Subclinical Thyroid Dysfunction and the Heart

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J. Clin. Endocrinol. Metab. 2007 92: 3404-3405, doi: 10.1210/jc.2007-1575

Anne R. Cappola

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Editorial: Subclinical Thyroid Dysfunction and the HeartThere is biological plausibility to the premise that subclinical

thyroid dysfunction may cause adverse cardiac consequences.Thyroid hormone has both inotropic and chronotropic effects, andit is clear from studies of individuals with overt thyroid diseasethat hyperthyroidism leads to increased heart rate, increased car-diac output, and decreased systemic vascular resistance, whereashypothyroidism has the opposite effects (1). In the continuum ofthyroid dysfunction, therefore, it is reasonable to propose that adose-response effect exists, with more subtle cardiac impairmentbeing present in less extreme degrees of thyroid dysfunction.

The key challenges are the measurement of these more subtlecardiac effects and, more importantly, determining their clinicalrelevance. Addressing these issues requires larger numbers ofstudy participants and more precise measurement of the cardiacphenotype than in overt thyroid disease. It also requires carefulconsideration of the age and underlying cardiac status of the pop-ulationstudied.Mildperturbationsincirculatingthyroidhormonelevels could either provide a tipping point for older individualswith marginal cardiac reserve or have negligible effects in the faceof stronger, competing risk factors for cardiac dysfunction.

Multiple studies have examined the relationships between en-dogenous (2, 3) or exogenous subclinical hyperthyroidism (4–6),endogenous subclinical hypothyroidism (7–13), and echocardio-graphic measures of systolic and diastolic function. These datahave consistently shown measurable adverse parameters, such asincreased left ventricular mass index, in subclinical hyperthyroid-ism. There has been greater heterogeneity in studies of subclinicalhypothyroidism. Two studies have shown no difference in leftventricular mass or function between individuals with and with-outsubclinicalhypothyroidism(7,8),and,of theremainingstudiesthat have detected systolic and/or diastolic abnormalities usingechocardiography, no pair of these studies report the same patternof abnormal parameters (9–13).

A related issue is the laboratory assessment of thyroid func-tion and the definition of a normal TSH. Currently, TSH levelsthat define subclinical thyroid dysfunction are outside of pop-ulation reference ranges and imply pituitary “dissatisfaction”with the ambient concentration of thyroid hormone. Given thatthe clinical consequences of these biochemical abnormalities arenot well-defined for the cardiovascular system and there are nodata from large, randomized trials to guide management ofthese conditions (14, 15), another approach is to define a treat-ment threshold at which clinical benefit would be expectedfrom altering thyroid status, rather than aiming to “normalize”levels to reference range in everyone. This is particularly rele-vant given the frequency of overreplacement with thyroid hor-mone in the community, which is a common occurrence due tothe narrow therapeutic window of levothyroxine (16, 17). Toattain greater certainty about gradations of risk and the optimalTSH treatment threshold, it is useful to subdivide the broader

categories of subclinical hyperthyroidism and hypothyroidisminto more extreme (TSH � 0.1 mU/liter, TSH � 10 mU/liter,respectively) or less extreme TSH derangements.

In the current issue of the Journal of Clinical Endocrinology andMetabolism, Iqbaletal. (18)haveexaminedtherelationshipbetweenthyroid status and cardiac function in two analyses of data fromthe Tromsø studies, a series of five health surveys focusing oncardiovascular epidemiology in selected birth cohorts in this Nor-wegian municipality. The first analysis was performed in a sub-group of 2035 men and women in the fourth Tromsø study whohadTSHmeasurementandechocardiography.Thisrepresents thelargest published epidemiological study of the relationship be-tween thyroid function and left ventricular mass index, and itdemonstrates no statistically or clinically significant association,when examined by thyroid function category or in linear models.In this large study, there was a tradeoff between sample size andphenotypic precision because there was no measurement of freeT4 levels in the study group, and echocardiographic measure-ments were determined from only one cardiac cycle. However, ifanything, the thyroid categorization without free T4 levels wouldbe expected to bias results toward positive findings, given theadmixture of subclinical and overt thyroid dysfunction.

The second analysis was performed using data from a nestedcase-control study conducted after the fifth Tromsø study, inwhich there were important refinements of the study subjects’phenotypes: participants’ thyroid function tests had to persistwithin their thyroid categories (subclinical hyperthyroid, euthy-roid, or subclinical hypothyroid) on two occasions separated by 6to 12 months. This requirement is a strength of the study designbecause it minimizes misclassification of thyroid status and im-proves clinical relevance, as practitioners are less interested in thecardiac effects of transient thyroid functional abnormalities. More-over, the echocardiographic technique was more refined, with theinclusion of detailed analyses of diastolic function through pulsedwave tissue Doppler echocardiography, which permits assess-ment of the velocity of a selected myocardial region to providequantitative measures of regional and global ventricular function.Again,noassociationwasfoundbetweenthyroidfunctionalstatusand left ventricular mass index, or with other standard echocar-diographic measures of left ventricular systolic and diastolic func-tion. Using pulsed wave tissue Doppler echocardiography, studyparticipants with persistent subclinical hypothyroidism (definedas a serum TSH level between 3.5 and 10.0 mU/liter with normalfree T4 and free T3 levels) did not differ from the euthyroid groupin any of the measures. However, subjects with persistent sub-clinical hyperthyroidism (defined as a TSH � 0.5 mU/liter andnormal free T4 and free T3 levels) had statistically significantlyhigher global S wave and A wave velocities than the euthyroidgroup, although the magnitude of this difference was only 10%.

What are the clinical implications of these findings? Theoreti-cally, the pulsed wave tissue Doppler echocardiography findingssuggest impaired diastolic function in individuals with subclinicalhyperthyroidism, which could represent the pathophysiologicallink to adverse clinical cardiac events, such as atrial fibrillation (19,

JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.

doi: 10.1210/jc.2007-1575

20).However, theclinical significanceofa10%difference inpulsedtissuewaveDoppler findings isunknown.Furthermore, therewassubstantial overlap in the Doppler measurements between thesubclinically hyperthyroid and euthyroid groups. At the level ofthe individual, therefore, there isunlikely tobeameaningfulcutoffthat would enable a physician to stratify patients who might bemore likely to benefit from treatment to prevent adverse clinicalsequelae.

The lack of echocardiographic findings in individuals with sub-clinical hypothyroidism in this study is somewhat surprising,giventhemanystudiesshowingechocardiographicabnormalities,including some that employed pulsed wave tissue Doppler (12,13). The study of Iqbal et al. (18) has excellent internal validity, withprecise definitions of both the predictors and the outcomes, andgood statistical power. The question then is, how generalizable arethese results? Nearly 8000 subjects were initially screened to obtainthe 66 individuals meeting all inclusion criteria for the subclinicalhypothyroidism arm of the nested case-control study. The meanTSH level of study participants with subclinical hypothyroidismwas5.4mU/liter; theirmeanagewas61yr;andtheywereselectedto have no underlying cardiac disease, including no use of anti-hypertensive medication. For individuals with these characteris-tics, the data suggest that there are no adverse effects of persistentsubclinical hypothyroidism on cardiac function. In other studiesthat includedparticipantswithhighermeanserumTSHlevelsandyounger age, there were measurable differences in echocardio-graphic parameters between subclinically hypothyroid and eu-thyroid subjects (9–13). This discrepancy highlights the impor-tance of refining the “at risk” population and the need to linkabnormalities in these surrogate echocardiographic markers withadverseclinicalcardiacevents,suchascongestiveheartfailure(21).

Whether to treat individuals with subclinical thyroid dysfunc-tion remains problematic. Large, definitive randomized clinicaltrials of individuals with subclinical hyperthyroidism and sub-clinical hypothyroidism are ultimately the only way to fully ad-dress this controversy. In the absence of such data, clinical studiessuch as the Tromsø study should be conducted with the goal ofcharacterizing the appropriate target populations for these trialsand quantifying the expected benefits, cardiac or otherwise, thatthese specific subpopulations would be expected to receive fromtreatment.

Anne R. CappolaDivision of Endocrinology, Diabetes, and MetabolismCenter for Clinical Epidemiology and BiostatisticsUniversity of Pennsylvania School of MedicinePhiladelphia, Pennsylvania 19104-6021

Acknowledgments

Received July 16, 2007. Accepted July 20, 2007.Address all correspondence and requests for reprints to: Anne R. Cappola,

M.D., Sc.M., Division of Endocrinology, Diabetes, and Metabolism, Center forClinical Epidemiology and Biostatistics, University of Pennsylvania School ofMedicine, 718 Blockley, 423 Guardian Drive, Philadelphia, Pennsylvania19104-6021. E-mail: acappola@mail.med.upenn.edu.

Disclosure Statement: The author has nothing to disclose.

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.

Cappola • Subclinical Thyroid Dysfunction and the Heart J Clin Endocrinol Metab, September 2007, 92(9):3404–3405 3405

Subclinical Thyroid Dysfunction and the Heart

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