Subclinical Hypothyroidism and the Heart: The Beat Goes On

W hile it is well established that overt hypothyroidism has predictable adverse effects on the heart and cardiovascular system, the changes that accompany subclinical hypothyroidism and the potential response to treatment remain unresolved (1,2). Hypercholesterolemia, diastolic hypertension, abnormal cardiac contractility with left ventricular diastolic dysfunction, and an increase in systemic vascular resistance with impaired endothelial mediated vasodilatation are all present in hypothyroidism to a varying degree (3). Most important is the observation that these modifiable cardiovascular risk factors respond to thyroid hormone replacement (Table 1). The cellular mechanisms for the actions of thyroid hormone on the heart and peripheral vasculature have been well worked out. For most parameters, including cardiac contractility, diastolic blood pressure, and hypercholesterolemia, there is a correlation with the degree of change and the extent of thyroid dysfunction (4). Thus, while subclinical hypothyroidism may indeed not yield overt clinical signs and symptoms from a cardiovascular perspective, it appears to reflect mild and treatable hypothyroidism.

Multiple recent epidemiologic studies have established an increase in cardiovascular morbidity and mortality for patients with subclinical hypothyroidism (5). This is not surprising in view of the fact that diastolic hypertension, hypercholesterolemia, and impaired cardiac contractility are well known cardiovascular risk factors. In addition, Hak and colleagues (6) made the novel observation that autoimmune thyroid disease (Hashimoto's thyroiditis) was also associated with an increase in attributable risk for both atherosclerotic vascular as well as ischemic myocardial disease. Despite this evidence, the consensus review on the treatment of subclinical hypothyroidism did not support a recommendation for thyroid hormone replacement of such patients, partly due to the fact that evidence to support the effectiveness of such therapy had not been established (2). Over the past 10 years, multiple studies have demonstrated that indeed, markers of atherosclerosis, left ventricular diastolic function, cholesterol metabolism, and endothelial mediated vasodilatation are improved with treatment and have the potential to lower cardiac morbidity and mortality. This was recently reviewed by Rodondi and colleagues (5), and in addition, an abstract presented at the International Thyroid Congress in 2010 showed that treatment with levothyroxine was associated with lowered cardiovascular disease disability.

In this context, the article by Traub-Weidinger et al. (7) in this issue of Thyroid takes on added significance. The demonstration that coronary vasoreactivity is altered in patients with thyroid autoimmunity and subclinical hypothyroidism provides an additional pathophysiologic mechanism for these changes. Most important is their finding that diastolic blood pressure, cardiac contractile work, coronary vascular flow, as measured by positron emission tomography, and myocardial vascular resistance are altered with mild thyroid disease and improve with thyrotropin (TSH) normalization.

To further explain their observations, it is important to recognize that triiodothyronine (T₃) exerts both genomic and nongenomic effects on the cardiac myocyte and the vascular smooth muscle cell. Many of the reported changes in blood pressure and systemic vascular resistance of both hyper- and hypothyroidism are explained by the finding that T₃ can act as a direct and novel vasodilator (8). The effects of T₃, in turn, can be mediated through the endothelium via changes in nitric oxide production or at the level of the vascular smooth muscle cell directly (9). Taddei and colleagues (10) showed that impaired endothelial dependent vasodilatation in subclinical hypothyroidism responded to thyroid hormone treatment through alterations in a nitric oxide–mediated pathway. The current finding that coronary flow reserve and myocardial vascular resistance during stress is also altered in subclinical hypothyroidism would likewise suggest impaired nitric oxide function.

With the goal of improving the increased cardiovascular morbidity and mortality associated with subclinical autoimmune thyroid disease, the body of data supports the potential benefit of thyroid hormone therapy with restoration of TSH levels to normal. As suggested previously, the risk of such treatment is indeed minimal, while the potential for clinical benefit is great (11).