Thyroid hormone has many effects on the heart and vascular system.1 Many of the clinical manifestations of hyperthyroidism are due to the ability of thyroid hormone to alter cardiovascular hemodynamics.2 The hemodynamic effects of hypothyroidism are opposite to those of hyperthyroidism, although the clinical manifestations are less obvious. This review will integrate what is known about the mechanisms of thyroid hormone action on the heart2–5 with recent observations from both experimental and clinical studies of hyperthyroidism and hypothyroidism. We will also address the potential role of thyroid hormone treatment in patients with acute or chronic cardiac disease. Effects of . . .

Thyroid hormone and the cardiovascular system.

According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D3 derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D3 and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.

Multiple Actions of Steroid Hormones—A Focus on Rapid, Nongenomic Effects

The cardiovascular signs and symptoms of thyroid disease are some of the most profound and clinically relevant findings that accompany both hyperthyroidism and hypothyroidism. On the basis of the understanding of the cellular mechanisms of thyroid hormone action on the heart and cardiovascular system, it is possible to explain the changes in cardiac output, cardiac contractility, blood pressure, vascular resistance, and rhythm disturbances that result from thyroid dysfunction. The importance of the recognition of the effects of thyroid disease on the heart also derives from the observation that restoration of normal thyroid function most often reverses the abnormal cardiovascular hemodynamics. In the present review, we discuss the appropriate thyroid function tests to establish a suspected diagnosis as well as the treatment modalities necessary to restore patients to a euthyroid state. We also review the alterations in thyroid hormone metabolism that accompany chronic congestive heart failure and the approach to the management of patients with amiodarone-induced alterations in thyroid function tests.

Thyroid Disease and the Heart

THE purpose of this review is to evaluate recent developments in our understanding of the inflammatory response to cardiac surgery. Scientific knowledge in this field is continually expanding, potentially significant advances are regularly reported, and this area constitutes a major interface of clinical and basic scientific research. The review is divided into four major sections. The first section describes the pathophysiology of the inflammatory response to cardiac surgery. Factors that influence the extent of the inflammatory response, including the immunomodulatory effects of drugs commonly administered perioperatively, are discussed in the second section. The third section examines the evidence that the inflammatory response contributes to adverse perioperative events, in particular organ dysfunction, while the final section evaluates potential therapeutic strategies to control this response. The review concludes with a summary of potential future research directions and key deficiencies in our knowledge regarding the inflammatory response to cardiac surgery.

The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist.

Subarachnoid haemorrhage (SAH) causes early brain injury (EBI) that is mediated by effects of transient cerebral ischaemia during bleeding plus effects of the subarachnoid blood. Secondary effects of SAH include increased intracranial pressure, destruction of brain tissue by intracerebral haemorrhage, brain shift, and herniation, all of which contribute to pathology. Many patients survive these phenomena, but deteriorate days later from delayed cerebral ischaemia (DCI), which causes poor outcome or death in up to 30% of patients with SAH. DCI is thought to be caused by the combined effects of angiographic vasospasm, arteriolar constriction and thrombosis, cortical spreading ischaemia, and processes triggered by EBI. Treatment for DCI includes prophylactic administration of nimodipine, and current neurointensive care. Prompt recognition of DCI and immediate treatment by means of induced hypertension and balloon or pharmacological angioplasty are considered important by many physicians, although the evidence to support such approaches is limited. This Review summarizes the pathophysiology of DCI after SAH and discusses established treatments for this condition. Novel strategies--including drugs such as statins, sodium nitrite, albumin, dantrolene, cilostazol, and intracranial delivery of nimodipine or magnesium--are also discussed.

Delayed neurological deterioration after subarachnoid haemorrhage

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)

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

After subarachnoid hemorrhage (SAH), large cerebral arteries are prone to vasospasm. Using a rat model of SAH, we examined whether cortical microvessels demonstrate vasomotor changes that may make them prone to spasm and whether endothelial dysfunction may account for any observed changes. Two days

Microvascular endothelial dysfunction and its mechanism in a rat model of subarachnoid hemorrhage

Previous in vitro studies on the effect of propofol on coronary arteries have shown variable results, ranging from constriction to no effect to dilation. Although most of these studies reported that the observed effect is endothelium-independent, propofol also releases nitric oxide from cultured porcine endothelial cells. The present study examines the direct effect of propofol in rat distal coronary arteries in vitro, especially in regard to endothelial dependence and involvement of the adenosine triphosphate (ATP)-sensitive potassium channels (KATP channels). Forty-three subepicardial arteries (size 91.1 +/- 15.8 microns) from Wistar rats were studied in vitro in a no-flow, pressurized (40 mm Hg) state, using an optical density video detection system. After preconstriction with the thromboxane analog U46619 1 microM, relaxation responses to increasing concentrations of propofol (10(-6)-10(-4) M) were measured after 1) endothelial denudation, 2) pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA), 3) pretreatment with the cyclooxygenase inhibitor indomethacin, 4) pretreatment with the KATP channel blocker glibenclamide, or 5) no intervention (control). Propofol produced a significant concentration-dependent vasodilation of the U46619-preconstricted coronary arteries. This effect was significantly attenuated by endothelial denudation, pretreatment with L-NNA, or indomethacin, but was not affected by glibenclamide. We conclude that propofol has a direct vasodilatory effect on distal coronary arteries in rats. This effect is primarily endothelium-dependent and is mediated by multiple substances, including nitric oxide (NO) and a vasodilatory prostanoid. The effect is not mediated by opening of the K(ATP) channels.

Propofol-associated dilation of rat distal coronary arteries is mediated by multiple substances, including endothelium-derived nitric oxide

UNLABELLED The bronchial epithelium releases substances that enhance bronchodilation in response to certain bronchodilators. We examined the hypothesis that the bronchodilatory effect of desflurane and sevoflurane depends on the epithelium in rat distal bronchial segments. Wistar rat subsegmental bronchial segments (diameter approximately 100 microm) were dissected. After preconstriction with 5-hydroxytryptamine, each segment was exposed to increasing concentrations of desflurane 0%-12% or sevoflurane 0%-4.8% under four conditions: after epithelial rubbing, after pretreatment with the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NNA), after pretreatment with the cyclooxygenase inhibitor indomethacin, or with no preintervention (control). Changes in bronchial diameter were monitored using an in vitro video detection system. Both desflurane and sevoflurane produced concentration-dependent bronchodilation (P < 0.001 for either anesthetic; 54% +/- 8% [mean +/- SD] dilation for 12% desflurane and 48% +/- 14% dilation for 4.8% sevoflurane). For both anesthetics, bronchodilation was significantly attenuated by epithelial rubbing (15% +/- 4% dilation for 12% desflurane and 13% +/- 10% dilation for 4.8% sevoflurane; P < 0.001 each), by pretreatment with indomethacin (12% +/- 3% dilation for 12% desflurane and 9% +/- 5% dilation for 4.8% sevoflurane; P < 0.001 each), and by L-NNA (24% +/- 8% dilation for 12% desflurane, P < 0.001; and 17% +/- 10% dilation for 4.8% sevoflurane, P < 0.01). Desflurane- and sevoflurane-mediated bronchodilation depends at least partially on the epithelium, and may involve both a prostanoid and NO in rat distal bronchi. IMPLICATIONS Bronchodilation by the volatile anesthetics desflurane and sevoflurane is at least partially epithelium-dependent and may be attenuated in diseases affecting the epithelium, such as asthma.

Epithelial Dependence of the Bronchodilatory Effect of Sevoflurane and Desflurane in Rat Distal Bronchi

We examined whether pulmonary endothelial dysfunction associated with cardiopulmonary bypass (CPB) may be mediated by complement C5a in pigs. Pigs were placed on normothermic CPB for 1 h with or without a previous administration of 1.6 mg/kg anti-C5a monoclonal antibody (MAb), then reperfused for 2 h. Pulmonary tissue myeloperoxidase activity was measured. Expression of nitric oxide synthase (NOS) was measured by reverse transcriptase polymerase chain reaction and Western blotting. Pulmonary arterioles approximately 100 m mi n diameter were preconstricted with the thromboxane analog U46619 1 mM, and relaxation responses to adenosine diphosphate 10 29 ‐10 24 M, substance P 10 212 ‐10 26 M, and sodium nitroprusside 10 29 ‐10 24 M were examined in vitro by videomicroscopy. Relaxation to the endothelium-dependent dilators adenosine diphosphate and substance P was attenuated after CPB; this attenuation was prevented by the previous administration of MAb. Relaxation to sodium nitroprusside was not affected by CPB. Neutrophil sequestration, as measured by MPO activity, increased after CPB, either with or without MAb. Transcription of NOS was unchanged by CPB, but translation of constitutive NOS was decreased after CPB, and this decrease was prevented by a previous administration of MAb. We conclude that pig pulmonary endothelial dysfunction associated with CPB may be mediated by C5a. The mechanism may involve changes in NOS translation. Implications: In pigs, pulmonary endothelial dysfunction may occur after cardiopulmonary bypass due to product(s) of complement activation.

Attenuation of endothelium-dependent dilation of pig pulmonary arterioles after cardiopulmonary bypass is prevented by monoclonal antibody to complement C5a.

Hai B. Dai

Papers

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

Microvascular endothelial dysfunction and its mechanism in a rat model of subarachnoid hemorrhage

Propofol-associated dilation of rat distal coronary arteries is mediated by multiple substances, including endothelium-derived nitric oxide

Epithelial Dependence of the Bronchodilatory Effect of Sevoflurane and Desflurane in Rat Distal Bronchi

Attenuation of endothelium-dependent dilation of pig pulmonary arterioles after cardiopulmonary bypass is prevented by monoclonal antibody to complement C5a.