Subclinical hypothyroidism--just a high serum thyrotropin (TSH) concentration or something else?

It is well recognized that thyroid hormone exerts profound effects upon the heart and cardiovascular system (1). With advances in our understanding of the cellular mechanisms of thyroid hormone on both the heart and vascular smooth muscle cells, it has become increasingly clear why many of the most characteristic signs of thyroid dysfunction are changes in blood pressure, heart rate, systemic vascular resistance,andcardiaccontractility.Treatmentparadigms for patients with both overt thyrotoxicosis and hypothyroidism often use cardiovascular endpoints as well as standard thyroid function testing to assess the response to treatment (2, 3). In essentially every instance, the restoration of the euthyroid state also returns cardiovascular hemodynamics and cholesterol metabolism to normal. Over 18 years ago, in what has become a landmark study by Sawin et al (4), it was first reported that a low serum TSH concentration posed a risk for the development of atrial fibrillation in older persons. At that time, using the definition of subclinical hyperthyroidism as a low serum TSH with normal serum levels of T4 and T3 and the “absence” of symptoms, additional studies confirmed that this was a condition of increasing prevalence, and perhaps, significance. Indeed, it was almost 10 years later that a scientific review was conducted to establish both the guidelines for diagnosis and the evidence-based recommendations for the management of subclinical thyroid disease. That report has been extensively reviewed, and many of those recommendations remain to the present time (5). However, it is recognized that there are many unanswered questions that only more clinical research and prospective randomized trials can definitively address to provide updated guidelines for the management of both subclinical hyperand hypothyroidism. The inability to translate many basic pathophysiological studies of the cellular and molecular mechanisms of thyroid hormone on such measures as cholesterol metabolism, systemic vascular resistance, and cardiac contractility to improvements in clinical outcomes posed a challenge to research in this field. When viewed from a primarily cardiovascular point of view, the notion that either mild hypothyroidism or mild hyperthyroidism is subclinical is problematic (elevated serum cholesterol, impaired endothelial-mediated vasodilation, diastolic hypertension, and impaired left ventricular contractility). As demonstrated by Sawin et al (4), TSH suppression to less than .1 mIU was associated with a 28% cumulative incidence of atrial fibrillation when followed over a 10-year period in patients 60 years of age or older. Indeed, this incidence appears to be even greater than that observed with overt hyperthyroidism (1) and suggests the possibility that long-standing albeit milder degrees of hyperthyroidism were more likely to lead to adverse cardiovascular events. Of interest in that and other studies is the observation that endogenous hyperthyroidism (toxic adenoma, multinodular goiter, or early Graves’ disease) more commonly results in adverse cardiovascular events than occurs with the development of a low TSH due to exogenous (thyroid hormone replacement therapy). In light of our recent understanding that it is T3 and not T4 that is primarily active on both the atrial and ventricular cardiomyocyte, this finding can be better understood. Because hypothyroidism is known to produce a variety of modifiable cardiovascular risk factors such as elevated cholesterol, diastolic hypertension, impaired endothelialmediated vasodilatation, and impaired left ventricular contractility (especially diastolic relation), it seemed quite attractive to suggest that thyroid hormone treatment of all