4 prescribing patterns. A specific effect of thyroid hormone on the LDL receptor was suggested by a lack of T3 effect on LDL concentration in cultured cells without LDL receptors (16). 2009 . with the Rotterdam study suggesting an important relationship. and direct effects on vascular smooth muscle. 88(6):2438 –2444 2439 bodies. In a cross-sectional analysis of 1149 women aged 55 yr or over. data from 3678 men and women enrolled in the Cardiovascular Health Study showed no differences between individuals with subclinical hypothyroidism and euthyroid individuals in their prevalences of angina.Cappola and Ladenson • Hypothyroidism and Atherosclerosis J Clin Endocrinol Metab.6 yr. These findings were supported by an in vivo study in a hypothyroid woman whose receptormediated LDL catabolism was reduced. These observations were limited. Over a follow-up of 4. Women with antibodies to thyroid peroxidase in the absence of thyroid function test abnormalities had a similar prevalence of aortic atherosclerosis and myocardial infarction to euthyroid women without antibodies to thyroid peroxidase. comparison with a healthier control group could lead to apparently greater atherosclerosis in hypothyroid patients. larger sample sizes are required to detect a Downloaded from jcem. myocardial infarction. compared with euthyroid controls.1– 4. In summary. 16 women had a first myocardial infarction. deletion of the upstream thyroid response elements in the LDL receptor promoter inhibited T3-mediated reporter gene activity. 95% CI. LDL cholesterol. specific stimulation by T3 of this chimeric gene’s activity was observed (20).1) of myocardial infarction for women with subclinical hypothyroidism relative to euthyroid women. stroke. and apolipoprotein B are well documented features of overt hypothyroidism (14). after adjustment for age.3. who may have been less aggressive in prescribing T4 therapy to patients with hypothyroidism and known or suspected atherosclerotic disease. or peripheral arterial disease (13).2. Furthermore.1] and a higher prevalence of myocardial infarction (odds ratio. Early studies in humans with hypothyroidism. However. blood pressure. whereas the Whickham Survey and Cardiovascular Health Studies have not substantiated this finding.endojournals. and diabetes mellitus. such studies are highly dependent on selection of an appropriate control group. all of these observational studies. with significant improvement after T4 replacement therapy (17). 1.

5%) (40). sex. (34) also reported that the HDL cholesterol level was significantly decreased among 29 women who had subclinical hypothyroidism. in turn. In addition. Althaus et al. whereas those with previously untreated subclinical hypothyroidism demonstrated an average decrease of only 0. Smokers with overt hypothyroidism have been shown to have higher serum concentrations of total and LDL cholesterol. were included for analysis. 28. demonstration that TSH-normalizing T4 therapy can lower the LDL cholesterol concentration in many patients with subclinical hypothyroidism. and hypertension was reversed by T4 treatment. the average LDL cholesterol declined by 0.org by on July 3. 31). Additional potentially atherogenic effects of hypothyroidism on lipid metabolism include a reversible reduction in clearance of chylomicron remnants (35). and body mass index. reduced activity of cholesteryl ester transfer protein. have also been reported in hypothyroidism. and decreased activity of hepatic lipase (38. The inverse relationships between atherosclerotic risk and concentrations of HDL cholesterol and its constituent apoprotein A1 are well known.26 mmol/ liter (10 mg/dl). (21) have performed a metaanalysis of these data using rigorous criteria to evaluate each study. Caron et al. which normalized the serum TSH concentration. Studies have also shown that hypothyroidism causes qualitative changes in circulating lipoproteins that increase their atherogenicity. if imperfect. more prolonged ankle-reflex times. respectively. Overall. T4 therapy decreased total cholesterol levels. Some studies have shown that hypothyroidism is associated with a lower HDL cholesterol level. Euthyroid normotensive patients in another report had an increase in diastolic blood pressure after thyroidectomy-induced hypothyroidism (41). who were enrolled in 13 studies of T4 therapy. compared with euthyroid controls. with the majority reporting a tendency toward beneficial effects. reflect the absence of demonstrated vasodilatory T3 effects on vascular smooth muscle (45) or be the result of a higher circulating noradrenaline level and a decrease in the number of vascular -adrenergic receptors mediating vasodilatation in skeletal muscle (40). with normalization after restoration of the euthyroid state (22. the strongest evidence for a salutary effect of thyroid hormone therapy is the considerable. which is involved in reverse cholesterol transport pathway (36. and higher creatine kinase concentrations than nonsmokers with hypothyroidism. 37). especially those with a serum TSH concentration greater than 10 –12 mU/liter and/or those with suboptimally treated overt hypothyroidism. 29). which showed a decrease in Lp(a) (32). Danese et al. Multiple small. a particularly atherogenic LDL variant in which apolipoprotein(a) and apo B are covalently bound. can be avoided.44 mmol/liter (17 mg/dl) was seen. 30. free T4. In a report comparing 52 patients with subclinical hypothyroidism and 18 with overt hypothyroidism with 46 euthyroid controls matched for age. P 0.6 mg/dl) after normalization of TSH levels. In one study of 169 women with overt hypothyroidism. Luboshitzky et al. and statin therapy. In those with suboptimally treated overt hypothyroidism. (34) observed a significant increase in the HDL cholesterol level with T4 therapy. Practically speaking. Potential mechanisms for reversible diastolic and systolic hypertension in hypothyroidism include increases in peripheral vascular resistance (43) and arterial stiffness (44).01). Several studies have shown decreases in the Lp(a) concentration after T4 treatment of hypothyroid patients (24 –27). suggesting a potential direct role of local T3 on vascular smooth muscle (46). with different degrees of cholesterol lowering in those with suboptimally treated overt hypothyroidism and those with previously untreated subclinical hypothyroidism. 88(6):2438 –2444 Cappola and Ladenson • Hypothyroidism and Atherosclerosis treatment effect in clinical trials. compared with 41 euthyroid women matched for age and metabolic parameters. (33) found a significantly lower HDL cholesterol fraction in even the subclinically hypothyroid patients. There is less published evidence regarding subclinical hypothyroidism and hypertension. Caron et al. without achieving statistical significance. In contrast. As described above. 39) and lipoprotein lipase (38). Downloaded from jcem. Synergistic effects between smoking and hypothyroidism have been reported. type II iodothyronine deiodinase has been found in cultured human coronary artery smooth muscle cells and human aortic smooth muscle cells. Overall. 5. there is currently insufficient epidemiological evidence to recommend thyroid hormone treatment for the sole purpose of reducing cardiovascular risk. These differences were noted despite similar concentrations of TSH. a controlled trial in which 66 women with subclinical hypothyroidism were randomly assigned to T4 or placebo treatment found no significant change in either HDL cholesterol or apolipoprotein A1 (30). a decrease in total cholesterol of 0. However. Furthermore. it seems advisable to institute a 3-month trial of T4 therapy in most subclinically hypothyroid patients with coexisting hypercholesterolemia to determine whether their hyperlipidemia can be corrected. Clinical trials have not demonstrated an effect of T4 on Lp(a) levels in subclinical hypothyroidism (27. suggesting that cigarette smoking may impair thyroid hormone action in target tissues (47). Two studies have shown that LDL is more susceptible to oxidation in patients with hypothyroidism.2440 J Clin Endocrinol Metab. Increased levels of lipoprotein(a) [Lp(a)]. The largest treatment effect was evident in those with higher baseline TSH levels and those with higher pretreatment lipid levels. However. June 2003. with the exception of one trial. the prevalence of hypertension was nearly 3 times higher than in a euthyroid control group (14. 2009 . 23). with its more common adverse reactions and greater expense. other reports have not confirmed this relationship (28. randomized trials have been performed examining the effect of T4 treatment on lipid parameters in subclinical hypothyroidism. 75 mm Hg.8% vs. higher clinical symptom scores. Hypothyroidism can also increase cardiovascular risk by causing diastolic hypertension.endojournals. for normocholesterolemic patients with subclinical hypothyroidism. Vasoconstriction may.14 mmol/liter (5. and triiodothyronine. Whether to treat subclinical hypothyroidism to reduce risk of future cardiovascular events is controversial. (42) did observe that mean diastolic blood pressure was higher in 57 women with subclinical hypothyroidism than in 34 euthyroid controls (82 vs. Data from 247 patients with subclinical hypothyroidism.

and higher levels of tissue plasminogen activator antigen and plasminogen activator inhibitor antigen. 50. heart failure. there are now considerable data showing that subclinical hypothyroidism is not associated with hyperhomocysteinemia. The impact of hypothyroidism on vascular and hemostatic risk factors for atherosclerosis has also been investigated in a few studies. whereas among insulin-sensitive individuals. In contrast. The normally salutary effects of thyroid hormone. 54). 2009 . These results suggest a greater risk for thrombosis. (50) measured CRP in 61 overtly hypothyroid and 63 subclinically hypothyroid patients and compared them with 40 euthyroid control subjects. including hyperhomocysteinemia. Metabolic and cardiac changes accompanying hypothyroidism also provided the rationale for the earlier practice of thyroid radioablation as a therapy for intractable angina. those with severe hypothyroidism had higher d-dimer levels. 55) have reported no difference in homocysteine levels between individuals with subclinical hypothyroidism and euthyroid controls. The magnitude of decline in homocysteine levels after T4 treatment is sufficient to lower cardiovascular risk. although an effect of thyroid hormone on enzymes involved in folate metabolism has also been proposed (52. the transition of coagulation parameters from a bleeding tendency in severe hypothyroidism to hypercoagulability in moderate hypothyroidism Downloaded from jcem. June 2003. A recent study has examined the relationship between thyroid status and another newly described risk factor for atherosclerotic disease. CRP levels did not decrease with T4 treatment of the subclinically hypothyroid patients. coagulation abnormalities. Christ-Crain et al. an acute phase protein that circulates in higher concentrations in a variety of acute and chronic disease states. However. Although hypothyroidism does not appear to cause insulin resistance (61). (62) postulated that relatively lower thyroid hormone levels might amplify the increased cardiovascular risk associated with insulin resistance. and the bradycardia and decreased myocardial contractility characteristic of hypothyroidism decrease cardiac work. with lower d-dimer levels. have been noted in patients with hypothyroidism (56). The degree of hypothyroidism may determine its ultimate effects on coagulation parameters (59). 54). Furthermore. One study of patients with spontaneous hypothyroidism showed a decrease of 4. It is uncertain whether this is attributable to a direct effect of thyroid hormone deficiency or mediated through the hypercholesterolemia induced by hypothyroidism (56). Several studies have demonstrated elevated homocysteine levels in hypothyroidism (48 –50). women with moderate hypothyroidism showed decreased fibrinolytic activity. with reports of improvement in anginal symptoms in 76% of patients in a series of over 1000 patients in the 1950s (63). and lower tissue plas- minogen activator antigen and plasminogen activator inhibitor antigen levels (59). with improvement after T4 replacement (51–53). with a decrease of 2–5 mol/liter when hypothyroid patients were treated with T4 to a level suppressing the serum TSH concentration (51. which could precipitate myocardial infarction. with resulting regional myocardial perfusion defects during exercise in four of six hypothyroid patients without coronary artery disease. Bernstein et al. (65) reported that radionuclide cardiac imaging showed impaired coronary vasodilatation in hypothyroid patients. The hypometabolic state of hypothyroidism is known to reduce peripheral oxygen utilization.org by on July 3. Some studies have shown that the insulin resistance or metabolic syndrome is an independent risk factor for cardiovascular disease even in individuals without diabetes (60). the short-term combination of increased myocardial oxygen consumption and impaired compensatory coronary vasodilatation creates a potentially treacherous scenario at the onset of T4 replacement. 52. 88(6):2438 –2444 2441 Hypothyroidism and newer cardiovascular risk factors In recent years several novel risk factors for atherosclerotic cardiovascular disease have been identified. Both increased (57) and decreased (58) platelet adhesiveness have been reported in hypothyroidism. Of course. in moderate hypothyroidism. (50) found no significant change in homocysteine levels after treatment of subclinical hypothyroidism. compared with controls. Three case-control studies (42. higher 2-antiplasmin activities. CRP levels were significantly higher in both hypothyroid groups. This is likely to be caused by impaired renal homocysteine clearance. Thyroid hormone replacement in patients with known atherosclerosis The management of hypothyroidism in a patient with known or suspected atherosclerotic coronary artery disease presents the clinician with a therapeutic dilemma. CRP. TSH concentration was unassociated with any difference in LDL level. Nonetheless. and insulin resistance. endotheliumdependent vasodilatation. give rise in this setting to concern that replacement therapy could provoke worsening myocardial ischemia. there remains considerable concern about the potential for new cardiac dysrhythmias. Bakker et al.6 mol/liter on restoring the euthyroid state (53). Furthermore. elevated C-reactive protein (CRP) levels. and/or myocardial infarction when thyroid hormone therapy is instituted in patients with coronary artery disease (64). Christ-Crain et al. A number of small clinical studies have related these new risk factors to thyroid status.Cappola and Ladenson • Hypothyroidism and Atherosclerosis J Clin Endocrinol Metab. lower 2-antiplasmin activities. Their study did confirm that insulin-resistant subjects with high normal TSH levels had higher LDL cholesterol concentrations. Although these investigators observed normalization of regional perfusion after euthyroidism was fully restored. Furthermore. endothelial dysfunction. and a bleeding tendency in severe hypothyroidism. In one study comparing moderate (TSH 10 to 50 mU/liter) and severe hypothyroidism ( 50 mU/liter) with the euthyroid state.endojournals. accelerating tissue calorigenesis and exerting positive chronotropic and inotropic effects on the heart. Alterations in flow-mediated. In contrast. which occurs early in atherogenesis. Conflicting data exist regarding the effect of hypothyroidism on coagulation. this relatively primitive approach has been abandoned with improvement in the medical and surgical treatments for coronary artery disease and the greater understanding that even the subclinically hypothyroid state may be associated with increased risk of progressive atherosclerotic disease.

Among 51 patients with hypothyroidism and coexisting angina studied by Levine (67). There are also factors. Seventy percent of those with preexisting angina actually reported subjective benefit from desiccated thyroid therapy. including but not limited to cardiac surgery.endojournals. 6%. One retrospective review of 18 hypothyroid patients suggested that cardiac ischemia may be induced by preoperative institution of full thyroid hormone replacement therapy. the fourth traditional determinant of myocardial oxygen demand. However.05) along with slow anesthetic recovery (14 vs. as previously noted. improve cardiac efficiency. with no perioperative benefit. hypothermia and absence of a febrile response to sepsis. Although positron emission tomography did confirm a reduction of myocardial oxygen consumption in the hypothyroid state. 38%.2442 J Clin Endocrinol Metab. sensitivity to medications. hypotension. coronary revascularization may be required. impaired renal free water excretion and hyponatremia. The 1-yr cardiovascular mortality in those with preexisting angina and treated hypothyroidism was 3%. Downloaded from jcem.to 25. Therapy with thyromimetic compounds has even been advocated for euthyroid individuals with atherosclerotic disease.g increments at 4. did not have greater perioperative complications than euthyroid individuals undergoing the same surgeries (71). 0%. A study employing myocardial positron emission tomography scanning supports the concept that thyroid hormone replacement can have beneficial effects. If therapy incites worsening angina. Thirty-five patients (2%) without preceding angina developed it after initiation of thyroid hormone therapy. 55 (3%) of whom had angina at the time of diagnosis. Among the cardiac surgery patients. but several retrospective reviews and case-control studies have addressed these issues. In a second study. June 2003. there is certainly no body of reliable evidence recommending thyroid hormone therapy for euthyroid individuals with atherosclerotic vascular disease. Three retrospective. and an increase in wall tension. and decrease risk of adverse cardiovascular events when thyroid hormone therapy is instituted. which was 44% of the expected rate from United States life tables. First. P 0.org by on July 3. P NS). controlled studies conducted since enhancements in our diagnosis and management of cardiovascular disease. desiccated thyroid was given to 347 patients with documentation of or a high risk for atherosclerosis. Particular concerns in hypothyroid surgical patients include heart failure. hypoventilation. which is actually less than the 9 –15% 1-yr cardiac mortality reported for angina patients during the same era (64). gastrointestinal hypomotility. No randomized trials have been performed to precisely define these potential risks. and other perioperative complications that might be more likely in the hypothyroid state. P 0. lower likelihood of postoperative fever (59 vs. In one uncontrolled study.05). There are no data from modern. Over the 5-yr period of study. standardization of T4 preparations. with worsening of angina in only 16%. that could be postulated to lessen myocardial oxygen demand. Revascularization procedures in patients with atherosclerosis and concomitant hypothyroidism For patients in whom medical management of coronary artery disease is no longer sufficiently effective. Keating et al. (68) reported a series of 1503 patients with hypothyroidism seen at the Mayo Clinic.5–25 g per day. lengthening of its end-diastolic and end-systolic dimensions. 17 hypothyroid patients undergoing cardiac surgery and 34 matched controls were analyzed separately from those undergoing noncardiac surgery (72). 54% good control. This improvement in myocardial efficiency with thyroid hormone replacement could lead to a concomitant improvement in anginal symptoms. the initial recommended dose of T4 therapy has been 12. with increases in 12. Among these patients with preexisting angina. in comparison with the nonrandomized experience in hypothyroid patients who did not receive preoperative T4 therapy (70). A common dilemma is whether to initiate treatment for hypothyroidism before cardiac surgery or angioplasty or to wait until after restoration of the coronary circulation by the procedure. Enhancement of myocardial contractility by thyroid hormone would reduce these determinants of preload.to 6-wk intervals until the serum TSH is in the normal range. 81% of whom were euthyroid before treatment (69). The anticipated reduction in afterload accompanying vasodilatation after thyroid hormone therapy could have a beneficial effect. surgical. a temporary reduction in the T4 dose should be accompanied by maximization of medical therapy and appropriate consideration of revascularization (64). although there are few data to support this approach. severe hypothyroidism can cause left ventricular dilatation. 2009 . and vulnerability to neuropsychiatric problems. 59 patients with mild to moderate hypothyroidism undergoing major surgery. Recommendations for initiation and titration of T4 replacement therapy in individuals with overt hypothyroidism and either known or suspected atherosclerotic disease have been based less on these older studies than on widespread acceptance of the dogma that starting low and going slow with T4 therapy is safe and effective in most patients with ischemic heart disease. In the first. implying lesser cardiac efficiency in the hypothyroid state (66). there were no detectable differences in the frequencies of perioperative myocardial infarction and cardiac arrhythmias between the hypothyroid and euthyroid groups (29 vs. hypothyroidism is associated with intense vasoconstriction resulting in increased peripheral vascular resistance and mean arterial pressure. improvement or no change in symptoms occurred in 84% after thyroid hormone replacement. Second. and use of accurate TSH assays for monitoring.5. 26% fair control. it also showed an even more substantial decrease in cardiac work. 11 patients died. 88(6):2438 –2444 Cappola and Ladenson • Hypothyroidism and Atherosclerosis (as described above) could precipitate acute thrombosis and myocardial infarction (59). Traditionally. however. and only 8% poor control. 100%. The concerns related to exacerbation of myocardial cardiac ischemia with preoperative thyroid hormone therapy must be weighed against the potential anesthetic. 13% had excellent control of anginal symptoms on replacement therapy. Uncontrolled clinical studies have shown considerable variability in the clinical responses of hypothyroid patients with angina for whom thyroid hormone replacement is begun. Congestive heart failure was reported as a more frequent postoperative complication in the hypothyroid patients (29 vs. matched case-control studies have been performed to address the question of whether patients with untreated hypothyroidism have worse perioperative outcomes than euthyroid individuals (71–73). This relative inefficiency was reversible by T4 replacement therapy.

Clin Sci 29:217–238 16. Brown NF. Will H. J Clin Endocrinol Metab 48:887– 889 17. Pols HA. Hayashi R. and low density lipoprotein receptor in rats. prolactin. the multiple direct and indirect actions of thyroid hormone on cardiac and peripheral vascular functions can complicate management of hypothyroid patients with atherosclerotic coronary disease. Ladenson PW. Wiersinga WM 1998 Effects of triiodothyronine and amiodarone on the promoter of the human LDL receptor gene. development of thyromimetic compounds capable of selectively regulat- Downloaded from jcem. based on the data available. These investigators also confirmed that subclinical hypothyroidism did not appear to be a risk factor for procedural failure. Middleton B. Burke G. Staub JJ. Greenfield WS 1878 Autopsy findings in a 58 year old woman with myxoedema. Endocr Rev 6:432– 440 7. whose decisions regarding how hypothyroidism should affect the threshold for surgery and whether it should have been treated preoperatively in individual patients may have distorted the findings.edu. 2003. Alterations of the metabolism and turnover of 131-I-low-density lipoproteins in hypothyroidism and thyrotoxicosis. In addition. Scott PJ.001). Bastenie PA 1967 Coronary artery disease in hypothyroidism. Weintraub BD 1992 Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin. Atkinson EA. Lupi GA. Aronow WS 2002 Subclinical hypothyroidism is associated with coronary artery disease in older persons. Salter AM. Kocher T 1883 Ueber Kropfexstirpation und ihre Folgen. The improved clinical outcomes for these patients over the past half-century have been principally attributable to advances in cardiovascular medicine rather than endocrine practice. Tunbridge WM. In hypothyroid patients there appear to be an excess only of complications that can be anticipated and prevented or managed effectively when they arise. J Am Geriatr Soc 16:686 – 695 6. Bleackley RC. Bates D. Althaus BU. Division of Endocrinology. Chait A. Sorensen O. June 2003. Auwerx J 1990 Alterations in thyroid status modulate apolipoprotein. 932 Blockley Hall. it appears that contemporary cardiac surgery need not be delayed for thyroid hormone replacement. Chailly P. Becker C 1985 Hypothyroidism and atherosclerotic heart disease: pathogenesis. Ann Intern Med 132:270 –278 13. Perk M. These data suggest that PTCA is a viable option with low morbidity in patients with hypothyroidism who require coronary revascularization. Brewis M. Can J Cardiol 13:273–276 10. Conclusions ing lipid metabolism and specific aspects of cardiovascular function could permit endocrinology and metabolism to make greater contributions to clinical practice in this field. Gutzwiller F. Clark F. physicians have appreciated that there is a relationship between hypothyroidism and atherosclerosis. J Gerontol A Biol Sci Med Sci 57: M658 –M659 9. Center for Clinical Epidemiology and Biostatistics. Hudig F. Powe NR 2000 Clinical review 115: For 125 yr. Wilson MC. and the lack of others. or complications were detected between those with hypothyroidism and euthyroid individuals (74). Ladenson PW. 0%. Sc. and modulation of other atherosclerotic factors now provide partial explanations for how hypothyroidism predisposes patients to cardiovascular disease. Engler H. Thyroid 6:155–160 12. A second study retrospectively compared 44 subclinically hypothyroid patients with euthyroid controls undergoing PTCA (75). 2003. al Seeni M. M. Kronmal R. Pennsylvania 19104-6021.D. Burgi H 1981 Borderline low thyroid function and thyroid autoimmunity. Van Tol A. Am J Med 92:631– 642 15. Drexhage HA. II. Trabucco P. Cappola. Evans JG. 88(6):2438 –2444 2443 P 0. effects on vascular reactivity and blood pressure. Accepted March 18. Marquardt K. and the role of coronary artery bypass surgery. Observations in clinical myxoedema. Appleton D. and metabolic impact on peripheral target tissues.upenn. Proc Natl Acad Sci USA 78:2591–2595 18. Studer H. In addition to this pathogenic relationship. Our growing understanding of thyroid hormone’s regulation of lipid and homocysteine metabolism.org by on July 3. Acknowledgments Received March 6. Tracy R. smaller.02). Danese MD. A third. Verhoeven G. Meijssen S. Address all correspondence and requests for reprints to: Anne R. Myant NB 1981 Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. Ryff AS. Chan L. Tieche M. 423 Guardian Drive. Davies JW 1965 The significance of alterations in serum lipids in thyroid dysfunction. those with hypothyroidism who underwent PTCA had fewer complications when compared with a historical cohort of hypothyroid patients who had undergone coronary artery bypass. today’s clinicians managing patients with hypothyroidism and atherosclerosis are still guided more by medical folklore than evidencebased medicine. O’Neill BJ 1997 The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Biochem J 276 (Pt 3):825– 832 20. 2009 .Cappola and Ladenson • Hypothyroidism and Atherosclerosis J Clin Endocrinol Metab. Clark F. Tunbridge F. Spengel FA. case-control study showed no difference in postoperative complications between 10 hypothyroid patients and 30 control patients undergoing cardiovascular surgery (73). Vanhaelst L. Dykes PW. Thompson GR. Burckhardt D. Tunbridge WM. Gardin J. In the decade ahead. Despite these advances. Fried LP 1994 Relationship of subclinical hypothyroidism to cardiovascular risk factors and disease in an elderly population. Young ET 1996 The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Smith PA 1977 Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. early reocclusions. Vanderpump MP. Bird T. Gavigan SJ. Hofman A. Kuller L. In one study examining the post-PTCA course of patients with hypothyroidism. Thyroid 4:S-18 14. All of these studies comparing surgical outcomes between treated and untreated hypothyroid patients or euthyroid controls should be interpreted with caution. Girard J.endojournals. Witteman JC 2000 Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. P 0. Albers JJ 1979 Regulatory role of triiodothyronine in the degradation of low density lipoprotein by cultured human skin fibroblasts. Bakker O. and more common occurrence of gastrointestinal symptoms (31 vs. Staels B. Meinert CL. Arch Klin Chir 29:254 –337 3. med. and thyroid reserve. Some of the reported differences in clinical outcomes. Published as an appendix to Ord WM Med Chir Trans 61:57 2. Bierman EL. Grob PJ. Grimley EJ. Biochem Biophys Res Commun 249:517–521 21. French JM. hepatic triglyceride lipase. Clin Endocrinol (Oxf) 7:495–508 11. and Metabolism. Walton KW. Evered DC. Bruce J. Lancet 2:800 – 802 4. Philadelphia. Appleton D. Visser TJ.. Steinberg AD 1968 Myxedema and coronary artery disease—a comparative autopsy study. Ann Intern Med 68:338 –344 5. Jadhav A. E-mail: acappola@cceb. Risk factors for coronary heart disease? Br Heart J 46:202–206 8. Diabetes. Gaspar IA 1968 Postmortem observations on the thyroid in atherosclerosis. Neve P. no differences in successful outcomes. Soutar AK. References 1. could be secondary to treatment biases by physicians and surgeons. University of Pennsylvania School of Medicine. significant morbidity or increased mortality. medical management.. Young E. Nevertheless. Mya MM. Brindley DN 1991 Effects of hypothyroidism and high-fat feeding on mRNA concentrations for the low-density-lipoprotein receptor and on acyl-CoA:cholesterol acyltransferase activities in rat liver. Hak AE. Rodgers H. Hall R. Percutaneous transluminal coronary angioplasty (PTCA) is often an attractive alternative to coronary artery bypass surgery in patients with higher operative risk because of associated medical conditions like hypothyroidism.M. Endocrinology 127:1144 –1152 19.

Linde-Sibenius TM. Mokuno T. Akveld MJ. Ratcliffe JG. Gerard P. Stern MP. Riesen W. Nekolla SG. Rosenberg IH 2001 Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third U. Rubinstein A. Smith J. Yeung RT 1986 High-density lipoprotein cholesterol. Herzog R. Prog Cardiovasc Dis 3:364 –381 69.org by on July 3. placebo-controlled trial (Basel Thyroid Study). Klein M. Falko JM 1997 Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. Hussein WI. Chango A. Miserez AR. endothelium-dependent vasodilation is impaired in subjects with hypothyroidism. J Clin Endocrinol Metab 85: 2993–3001 Sundaram V. vitamin B12. Kotake M. J Clin Endocrinol Metab 76:121–126 Martinez-Triguero ML.and hypothyroidism. Ziegler SI. Nakai A. Ridgway EC. Giral P. 88(6):2438 –2444 Cappola and Ladenson • Hypothyroidism and Atherosclerosis 22. Piperingos G. 39. Bagdade JD 1996 The effects of hypothyroidism and replacement therapy on cholesteryl ester transfer. Bengel FM. Selhub J. Meier C. J Clin Endocrinol Metab 86:1845–1846 55. Wiersinga WM 1998 Increased oxidizability of low-density lipoproteins in hypothyroidism. Arch Intern Med 145:1585–1587 74. Saruta T 1994 Hypertension in thyroid disorders. Pluth JR 1981 Thyroxine therapy in hypothyroid patients undergoing coronary revascularization: A retrospective analysis. Morillas C. Drucker DJ. Gaw A. Lasuncion MA 1995 Long-term thyroid replacement therapy and levels of lipoprotein(a) and other lipoproteins. Solem JH 1975 The adhesiveness of human blood platelets and thyroid function. Metabolism 47:89 –93 49. van Barlingen H. Kato R. Lekakis J. Erkelens DW 1993 Lipoprotein(a) and apolipoprotein B plasma concentrations in hypothyroid. Hanley AJ. N Engl J Med 333:964 –969 48. Guglielmetti M. Kutluay T 1996 Lipoprotein(a) concentration in subclinical hypothyroidism before and after levo-thyroxine therapy. Q J Med 59:513–521 Packard CJ. Stamatelopoulos S. Varhaug JE. Sherman SI. Drewe J. Huber P. placebo-controlled trial. Metabolism 46:1128 –1131 58. Mayo Clin Proc 73:837– 841 Becerra A. Gans RO 2001 The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. 29. O’Fallon WM 1983 Outcome of anesthesia and surgery in hypothyroid patients. Bougoulia M 2000 Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment. lipids. Davies JS. Yilmaz K. 33. Jacobsen DW. Guglielmetti M. Atherosclerosis 166:379 –386 51. and high-normal serum thyrotropin (TSH) values. Staub JJ 1995 Impaired action of thyroid hormone associated with smoking in women with hypothyroidism. Hanna AN. Muller B 2003 Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind. J Clin Endocrinol Metab 83:1752–1755 de Bruin TW. Morrisett JD. Clin Endocrinol (Oxf) 33:519 –523 Weintraub M. J Clin Endocrinol Metab 86:1206 –1211 63. Arem N. Weinberg AD. Levin AA.070 patients with angina pectoris or congestive failure. Mantzoros CS. Aakvaag A. Endocrinol Metab Clin North Am 23:379 –386 Fommei E. J Clin Endocrinol Metab 85:1049 –1053 53. Roth CB. Barbe F. Mori M 2001 Thyroid hormone activation in human vascular smooth muscle cells: expression of type II iodothyronine deiodinase. Koneru L. Campbell JA 1958 A correlation of clinical and hemodynamic studies in patients with hypothyroidism. Haffner SM 2002 Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Weniger C. Iervasi G 2002 The role of thyroid hormone in blood pressure homeostasis: evidence from short-term hypothyroidism in humans. 27. 34. Calazel C. Shah JH. Luengo A. Williams GA 1975 Insulin metabolism in hypothyroidism. Summary of results in treatment of 1. Evagelopoulou K. Kung AW 1998 Plasma cholesteryl ester transfer protein activity in hyper.endojournals. Lazarus JH 2002 Increased central arterial stiffness in hypothyroidism. Staub JJ. J Clin Endocrinol Metab 81:797– 800 Tan KC. 38. Lien EA 1998 Plasma total homocysteine levels in hyperthyroid and hypothyroid patients. Segaard E. Ladenson PW. Burrow GN 1985 Cardiovascular surgery in the hypothyroid patient. Grosskopf I. Herer P. Trostanesky Y. Oda N. J Clin Endocrinol Metab 87:4662–4666 Ojamaa K. Am J Med 69:411– 418 68. Thyroid 5:383–387 Downloaded from jcem. 31. Taskinen MR 1993 Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-B metabolism in hypothyroidism. 32. Marsh HM. Hertzenberg L 1995 Silent myocardial ischemia in hypothyroidism. van Vuurst de Vries AR. Alevizaki M. with special reference to lipoprotein(a). Staub JJ. Thyroid 6:505–512 Mizuma H. Sawai Y. Demacker PN. J Clin Endocrinol Metab 76:1209 –1216 Saito I. Kunz M. 44. J Clin Endocrinol Metab 83:140 –143 Lam KS. J Am Geriatr Soc 19:7–22 70. Ladenson PW 1990 Recognition and management of cardiovascular disease related to thyroid dysfunction. Checchia CS. Staub JJ. De Luis DA 1999 Lipoprotein(a) and other lipoproteins in hypothyroid patients before and after thyroid replacement therapy. Muller C. Stern N 1999 Thyroxine replacement therapy enhances clearance of chylomicron remnants in patients with hypothyroidism. Ueland PM 2000 Plasma total homocysteine levels during short-term iatrogenic hypothyroidism. Wren JC 1971 Symptomatic atherosclerosis: prevention or modification by treatment with desiccated thyroid. Atherosclerosis 155:195–200 50. Rubies-Prat J. Ankri A. Nagasaka A.S. Bruckert E. Ueland PM. Gorman CA. Aanderud S. Kurland G 1955 Treatment of incapacitated euthyroid cardiac patients with radioactive iodine. 40. Koutras DA 1997 Flow-mediated. Am J Med 88:638 – 641 65. Heine RJ. 43. and hyperthyroid subjects. 45. Gundogan MA. J Clin Endocrinol Metab 86:4860 – 4866 Caraccio N. Christ-Crain M. Ozata M. Kilinc C. Stahelin HB 1988 LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Moses AC 1995 Outcome of percutaneous transluminal coronary angioplasty in patients with subclinical hypothyroidism. ter Maaten JC. J Clin Endocrinol Metab 86:732–737 60. Gueant JL. Monzani F 2002 Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement. 42. Lavie L 2002 Risk factors for cardiovascular disease in women with subclinical hypothyroidism. Oberhansli A. National Health and Nutrition Examination Survey. effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. Piedrola G. euthyroid. Morris MS. Hayakawa N. Metabolism 44:1559 –1563 Pazos F. Am J Med 90:367–370 75. Circ Res 88:313–318 Muller B. Pena H. 28. Ann Intern Med 95:456 – 457 71. Evans LM. Papagiannes E. Leenhardt L. folate. Duick DS. 30. Shimazaki K. Faiman C 1999 Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Patsch W 1995 Effect of L-thyroxine therapy on lipoprotein fractions in overt and subclinical hypothyroidism. Lindsay GM. van der Put NM. Bakker SJ. and transcobalamins in patients undergoing successive hypo. Murakami M. Thyroid 7:411–414 57. Muenster JJ. Diabetes Care 25:1177–1184 61. 36. Williams K. Hagiwara M. 23. Maloney JD. Selby JB. Smith G. Molina E 1998 Effect of thyroid hormone replacement on lipoprotein(a). Keating F. Mantzos J. Grisson RL. Nygard O. Louvet JP 1990 Decreased HDL cholesterol in subclinical hypothyroidism: the effect of L-thyroxine therapy. Papamichael C. Ann Intern Med 131:348 –351 52.2444 J Clin Endocrinol Metab. 35. Ferrannini E. J Clin Endocrinol Metab 82:3421–3424 Diekman T. Shepherd J. Chadarevian R. Popp-Snijders C. Endocr J 43:731–736 Althaus BU. J Clin Endocrinol Metab 87:1533–1538 Yildirimkaya M. Dickinson L 1961 Treatment of heart disease associated with myxedema. Am J Med 77:261–266 73. Newman HA. hepatic lipase and lipoprotein lipase activities in thyroid dysfunction— effects of treatment. Green R. Escalante DA. John R. Parra HJ. J Clin Endocrinol Metab 85:1822–1827 67. Stalenhoef AF. Hellem AJ. Zulewski H. Ibrahim T. Munoz ML. Varela C. J Clin Endocrinol Metab 87:1996 –2000 Luboshitzky R. Shiu SW. Tijssen JG. J Clin Invest 9:502–510 Obuobie K. Huber P. Vlietstra RE. Arch Intern Med 143:893– 897 72. Diekman MJ. Lien EA. Kastelein JJ. Clin Endocrinol (Oxf) 28:157–163 Caron P. Brennan MD. Krassas GE. Levine H 1980 Compromise therapy in the patient with angina pectoris and hypothyroidism. June 2003. Slaets JP. Lluch I. Vierhapper H 2002 Homocysteine: a risk factor for cardiovascular disease in subclinical hypothyroidism? Thyroid 12:733–736 56. J Clin Endocrinol Metab 80:562–566 Meier C. Masunaga R. Thyroid 5:443– 447 66. Nguyen TT. Deicher R. Schwaiger M 2000 Effect of thyroid hormones on cardiac function. Lorente D. Acta Med Scand 197:15–17 59. and apolipoproteins in subjects with hypothyroidism. a randomized placebo-controlled study. Weryha G. Ericsson UB. Fremont S. Ladenson PW 1991 Percutaneous transluminal coronary angioplasty in hypothyroidism. Daniels GH 1984 Complications of surgery in hypothyroid patients. Konstantinidis T. Nedrebo BG. Alvarez JJ. Jacques PF. Freedberg A. Thyroid 12:421– 425 Graettinger JS. J Clin Endocrinol Metab 84:2532–2536 Ritter MC. Chan MK. Aakvaag A. Diabetes 24:922–925 62.and hyperthyroid states. 25. Klemperer JD. Wiersinga WM 2001 Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism. 46. Blumgart H. 2009 . JAMA 157:1–4 64. Nedrebo BG. Hernandez-Mijares A. Blom HJ. 37. Ryff-De Leche A. Hidaka H 1997 Alteration of platelet aggregation in patients with thyroid disorders. Nicolas JP 2001 Homocysteine. Clin Endocrinol (Oxf) 54:197–204 54. Bernstein R. Hay I. Thyroid 10:803– 808 Arem R. Aviv A. Midtbo K. Huber PR. Hirano E. borderline hypothyroidism. 41. Marafelia P. Klein I 1996 Acute effects of thyroid hormone on vascular smooth muscle. 26. 24. Nygard O. geometry. 47. Bostom AG. Muller B 2001 TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind. Haug E. Bellido D. Motto GS. and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging. Hoff M. Turpin G 2001 Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. Refsum H. Charach G. Parkin T. Kannan CR. Clin Nutr 18:319 –322 Tzotzas T.