In this large, population-based study of older adults, subclinical hypothyroidism was associated with a moderately elevated risk of HF among older adults with TSH≥10.0 mU/L, consistent with another large cohort study of older individuals(10
). The risk of CHF was not increased among the high proportions of older adults with TSH levels between 4.5 and 9.9 mU/L or among those with TSH<0.45. Adverse alterations in two echocardiographic measurements, peak E velocity at baseline - an echocardiographic measurement of diastolic function associated with HF in this cohort sample and previous CHS analysis(14
) - and increase in left ventricular mass over 5 years, were also found exclusively in the subgroup of subclinical hypothyroidism with TSH≥10.0 mU/L.
To our knowledge, only one previous population-based prospective study directly examined the relationship between subclinical hypothyroidism and HF events, and found that adults aged 70–79 with TSH≥7.0 mU/L had a higher risk of HF (HR: 2.88, 95%CI 1.39–5.99) in multivariate analysis compared to euthyroid participants, with a more pronounced risk in those with TSH≥10 (HR 3.10, 95%CI: 1.30–7.39), and no increased risk in those with TSH 4.5–6.9(10
). Possible explanations for the weaker point estimate found in CHS as compared to the Health, Aging, and Body Composition (Health ABC) Study include differences in the study population that was mainly white in CHS (40% were black in Health ABC), younger mean age (72.6 vs. 74.7), different length of follow-up (12 vs. 4 years), no upper TSH cut-off in Health ABC analysis (1% with TSH≥20) and less precision due to lower power in the Health ABC. In the present study, the fact that HF risk was limited to participants with TSH≥10 who were not taking thyroxine, with a HF risk similar to the euthyroid group under thyroxine replacement, strengthens the case for a potential causal relationship, which could only be definitively proven by RCTs. Potential mechanisms for the impact of thyroid dysfunction on HF may be related to the effects of thyroid hormones on the heart(5
), notably by the regulation of genes coding for cardiac proteins(5
). Overt hypothyroidism also alters cardiovascular function(24
For most echocardiographic measurements, we found no significant differences for subclinical hypothyroidism or hyperthyroidism compared to euthyroidism, in contrast to several non population-based studies(6
), but consistent with other population-based studies(28
). Several explanations exist for these discrepant findings, including the age of the underlying study population and the degree of subclinical thyroid dysfunction(8
). All of these previous studies had insufficient sample sizes with subclinical hypothyroidism (n=8–66 as compared to 474 in the present study) to investigate different TSH cutoffs(7
), and none linked abnormalities in the surrogate echocardiographic markers with HF events(8
). Indeed, our participants with subclinical hyperthyroidism demonstrated some differences in baseline echocardiographic measurements, but no increase in HF events, suggesting that these echocardiographic abnormalities, while statistically significant, do not result in HF. In our cohort, those with TSH≥10.0 had a higher peak E velocity at baseline, an echocardiographic measurement of diastolic function that was associated with incident HF in this cohort sample and previous CHS analysis(14
). The higher early diastolic filling velocity we found in participants with TSH≥10 may reflect increased left atrial pressure and diastolic dysfunction from more marked subclinical hypothyroidism. Some small RCTs have been performed that have shown improvement in echocardiographic measures of cardiac function(30
), supporting our findings of reduction of risk of HF after thyroxine initiation.
Limitations and Strengths
Among limitations, our data may not be generalizable to younger age groups and it has been suggested that there may be age differences in the associations between subclinical thyroid dysfunction and adverse outcomes(33
). Thyroid function testing was performed at a single point in time, which is a limitation of all published observational cohorts(10
). Our power was limited in those with TSH≥10, as this group was small. Our echocardiographic findings could be affected by multiple comparisons and missing data for 5-year and incident HF echocardiograms; we could not definitively conclude on the type of cardiac dysfunction (systolic or diastolic) involved in those with TSH≥10, which needs to be explored in future studies.
These data have a number of strengths: the large, population-based cohort of older adults, designed to examine cardiovascular risk factors; the mean 12-year follow-up; the formal adjudication of HF events; the exclusion of individuals taking thyroxine or other medications that could affect thyroid function testing; and the incorporation of thyroxine use over time analytically(9
). In addition, few large prospective studies have the availability of baseline and follow-up echocardiography data.
Our data suggest that subclinical hypothyroidism with a TSH≥10.0 mU/L represents a potentially modifiable risk factor for HF in older adults, but not subclinical hypothyroidism with moderate TSH levels (TSH 4.5–9.9 mU/L) and subclinical hyperthyroidism. Our study builds on the prior study demonstrating increased HF risk in marked subclinical hypothyroidism(10
), with additional mechanistic support in our study from echocardiographic data and information on reversibility of HF risk with thyroxine replacement. Our findings of a lack of HF risk in the high proportions of older adults with less severe subclinical hypothyroidism are also important, as many patients with TSH levels of 4.5–9.9 mU/L are treated in clinical practice(35
), without consistent evidence to support increased risk without thyroxine replacement and improved risk with replacement(1
). This and previous studies have mostly found no increased cardiovascular risk in subjects with TSH<10(9
), with some conflicting data(11
). Moreover, about 20 % of patients are currently overtreated by thyroxine replacement with an increased risk of subclinical hyperthyroidism that has been associated with atrial fibrillation and increased fracture risk(3
). In aggregate, our findings might help refine a treatment threshold at which clinical benefit would be expected(8
) and demonstrate a subpopulation at risk for a life-threatening condition. Clinical trials should examine the efficacy of screening for and treating subclinical thyroid dysfunction, and assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH levels above 10.0 mU/L.