The most important finding of our study is that abnormal thyroid function, whether present at baseline or developing in follow-up, is a significant independent prognostic factor in patients with moderately symptomatic HF and EFs ≤35%. Treatment for hypothyroidism, which was present in almost 11% of the patients at baseline, did not reduce or eliminate the adverse prognostic effects of this abnormality. Abnormal thyroid function was not associated with the severity of HF and did not have any discernible influence on left ventricular function over time.
The American College of Cardiology and American Heart Association HF guidelines (3
) support performing thyroid function tests in patients with HF, especially measurement of TSH, in recognition that both hyperthyroidism and hypothyroidism can be primary or contributory causes of HF. The Heart Failure Society of America guideline (14
) recommends that for patients suspected of having HF, evaluation of thyroid disorder should be part of the standard laboratory tests. They further note that because up to 20% of patients hospitalized for decompensated HF are already being treated for thyroid disease, evaluation of their thyroid therapy is recommended.
However, both the American College of Cardiology and American Heart Association and the Heart Failure Society of America recommendations are based largely on consensus agreement rather than from evidence from large randomized placebo-controlled clinical trials.
Studies tracking outcome as a function of thyroid status in cardiovascular disease have reported vastly disparate results. An observational study, the Framingham Heart Study, examining 4,331 patients, found no link between subclinical abnormal TSH levels and an increased risk for cardiovascular disease or mortality (7
). Different findings were observed in another community-based prospective 4-year study of 2,730 men and women aged 70 to 79 years (8
). Compared with euthyroid adults, this study found that people with moderate or severe subclinical hypothyroidism had a 2-fold to 3-fold increased risk for congestive HF events, both incident and recurrent. This association between significant thyroid abnormality and HF events was supported by a study performed by Gencer et al. (15
). The individual data analysis of 25,390 participants from 6 prospective cohorts from the United States and Europe showed that the risks for HF events, mainly related to hospitalizations, were increased with both higher and lower TSH values, particularly for TSH >10 mIU/l and TSH <0.10 mIU/l.
Also demonstrating that patients with subclinical hypothyroidism differed from euthyroid subjects, Tseng et al. (16
) found that subclinical hypothyroidism was associated with an increased risk for all-cause and cardiovascular mortality in adults. They collected data on 115,746 adult Taiwanese with subclinical hypothyroidism from 4 private nationwide health screening centers in Taiwan from 1998 to 1999. They showed that after adjustment of cardiovascular disease risk factors, the subjects had a 30% increase in the relative risk for all-cause mortality and a 68% increase in the relative risk for cardiovascular disease death.
Examining the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction, Walsh et al. (17
) found an increased risk for coronary artery disease in patients with subclinical hypothyroidism, even after controlling for age and sex. The relationship remained after further adjustment for standard cardiovascular risk factors. Because coronary artery disease is arguably the most common etiology of HF, the potential contribution of thyroid abnormality to the development of HF is evident.
Probably the most consistent and tightest link between thyroid abnormality and cardiovascular disease is found between hyperthyroidism and the development of AF. Heeringa et al. (10
) found in a population-based study in the elderly that those in the lowest quartile of the normal range of serum TSH had an almost 2-fold increased risk for AF compared with those who were in the highest quartile.
There are a couple of possible reasons why our study did not show a link between thyroid abnormality and AF. First, the percent of our population with evidence of hyperthyroidism, at baseline plus new onset, was small (5.0%), and among these patients, AF was a relatively rare occurrence (18 cases). Second, clinically overt hyperthyroidism, a recognized prominent risk factor for AF (6
), was present in only 0.4% of our population.
One arm of SCD-HeFT was treatment with amiodarone. This therapy is well known to be associated with the development of thyroid abnormality because of its high iodine content. It can be the cause of primary hypothyroidism, which occurs more frequently in women than in men (in a 1.5:1.0 ratio) or can cause hyperthyroidism. In the United States, approximately 2% of patients receiving long-term treatment with amiodarone develop hyperthyroidism, and about 22% develop hypothyroidism (18
). Despite this increased incidence of biochemical thyroid abnormality, patients are usually clinically euthyroid. However, because certain signs of hypothyroidism, such as bradycardia, are among the features expected secondary to the pharmacological action of the drug, clinically, we may be underrecognizing evidence of thyroid disease. With the use of amiodarone, periodic surveillance over the course of treatment for potential side effects, including thyroid abnormality, is recommended. It is important to state that although thyroid abnormality was more likely to be associated with patients taking amiodarone, it was the state (in particular hypothyroidism) that portended a worse prognosis. Hypothyroidism in our study also carried a higher relative risk for death when present in patients not on the drug.
The “low-T3 syndrome” (19
) is a profile of low serum triiodothyronine (T3), normal thyroxine (T4), and normal TSH that can be seen in acute or chronic illness and can be induced by weight loss due to chronic caloric restriction. In experimental animal studies (19
), the low-T3 syndrome leads to the same changes in cardiac function (decreased maximal rate of contraction and relaxation) and gene expression (alteration in myosin heavy chain isoform expression) as does primary hypothyroidism. Although hypothesized as a potentially beneficial response by way of energy conservation in patients with nonthyroidal illnesses, 1 study (20
) found the syndrome to be a strong predictor of death in patients with cardiac disease. In this study, the findings were independent of treatment with amiodarone, a drug with a known ability to reduce T3 serum concentration. Only TSH levels were collected in SCD-HeFT, so the prevalence of the low-T3 syndrome and its effects could not be examined. We may have underestimated the potential effect of thyroid abnormality in our cohort by not considering this “hypothyroid-like equivalent.”
Patients on TRT did not fare better than those not on TRT, although caution must be used in interpreting results of any nonrandomized therapy comparison, especially in a small subgroup. Whether treatment of hypothyroidism will affect mortality risk or HF events in patients with HF requires a prospective study. To date, no such large randomized controlled trial has been conducted. A similar call for an appropriately powered randomized controlled trial of replacement therapy was echoed by Razvi et al. (21
), who, using the United Kingdom General Practitioner Database, recently found that treatment of subclinical hypothyroidism was associated with fewer ischemic heart disease events and all-cause mortality in younger (age ≤70 years) patients. Gencer et al. (15
) believed that their study showing the values associated with the highest risk for HF events may be useful in defining the threshold for treatment among patients with thyroid dysfunction. Nevertheless, they pointed out the limitations of using this approach and recommended caution in making clinical decisions based only on observational studies.
The single-lead ICD arm of SCD-HeFT had significantly lower mortality compared with the placebo and amiodarone arms. The benefits experienced by patients with ICDs were not affected by thyroid dysfunction.
Last, and not unexpectedly, diabetes was associated with increased risk for new hypothyroidism in our study. This well-established cardiovascular risk factor has been proposed as possibly playing a role in the mechanism of the increased cardiovascular disease risk linked to this subset (15
). Our analysis agrees with a recent study of Tseng et al. (16
) showing that even after adjusting for known mortality predictors, including diabetes, the increased relative risk for death associated with thyroid abnormality persisted.
Study limitations include the relatively small percent of patients with hyperthyroidism. Variation in TSH values, related to the time the sample is obtained and the type of assay used, has been reported. Neither was standardized across centers or countries in SCD-HeFT. The low-T3 syndrome, defined after SCD-HeFT was completed, could not be identified with the available data from this trial, because only TSH values were recorded. We may have underestimated the mortality associated with thyroid abnormality.
Only the first abnormal thyroid change during the trial was analyzed. We therefore cannot comment on the number of patients whose thyroid function may have normalized spontaneously or the number who progressed to overt hypothyroidism or hyperthyroidism. Changes from hypothyroid state to hyperthyroid state and vice versa over time can be seen with continued use of amiodarone. In addition, drug-induced hyperthyroidism can vary directly with the duration of amiodarone treatment (22
). The length of follow-up, although extensive, may have limited the number of patients with hyperthyroidism observed. The effort, by trial design, to provide consistent dosing for all amiodarone patients in the study may have limited our ability to find any relationship between amiodarone dose and abnormal thyroid function.
Our findings in patients with moderately symptomatic HF with EFs ≤35% highlight the need for careful consideration and monitoring of these patients with abnormal thyroid function. They have a worse prognosis. A recent study found that treatment improved outcomes in ischemic heart disease events and all-cause mortality in younger patients with subclinical hypothyroidism (21
). However, prospective randomized controlled clinical trials in patients with HF and abnormal thyroid function are lacking.