Irwin Klein

Thyroid hormone and the cardiovascular system

Thyroid hormone is an important regulator of cardiac function and cardiovascular hemodynamics. Triiodothyronine, (T(3)), the physiologically active form of thyroid hormone, binds to nuclear receptor proteins and mediates the expression of several important cardiac genes, inducing transcription of the positively regulated genes including alpha-myosin heavy chain (MHC) and the sarcoplasmic reticulum calcium ATPase. Negatively regulated genes include beta-MHC and phospholamban, which are down regulated in the presence of normal serum levels of thyroid hormone. T(3) mediated effects on the systemic vasculature include relaxation of vascular smooth muscle resulting in decreased arterial resistance and diastolic blood pressure. In hyperthyroidism, cardiac contractility and cardiac output are enhanced and systemic vascular resistance is decreased, while in hypothyroidism, the opposite is true. Patients with subclinical hypothyroidism manifest many of the same cardiovascular changes, but to a lesser degree than that which occurs in overt hypothyroidism. Cardiac disease states are sometimes associated with the low T(3) syndrome. The phenotype of the failing heart resembles that of the hypothyroid heart, both in cardiac physiology and in gene expression. Changes in serum T(3) levels in patients with chronic congestive heart failure are caused by alterations in thyroid hormone metabolism suggesting that patients may benefit from T(3) replacement in this setting.

Thyroid hormone treatment after coronary-artery bypass surgery.

BACKGROUNDnThyroid hormone has many effects on the cardiovascular system. During and after cardiopulmonary bypass, serum triiodothyronine concentrations decline transiently, which may contribute to postoperative hemodynamic dysfunction. We investigated whether the perioperative administration of triiodothyronine (liothyronine sodium) enhances cardiovascular performance in high-risk patients undergoing coronary-artery bypass surgery.nnnMETHODSnWe administered triiodothyronine or placebo to 142 patients with coronary artery disease and depressed left ventricular function. The hormone was administered as an intravenous bolus of 0.8 microgram per kilogram of body weight when the aortic cross-clamp was removed after the completion of bypass surgery and then as an infusion of 0.113 microgram per kilogram per hour for six hours. Clinical and hemodynamic responses were serially recorded, as was any need for inotropic or vasodilator drugs.nnnRESULTSnThe patients preoperative serum triiodothyronine concentrations were normal (mean [+/- SD] value, 81 +/- 22 ng per deciliter [1.2 +/- 0.3 nmol per liter]), and they decreased by 40 percent (P < 0.001) 30 minutes after the onset of cardiopulmonary bypass. The concentrations in patients given intravenous triiodothyronine became supranormal and were significantly higher than those in patients given placebo (P < 0.001). However, the concentrations were once again similar in the two groups 24 hours after surgery. The mean postoperative cardiac index was higher in the triiodothyronine group (2.97 +/- 0.72 vs. 2.67 +/- 0.61 liters per minute per square meter of body-surface area, P = 0.007), and systemic vascular resistance was lower (1073 +/- 314 vs. 1235 +/- 387 dyn.sec.cm-5, P = 0.003). The two groups did not differ significantly in the incidence of arrhythmia or the need for therapy with inotropic and vasodilator drugs during the 24 hours after surgery, or in perioperative mortality and morbidity.nnnCONCLUSIONSnRaising serum triiodothyronine concentrations in patients undergoing coronary-artery bypass surgery increases cardiac output and lowers systemic vascular resistance, but does not change outcome or alter the need for standard postoperative therapy.

Hypothyroidism as a risk factor for cardiovascular disease

The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The “traditional” risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH>10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels<10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of l-thyroxine outweigh the risk.

Catecholamine-thyroid hormone interactions and the cardiovascular manifestations of hyperthyroidism

The spectrum of classic symptoms of hyperthyroidism suggests that in addition to the effects of increased thyroid hormone, affecting various organ systems, there is also a hyperadrenergic state. Despite this clinical impression, direct measures of serum levels of catecholamines and their urinary metabolites demonstrate values that are equal to or less than normal. In contrast, the hypothyroid patient who clinically manifests signs of decreased adrenergic stimulation can be expected to have increased levels of epinephrine, norepinephrine, and its metabolites. This review discusses possible mechanisms to explain this seeming paradox. Treatment of hyperthyroidism includes the rapid reversal of many of the adrenergic symptoms with use of beta-blocking drugs. Return to a clinically and chemically euthyroid state, however, requires antithyroid therapy accomplished over a longer period of time. A knowledge of the interaction of the cardiovascular and extracardiovascular manifestations of hyperthyroidism and the role of the adrenergic nervous system is important in the rational management of these patients.

The Direct Vasomotor Effect of Thyroid Hormones on Rat Skeletal Muscle Resistance Arteries

The present study examines the hypothesis that the hormones have direct vasodilatory effects and attempts to determine whether the effects are endothelium-dependent. Rat skeletal muscle resistance arteries of approximately 100 micro m were dissected, and vessel diameter changes were monitored using a videodetection system. After equilibration at 37[degree sign]C, each vessel was preconstricted with the thromboxane analog U46619 1 micro M, and the percentage of dilation was measured after exposure to increasing concentrations of triiodothyronine (T3) or levothyroxine (T4) (10-10 to 10-7 M). Dilation in response to T3 was also measured after endothelial denudation and pretreatment with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA) 10 micro M, the cyclooxygenase inhibitor indomethacin 10 micro M, the adenosine triphosphate-sensitive K+ channel blocker glibenclamide 1 micro M, or the beta-adrenergic antagonist propranolol 1 micro M. Both T3 and T4 demonstrated concentration-dependent dilation of the U46619-preconstricted vessels (P < 0.001 each), with T3 having a greater effect than T4 (P < 0.05) (36% +/- 9% [mean +/- SD] dilation at 10-7 M T3 vs 24% +/- 6% dilation at 10-7 M T4). In comparison, isoproterenol 10-7 M produced 56% +/- 6% dilation. T3-mediated vasodilation was attenuated but not abolished by endothelial denudation (18% +/- 3% dilation at 10-7 M T3) (P < 0.01), L-NNA (15% +/- 7% dilation at 10-7 M T3) (P < 0.01), indomethacin (20% +/- 9% dilation at 10-7 M T3) (P < 0.05), and glibenclamide (22% +/- 7% dilation at 10-7 M T3) (P < 0.01), but it was not affected by propranolol (37% +/- 20% dilation at 10-7 M T3) (P = 0.99). We conclude that thyroid hormones possess direct vasodilatory effects with both endothelium-independent and endothelium-dependent components. Implications: Thyroid hormones may have modest direct vasodilatory effects. This may partially account for the cardiovascular actions of the hormones in hyperthyroidism or when administered pharmacologically in cardiac surgery. (Anesth Analg 1997;85:734-8)

Effects of amiodarone therapy on thyroid function

Amiodarone is a benzofuran derivative approved for the treatment of cardiac arrhythmias. Traditionally classified as a class III antiarrhythmic agent, amiodarone possesses electrophysiologic properties of all four Vaughan–Williams classes. This drug, however, has high iodine content, and this feature plus the intrinsic effects on the body make amiodarone especially toxic to the thyroid gland. Treatment can result in a range of effects from mild derangements in thyroid function to overt hypothyroidism or thyrotoxicosis. The diagnosis and treatment of amiodarone-induced hypothyroidism is usually straightforward, whereas that of amiodarone-induced thyrotoxicosis and the ability to distinguish between the type 1 and type 2 forms of the disease are much more challenging. Dronedarone was approved in 2009 for the treatment of patients with atrial fibrillation. As amiodarone, dronedarone is a benzofuran derivative with similar electrophysiologic properties. In contrast to amiodarone, however, dronedarone is structurally devoid of iodine and has a notably shorter half-life. In studies reported before FDA approval, dronedarone proved to be associated with significantly fewer adverse effects than amiodarone, making it a more attractive choice for patients with atrial fibrillation or flutter, who are at risk of developing amiodarone-induced thyroid dysfunction.

Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia.

Cardiopulmonary bypass results in a euthyroid sick state. Recently, interest has focused on the relationship between low serum triiodothyronine levels and postoperative cardiovascular hemodynamics. The present study was undertaken to more clearly define the acute effects of triiodothyronine on myocardial mechanics and energetics after hypothermic global ischemia using an ex-vivo canine heart preparation to model the clinical condition. Experiments were performed on isolated hearts subjected to hyperkalemic arrest with 90 minutes of hypothermic (10 degrees C) ischemia. Isolated hearts were cross-perfused by euthyroid support dogs in which triiodothyronine levels spontaneously decreased by 65% to 75% (p < 0.01) after the initiation of cross-perfusion. In nine heart preparations, triiodothyronine (Triostat) was given as a bolus dose (0.2 micrograms/kg) after 1 hour of baseline data collection with a subsequent measurable rise in serum triiodothyronine levels (p < 0.01). In six postischemic hearts, reverse triiodothyronine was given as a 0.2 micrograms/kg bolus. Triiodothyronine was also administered to a group of eight nonischemic, continuously perfused isolated hearts. Intrinsic myocardial contractility was assessed by analysis of the preload recruitable stroke work area, energetic efficiency from the myocardial oxygen consumption-pressure-volume area relationship, and coronary vascular resistance from analysis of coronary flow and perfusion pressure. Acute administration of triiodothyronine to postischemic hearts improved the preload recruitable stroke work area from 9.5 +/- 1.42 to 14.9 +/- 2.03 x 10(7) erg/ml, a 56% increase from baseline (p < 0.001), but had no effect on the preload recruitable stroke work area of the nonischemic hearts. The inotropic response resulting from triiodothyronine treatment did not alter the myocardial oxygen consumption-pressure-volume area relationship. Triiodothyronine treatment was associated with significantly decreased coronary resistance and increased coronary flow through a range of diastolic loading conditions in the postischemic hearts. The biologically inactive thyroid hormone metabolite reverse triiodothyronine was without effect on any of the measured parameters. On the basis of these results, we conclude that the low triiodothyronine state of cardiopulmonary bypass can be reproduced in this isolated heart model and that acute triiodothyronine treatment results in a unique inotropic action manifest only in the postischemic reperfused myocardium and is accomplished without oxygen wasting effects.

Graves' Disease: An Analysis of Thyroid Hormone Levels and Hyperthyroid Signs and Symptoms

PURPOSEnAssessment of disease severity for patients with hyperthyroidism involves clinical evaluation and laboratory testing. To determine if there is a correlation between symptoms and thyroid function test results, we prospectively studied hyperthyroid patients using a standardized symptom rating scale and serum thyroid function parameters.nnnPATIENTS AND METHODSnWe examined 25 patients with untreated, newly diagnosed Graves disease using the Hyperthyroid Symptom Scale (HSS) and serum levels of thyroxine (T4), triiodothyronine (T3) relative insulin area (RIA), and estimates of free thyroxine index (FTI). In addition, we compared thyroid hormone levels with standard measures of depression and anxiety in these patients.nnnRESULTSnWhen regression analyses controlling for age were performed, none of these symptom ratings were associated with FTI or T3 RIA. The HSS was correlated with goiter size and anxiety ratings and was inversely correlated with age.nnnCONCLUSIONnThe present study suggests that there is no relationship between the clinical assessment of disease severity and serum levels of thyroid hormone in untreated Graves disease.

Physiological Replacement of T3 Improves Left Ventricular Function in an Animal Model of Myocardial Infarction-Induced Congestive Heart Failure

Background—Patients with congestive heart failure (CHF) often have low serum triiodothyronine (T3) concentrations. In a rodent model of myocardial infarction-induced CHF and low serum T3, we hypothesized that replacing T3 to euthyroid levels would improve left ventricular function without producing untoward signs of thyrotoxicosis. Methods and Results—Adult male Sprague-Dawley rats were subjected to left anterior descending coronary artery ligation (myocardial infarction). One week post-myocardial infarction, left ventricular fractional shortening was significantly reduced to 22±1% in CHF animals versus 38±1% for sham-operated controls (P<0.001). Serum T3 concentration was also significantly reduced (80±3 versus 103±6 ng/dL; P<0.001), in CHF animals versus Shams. At 9 weeks post-myocardial infarction, systolic function (+dP/dt max) was significantly attenuated in CHF animals (4773±259 versus 6310±267 mm Hg/s; P<0.001) as well as diastolic function measured by half time to relaxation (15.9±1.2 versus 11.1±0.3 ms; P<0.001). &agr;-myosin heavy chain expression was also significantly reduced by 77% (P<0.001), and &bgr;-myosin heavy chain expression was increased by 21%. Continuous T3 replacement was initiated 1 week post-myocardial infarction with osmotic mini-pumps (6 &mgr;g/kg/d), which returned serum T3 concentrations to levels similar to Sham controls while resting conscious heart rate, arterial blood pressure and the incidence of arrhythmias were not different. At 9 weeks, systolic function was significantly improved by T3 replacement (6279±347 mm Hg/s; P<0.05) and a trend toward improved diastolic function (12.3±0.6 ms) was noted. T3 replacement in CHF animals also significantly increased &agr;- and reduced &bgr;-MHC expression, (P<0.05). Conclusions—These data indicate that T3 replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression.

Acute effects of triiodothyronine on arterial smooth muscle cells.

Thyroid hormone has profound effects on the heart and cardiovascular system. Systemic vascular resistance is uniformly decreased in both naturally occurring and experimental hyperthyroidism, and it is increased in thyroid hormone deficiency. Because vascular smooth muscle cell contraction is a major determinant of systemic vascular resistance, the present studies were designed to address the acute effects of the thyroid hormones, specifically triiodothyronine, on vascular smooth muscle cell contractile activity. Our data indicate that triiodothyronine causes smooth muscle relaxation; this property may account for some of its marked effects on the cardiovascular system. As a novel vasodilatory agent, the potential therapeutic implications for triiodothyronine may be numerous.