Hypothyroidism and Atherosclerosis

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1 /03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(6): Printed in U.S.A. Copyright 2003 by The Endocrine Society doi: /jc 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 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. Abbreviations: CI, Confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); PTCA, percutaneous transluminal coronary angioplasty. 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, compared 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 T 4 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- 2438

2 Cappola and Ladenson Hypothyroidism and Atherosclerosis J Clin Endocrinol Metab, June 2003, 88(6): bodies, and/or TSH greater than 6 mu/liter) and incident ischemic heart disease or mortality in men or women (11). Furthermore, 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. These observations were limited, however, in that hypothyroid individuals were often treated, particularly in this community in which awareness of thyroid dysfunction had been heightened. The most compelling data suggesting a greater cardiovascular risk in patients with subclinical hypothyroidism come from the Rotterdam Study (12). In a cross-sectional analysis of 1149 women aged 55 yr or over, women with subclinical hypothyroidism had a higher prevalence of aortic atherosclerosis on chest radiographs [odds ratio, 1.9; 95% confidence interval (CI), ] and a higher prevalence of myocardial infarction (odds ratio, 2.3; 95% CI, ) than euthyroid women, after adjustment for age, body mass index, high-density lipoprotein (HDL), blood pressure, and smoking status. Each of these odds ratio estimates was even greater in women with the combination of subclinical hypothyroidism and antibodies to thyroid peroxidase (odds ratio, 2.2; 95% CI, for aortic atherosclerosis; and odds ratio, 3.5, 95% CI, for myocardial infarction). 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, suggesting that the increased atherosclerosis was mediated by relative T 4 deficiency rather than immune dysfunction. Serological evidence of autoimmune thyroiditis may have reflected longer duration of preceding hypothyroidism. Over a follow-up of 4.6 yr, 16 women had a first myocardial infarction, giving a statistically insignificant adjusted relative risk of 2.5 (95% CI, ) of myocardial infarction for women with subclinical hypothyroidism relative to euthyroid women. 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, including hypercholesterolemia, hypertension, smoking, and diabetes mellitus. However, 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, myocardial infarction, transient ischemic attack, stroke, or peripheral arterial disease (13). In summary, autopsy data suggest that those with overt hypothyroidism have more atherosclerotic disease. Several case-control studies have also shown higher prevalences of atherosclerotic disorders in small sets of overtly and subclinically hypothyroid patients. However, such studies are highly dependent on selection of an appropriate control group; comparison with a healthier control group could lead to apparently greater atherosclerosis in hypothyroid patients. Larger cohort studies addressing the impact of subclinical hypothyroidism have yielded conflicting results, with the Rotterdam study suggesting an important relationship, whereas the Whickham Survey and Cardiovascular Health Studies have not substantiated this finding. Furthermore, all of these observational studies, both case control and cohort, fail to account for the practices of the treating physicians, who may have been less aggressive in prescribing T 4 therapy to patients with hypothyroidism and known or suspected atherosclerotic disease. In the absence of data about the physicians thyroid testing and T 4 prescribing patterns, the true direction of causality is uncertain. Hypothyroidism and traditional cardiovascular risk factors There is substantial evidence that overt hypothyroidism alters several of the traditional risk factors for cardiovascular disease. These studies support a biologically plausible role for hypothyroidism increasing the risk of atherosclerotic cardiovascular diseases, via increases in circulating levels of highly atherogenic low-density lipoprotein (LDL) cholesterol particles, induction of diastolic hypertension, altered coagulability, and direct effects on vascular smooth muscle. Furthermore, some evidence suggests that hypothyroidism may exacerbate the cardiovascular risks associated with cigarette smoking and insulin resistance. Elevated levels of total cholesterol, LDL cholesterol, and apolipoprotein B are well documented features of overt hypothyroidism (14). Significant progress has been made in clarifying the mechanisms leading to these adverse changes in circulating lipid concentrations. Early studies in humans with hypothyroidism, using isotopically labeled LDL, demonstrated a prolonged half-life of LDL cholesterol because of decreased catabolism, an effect that was reversible with T 4 therapy (15). Additional data in human fibroblasts verified that the T 3 -induced increase in LDL degradation was mediated through an increase in LDL receptor number, without any change in the affinity of LDL for its receptor. A specific effect of thyroid hormone on the LDL receptor was suggested by a lack of T 3 effect on LDL concentration in cultured cells without LDL receptors (16). These findings were supported by an in vivo study in a hypothyroid woman whose receptormediated LDL catabolism was reduced, compared with euthyroid controls, with significant improvement after T 4 replacement therapy (17). Further studies in rats with propylthiouracil-induced hypothyroidism showed a reduction in LDL receptor mrna levels by 50% (18, 19). Molecular mapping has revealed functional thyroid response elements in the promoter region of the LDL receptor. 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, specific stimulation by T 3 of this chimeric gene s activity was observed (20). Furthermore, deletion of the upstream thyroid response elements in the LDL receptor promoter inhibited T 3 -mediated reporter gene activity. Although T 4 therapy in overt hypothyroidism is standard practice, controversy exists regarding the indications for therapy in subclinical hypothyroidism. One rationale for treating subclinical hypothyroidism is to lower levels of LDL cholesterol and thereby decrease atherosclerotic risk. Because the magnitude of the expected effect from treatment of subclinical hypothyroidism is smaller than that from overt hypothyroidism, larger sample sizes are required to detect a

3 2440 J Clin Endocrinol Metab, June 2003, 88(6): Cappola and Ladenson Hypothyroidism and Atherosclerosis treatment effect in clinical trials. Multiple small, randomized trials have been performed examining the effect of T 4 treatment on lipid parameters in subclinical hypothyroidism, with the majority reporting a tendency toward beneficial effects, without achieving statistical significance. Danese et al. (21) have performed a metaanalysis of these data using rigorous criteria to evaluate each study. Data from 247 patients with subclinical hypothyroidism, who were enrolled in 13 studies of T 4 therapy, were included for analysis. Overall, T 4 therapy decreased total cholesterol levels, with different degrees of cholesterol lowering in those with suboptimally treated overt hypothyroidism and those with previously untreated subclinical hypothyroidism. In those with suboptimally treated overt hypothyroidism, a decrease in total cholesterol of 0.44 mmol/liter (17 mg/dl) was seen, whereas those with previously untreated subclinical hypothyroidism demonstrated an average decrease of only 0.14 mmol/liter (5.6 mg/dl) after normalization of TSH levels. The largest treatment effect was evident in those with higher baseline TSH levels and those with higher pretreatment lipid levels. Overall, the average LDL cholesterol declined by 0.26 mmol/ liter (10 mg/dl). Studies have also shown that hypothyroidism causes qualitative changes in circulating lipoproteins that increase their atherogenicity. Two studies have shown that LDL is more susceptible to oxidation in patients with hypothyroidism, with normalization after restoration of the euthyroid state (22, 23). Increased levels of lipoprotein(a) [Lp(a)], a particularly atherogenic LDL variant in which apolipoprotein(a) and apo B are covalently bound, have also been reported in hypothyroidism, compared with euthyroid controls. Several studies have shown decreases in the Lp(a) concentration after T 4 treatment of hypothyroid patients (24 27). However, other reports have not confirmed this relationship (28, 29). Clinical trials have not demonstrated an effect of T 4 on Lp(a) levels in subclinical hypothyroidism (27, 28, 30, 31), with the exception of one trial, which showed a decrease in Lp(a) (32). The inverse relationships between atherosclerotic risk and concentrations of HDL cholesterol and its constituent apoprotein A1 are well known. Some studies have shown that hypothyroidism is associated with a lower HDL cholesterol level. In a report comparing 52 patients with subclinical hypothyroidism and 18 with overt hypothyroidism with 46 euthyroid controls matched for age, sex, and body mass index, Althaus et al. (33) found a significantly lower HDL cholesterol fraction in even the subclinically hypothyroid patients. Caron et al. (34) also reported that the HDL cholesterol level was significantly decreased among 29 women who had subclinical hypothyroidism, compared with 41 euthyroid women matched for age and metabolic parameters. Furthermore, Caron et al. (34) observed a significant increase in the HDL cholesterol level with T 4 therapy, which normalized the serum TSH concentration. However, a controlled trial in which 66 women with subclinical hypothyroidism were randomly assigned to T 4 or placebo treatment found no significant change in either HDL cholesterol or apolipoprotein A1 (30). Additional potentially atherogenic effects of hypothyroidism on lipid metabolism include a reversible reduction in clearance of chylomicron remnants (35); reduced activity of cholesteryl ester transfer protein, which is involved in reverse cholesterol transport pathway (36, 37); and decreased activity of hepatic lipase (38, 39) and lipoprotein lipase (38). Hypothyroidism can also increase cardiovascular risk by causing diastolic hypertension. In one study of 169 women with overt hypothyroidism, the prevalence of hypertension was nearly 3 times higher than in a euthyroid control group (14.8% vs. 5.5%) (40). Euthyroid normotensive patients in another report had an increase in diastolic blood pressure after thyroidectomy-induced hypothyroidism (41), and hypertension was reversed by T 4 treatment. There is less published evidence regarding subclinical hypothyroidism and hypertension. Luboshitzky et al. (42) did observe that mean diastolic blood pressure was higher in 57 women with subclinical hypothyroidism than in 34 euthyroid controls (82 vs. 75 mm Hg; P 0.01). Potential mechanisms for reversible diastolic and systolic hypertension in hypothyroidism include increases in peripheral vascular resistance (43) and arterial stiffness (44), respectively. Vasoconstriction may, in turn, reflect the absence of demonstrated vasodilatory T 3 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). In addition, type II iodothyronine deiodinase has been found in cultured human coronary artery smooth muscle cells and human aortic smooth muscle cells, suggesting a potential direct role of local T 3 on vascular smooth muscle (46). Synergistic effects between smoking and hypothyroidism have been reported. Smokers with overt hypothyroidism have been shown to have higher serum concentrations of total and LDL cholesterol, higher clinical symptom scores, more prolonged ankle-reflex times, and higher creatine kinase concentrations than nonsmokers with hypothyroidism. These differences were noted despite similar concentrations of TSH, free T 4, and triiodothyronine, suggesting that cigarette smoking may impair thyroid hormone action in target tissues (47). Whether to treat subclinical hypothyroidism to reduce risk of future cardiovascular events is controversial. As described above, the strongest evidence for a salutary effect of thyroid hormone therapy is the considerable, if imperfect, demonstration that TSH-normalizing T 4 therapy can lower the LDL cholesterol concentration in many patients with subclinical hypothyroidism, especially those with a serum TSH concentration greater than mu/liter and/or those with suboptimally treated overt hypothyroidism. Practically speaking, it seems advisable to institute a 3-month trial of T 4 therapy in most subclinically hypothyroid patients with coexisting hypercholesterolemia to determine whether their hyperlipidemia can be corrected, and statin therapy, with its more common adverse reactions and greater expense, can be avoided. In contrast, for normocholesterolemic patients with subclinical hypothyroidism, there is currently insufficient epidemiological evidence to recommend thyroid hormone treatment for the sole purpose of reducing cardiovascular risk.

4 Cappola and Ladenson Hypothyroidism and Atherosclerosis J Clin Endocrinol Metab, June 2003, 88(6): Hypothyroidism and newer cardiovascular risk factors In recent years several novel risk factors for atherosclerotic cardiovascular disease have been identified, including hyperhomocysteinemia, elevated C-reactive protein (CRP) levels, coagulation abnormalities, endothelial dysfunction, and insulin resistance. A number of small clinical studies have related these new risk factors to thyroid status. Several studies have demonstrated elevated homocysteine levels in hypothyroidism (48 50), with improvement after T 4 replacement (51 53). This is likely to be caused by impaired renal homocysteine clearance, although an effect of thyroid hormone on enzymes involved in folate metabolism has also been proposed (52, 54). The magnitude of decline in homocysteine levels after T 4 treatment is sufficient to lower cardiovascular risk, with a decrease of 2 5 mol/liter when hypothyroid patients were treated with T 4 to a level suppressing the serum TSH concentration (51, 52, 54). One study of patients with spontaneous hypothyroidism showed a decrease of 4.6 mol/liter on restoring the euthyroid state (53). In contrast, there are now considerable data showing that subclinical hypothyroidism is not associated with hyperhomocysteinemia. Three case-control studies (42, 50, 55) have reported no difference in homocysteine levels between individuals with subclinical hypothyroidism and euthyroid controls. Furthermore, Christ-Crain et al. (50) found no significant change in homocysteine levels after treatment of subclinical hypothyroidism. A recent study has examined the relationship between thyroid status and another newly described risk factor for atherosclerotic disease, CRP, an acute phase protein that circulates in higher concentrations in a variety of acute and chronic disease states. Christ-Crain et al. (50) measured CRP in 61 overtly hypothyroid and 63 subclinically hypothyroid patients and compared them with 40 euthyroid control subjects. CRP levels were significantly higher in both hypothyroid groups, compared with controls. However, CRP levels did not decrease with T 4 treatment of the subclinically hypothyroid patients. The impact of hypothyroidism on vascular and hemostatic risk factors for atherosclerosis has also been investigated in a few studies. Alterations in flow-mediated, endotheliumdependent vasodilatation, which occurs early in atherogenesis, have been noted in patients with hypothyroidism (56). It is uncertain whether this is attributable to a direct effect of thyroid hormone deficiency or mediated through the hypercholesterolemia induced by hypothyroidism (56). Conflicting data exist regarding the effect of hypothyroidism on coagulation. Both increased (57) and decreased (58) platelet adhesiveness have been reported in hypothyroidism. The degree of hypothyroidism may determine its ultimate effects on coagulation parameters (59). In one study comparing moderate (TSH 10 to 50 mu/liter) and severe hypothyroidism ( 50 mu/liter) with the euthyroid state, women with moderate hypothyroidism showed decreased fibrinolytic activity, with lower d-dimer levels, higher 2 -antiplasmin activities, and higher levels of tissue plasminogen activator antigen and plasminogen activator inhibitor antigen. In contrast, those with severe hypothyroidism had higher d-dimer levels, lower 2 -antiplasmin activities, and lower tissue plasminogen activator antigen and plasminogen activator inhibitor antigen levels (59). These results suggest a greater risk for thrombosis, which could precipitate myocardial infarction, in moderate hypothyroidism, and a bleeding tendency in severe hypothyroidism. 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). Although hypothyroidism does not appear to cause insulin resistance (61), Bakker et al. (62) postulated that relatively lower thyroid hormone levels might amplify the increased cardiovascular risk associated with insulin resistance. Their study did confirm that insulin-resistant subjects with high normal TSH levels had higher LDL cholesterol concentrations, whereas among insulin-sensitive individuals, TSH concentration was unassociated with any difference in LDL level. 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. The hypometabolic state of hypothyroidism is known to reduce peripheral oxygen utilization, and the bradycardia and decreased myocardial contractility characteristic of hypothyroidism decrease cardiac work. The normally salutary effects of thyroid hormone, accelerating tissue calorigenesis and exerting positive chronotropic and inotropic effects on the heart, give rise in this setting to concern that replacement therapy could provoke worsening myocardial ischemia. Metabolic and cardiac changes accompanying hypothyroidism also provided the rationale for the earlier practice of thyroid radioablation as a therapy for intractable angina, with reports of improvement in anginal symptoms in 76% of patients in a series of over 1000 patients in the 1950s (63). Of course, 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. Nonetheless, there remains considerable concern about the potential for new cardiac dysrhythmias, heart failure, and/or myocardial infarction when thyroid hormone therapy is instituted in patients with coronary artery disease (64). Furthermore, Bernstein et al. (65) reported that radionuclide cardiac imaging showed impaired coronary vasodilatation in hypothyroid patients, with resulting regional myocardial perfusion defects during exercise in four of six hypothyroid patients without coronary artery disease. Although these investigators observed normalization of regional perfusion after euthyroidism was fully restored, the short-term combination of increased myocardial oxygen consumption and impaired compensatory coronary vasodilatation creates a potentially treacherous scenario at the onset of T 4 replacement. Furthermore, the transition of coagulation parameters from a bleeding tendency in severe hypothyroidism to hypercoagulability in moderate hypothyroidism

5 2442 J Clin Endocrinol Metab, June 2003, 88(6): Cappola and Ladenson Hypothyroidism and Atherosclerosis (as described above) could precipitate acute thrombosis and myocardial infarction (59). There are also factors, however, that could be postulated to lessen myocardial oxygen demand, improve cardiac efficiency, and decrease risk of adverse cardiovascular events when thyroid hormone therapy is instituted. First, as previously noted, hypothyroidism is associated with intense vasoconstriction resulting in increased peripheral vascular resistance and mean arterial pressure. The anticipated reduction in afterload accompanying vasodilatation after thyroid hormone therapy could have a beneficial effect. Second, severe hypothyroidism can cause left ventricular dilatation, lengthening of its end-diastolic and end-systolic dimensions, and an increase in wall tension. Enhancement of myocardial contractility by thyroid hormone would reduce these determinants of preload, the fourth traditional determinant of myocardial oxygen demand. A study employing myocardial positron emission tomography scanning supports the concept that thyroid hormone replacement can have beneficial effects. Although positron emission tomography did confirm a reduction of myocardial oxygen consumption in the hypothyroid state, it also showed an even more substantial decrease in cardiac work, implying lesser cardiac efficiency in the hypothyroid state (66). This relative inefficiency was reversible by T 4 replacement therapy. This improvement in myocardial efficiency with thyroid hormone replacement could lead to a concomitant improvement in anginal symptoms. Uncontrolled clinical studies have shown considerable variability in the clinical responses of hypothyroid patients with angina for whom thyroid hormone replacement is begun. Among 51 patients with hypothyroidism and coexisting angina studied by Levine (67), 13% had excellent control of anginal symptoms on replacement therapy, 54% good control, 26% fair control, and only 8% poor control. Keating et al. (68) reported a series of 1503 patients with hypothyroidism seen at the Mayo Clinic, 55 (3%) of whom had angina at the time of diagnosis. Among these patients with preexisting angina, improvement or no change in symptoms occurred in 84% after thyroid hormone replacement, with worsening of angina in only 16%. Thirty-five patients (2%) without preceding angina developed it after initiation of thyroid hormone therapy. The 1-yr cardiovascular mortality in those with preexisting angina and treated hypothyroidism was 3%, which is actually less than the 9 15% 1-yr cardiac mortality reported for angina patients during the same era (64). Therapy with thyromimetic compounds has even been advocated for euthyroid individuals with atherosclerotic disease, although there are few data to support this approach. In one uncontrolled study, desiccated thyroid was given to 347 patients with documentation of or a high risk for atherosclerosis, 81% of whom were euthyroid before treatment (69). Seventy percent of those with preexisting angina actually reported subjective benefit from desiccated thyroid therapy. Over the 5-yr period of study, 11 patients died, which was 44% of the expected rate from United States life tables. However, there is certainly no body of reliable evidence recommending thyroid hormone therapy for euthyroid individuals with atherosclerotic vascular disease. Recommendations for initiation and titration of T 4 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 T 4 therapy is safe and effective in most patients with ischemic heart disease. There are no data from modern, controlled studies conducted since enhancements in our diagnosis and management of cardiovascular disease, standardization of T 4 preparations, and use of accurate TSH assays for monitoring. Traditionally, the initial recommended dose of T 4 therapy has been g per day, with increases in to 25- g increments at 4- to 6-wk intervals until the serum TSH is in the normal range. If therapy incites worsening angina, a temporary reduction in the T 4 dose should be accompanied by maximization of medical therapy and appropriate consideration of revascularization (64). Revascularization procedures in patients with atherosclerosis and concomitant hypothyroidism For patients in whom medical management of coronary artery disease is no longer sufficiently effective, coronary revascularization may be required. 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. The concerns related to exacerbation of myocardial cardiac ischemia with preoperative thyroid hormone therapy must be weighed against the potential anesthetic, surgical, and other perioperative complications that might be more likely in the hypothyroid state. Particular concerns in hypothyroid surgical patients include heart failure, hypotension, hypoventilation, impaired renal free water excretion and hyponatremia, gastrointestinal hypomotility, sensitivity to medications, hypothermia and absence of a febrile response to sepsis, and vulnerability to neuropsychiatric problems. No randomized trials have been performed to precisely define these potential risks, but several retrospective reviews and case-control studies have addressed these issues. One retrospective review of 18 hypothyroid patients suggested that cardiac ischemia may be induced by preoperative institution of full thyroid hormone replacement therapy, with no perioperative benefit, in comparison with the nonrandomized experience in hypothyroid patients who did not receive preoperative T 4 therapy (70). Three retrospective, 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). In the first, 59 patients with mild to moderate hypothyroidism undergoing major surgery, including but not limited to cardiac surgery, did not have greater perioperative complications than euthyroid individuals undergoing the same surgeries (71). In a second study, 17 hypothyroid patients undergoing cardiac surgery and 34 matched controls were analyzed separately from those undergoing noncardiac surgery (72). Among the cardiac surgery patients, there were no detectable differences in the frequencies of perioperative myocardial infarction and cardiac arrhythmias between the hypothyroid and euthyroid groups (29 vs. 38%, P NS). Congestive heart failure was reported as a more frequent postoperative complication in the hypothyroid patients (29 vs. 6%, P 0.05) along with slow anesthetic recovery (14 vs. 0%, P 0.05), lower likelihood of postoperative fever (59 vs. 100%,

6 Cappola and Ladenson Hypothyroidism and Atherosclerosis J Clin Endocrinol Metab, June 2003, 88(6): P 0.001), and more common occurrence of gastrointestinal symptoms (31 vs. 0%, P 0.02). A third, smaller, case-control study showed no difference in postoperative complications between 10 hypothyroid patients and 30 control patients undergoing cardiovascular surgery (73). All of these studies comparing surgical outcomes between treated and untreated hypothyroid patients or euthyroid controls should be interpreted with caution. Some of the reported differences in clinical outcomes, and the lack of others, could be secondary to treatment biases by physicians and surgeons, 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. Nevertheless, based on the data available, it appears that contemporary cardiac surgery need not be delayed for thyroid hormone replacement. In hypothyroid patients there appear to be an excess only of complications that can be anticipated and prevented or managed effectively when they arise. 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. In one study examining the post-ptca course of patients with hypothyroidism, no differences in successful outcomes, early reocclusions, or complications were detected between those with hypothyroidism and euthyroid individuals (74). In addition, those with hypothyroidism who underwent PTCA had fewer complications when compared with a historical cohort of hypothyroid patients who had undergone coronary artery bypass. A second study retrospectively compared 44 subclinically hypothyroid patients with euthyroid controls undergoing PTCA (75). These investigators also confirmed that subclinical hypothyroidism did not appear to be a risk factor for procedural failure, significant morbidity or increased mortality. These data suggest that PTCA is a viable option with low morbidity in patients with hypothyroidism who require coronary revascularization. Conclusions For 125 yr, physicians have appreciated that there is a relationship between hypothyroidism and atherosclerosis. Our growing understanding of thyroid hormone s regulation of lipid and homocysteine metabolism, effects on vascular reactivity and blood pressure, and modulation of other atherosclerotic factors now provide partial explanations for how hypothyroidism predisposes patients to cardiovascular disease. In addition to this pathogenic relationship, 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. Despite these advances, today s clinicians managing patients with hypothyroidism and atherosclerosis are still guided more by medical folklore than evidencebased medicine. 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. In the decade ahead, development of thyromimetic compounds capable of selectively regulating lipid metabolism and specific aspects of cardiovascular function could permit endocrinology and metabolism to make greater contributions to clinical practice in this field. Acknowledgments Received March 6, Accepted March 18, Address all correspondence and requests for reprints to: Anne R. Cappola, M.D., Sc.M., Division of Endocrinology, Diabetes, and Metabolism, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 932 Blockley Hall, 423 Guardian Drive, Philadelphia, Pennsylvania acappola@cceb. med.upenn.edu. References 1. Greenfield WS 1878 Autopsy findings in a 58 year old woman with myxoedema. Published as an appendix to Ord WM Med Chir Trans 61:57 2. Kocher T 1883 Ueber Kropfexstirpation und ihre Folgen. Arch Klin Chir 29: Vanhaelst L, Neve P, Chailly P, Bastenie PA 1967 Coronary artery disease in hypothyroidism. Observations in clinical myxoedema. Lancet 2: Steinberg AD 1968 Myxedema and coronary artery disease a comparative autopsy study. Ann Intern Med 68: Gaspar IA 1968 Postmortem observations on the thyroid in atherosclerosis. J Am Geriatr Soc 16: Becker C 1985 Hypothyroidism and atherosclerotic heart disease: pathogenesis, medical management, and the role of coronary artery bypass surgery. 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