Zainal Thyroid DISEASE

Chapter 64Chapter 64The Heart in Endocrine The Heart in Endocrine Disorders : THYROID DISEASEDisorders : THYROID DISEASE

BYBYELLEN W. SEELY, M.D. ELLEN W. SEELY, M.D.

GORDON H. WILLIAMS,M.D.GORDON H. WILLIAMS,M.D.Braunwald's Heart Braunwald's Heart

DiseaseDisease

ACTION OF THYROID HORMONEACTION OF THYROID HORMONE Two active hormones are secreted Two active hormones are secreted

by the thyroid: thyroxine (T4) and by the thyroid: thyroxine (T4) and triiodothyronine (T3). triiodothyronine (T3).

Most studies support the Most studies support the hypothesis that T3 is the final hypothesis that T3 is the final mediator and T4 is a prohormone, mediator and T4 is a prohormone,

Nuclear-Mediated Effects of Thyroid Nuclear-Mediated Effects of Thyroid HormoneHormone

This process begins with diffusion of T4 and T3 This process begins with diffusion of T4 and T3 across the plasma membrane.across the plasma membrane.In the cytosol, T4 is converted into T3 by the action In the cytosol, T4 is converted into T3 by the action of 5´-monodelodinase. of 5´-monodelodinase.

Thyroid hormone's effectThyroid hormone's effect

Thyroid hormone (TH) can have a (+) or (-) effect on Thyroid hormone (TH) can have a (+) or (-) effect on regulating gene transcription.regulating gene transcription.

Positive effects : myosin heavy-chain alpha, Ca2+-ATPase, Positive effects : myosin heavy-chain alpha, Ca2+-ATPase, Na+, K+-ATPase, beta1-adrenergic receptor, glucose Na+, K+-ATPase, beta1-adrenergic receptor, glucose transporter, cardiac troponin, and atrial natriuretic protein.transporter, cardiac troponin, and atrial natriuretic protein.

Negative effects regulate genes, e.g., myosin heavy-chain Negative effects regulate genes, e.g., myosin heavy-chain beta and the glucose transporter Glut-1.beta and the glucose transporter Glut-1.

Thyroid Extranuclear Actions

T3 increases both glucose and Ca T3 increases both glucose and Ca uptake by the heart. uptake by the heart.

Extranuclear effects include TH’s Extranuclear effects include TH’s direct effect on Ca current and direct effect on Ca current and cytosolic Ca changes induced by cytosolic Ca changes induced by inotropic factors. inotropic factors.

RELATIONSHIP BETWEEN THE THYROID AND THE RELATIONSHIP BETWEEN THE THYROID AND THE SYMPATHETIC NERVOUS SYSTEMSYMPATHETIC NERVOUS SYSTEM

The effects of TH on the heart are indirect and secondary to The effects of TH on the heart are indirect and secondary to changes in activity of the sympathetic nervous system. changes in activity of the sympathetic nervous system. The cardiovascular effects of hyperthyroidism, i.e., The cardiovascular effects of hyperthyroidism, i.e., tachycardia, systolic hypertension, increased cardiac tachycardia, systolic hypertension, increased cardiac output, and myocardial contractility, can be abolished or output, and myocardial contractility, can be abolished or reduced by blocking the activity of the sympathetic nervous reduced by blocking the activity of the sympathetic nervous system. system. TH is increasing the activity of the sympathoadrenal system TH is increasing the activity of the sympathoadrenal system or by enhancing the response of cardiac tissue to normal or by enhancing the response of cardiac tissue to normal sympathetic stimulation. sympathetic stimulation.


TH's effect in three areas has been explored: adrenergic TH's effect in three areas has been explored: adrenergic output, adrenergic receptors, and adrenergic transduction output, adrenergic receptors, and adrenergic transduction mechanisms. mechanisms.

Administration of TH causes an increase in both the Administration of TH causes an increase in both the number of receptors and their affinity for their ligand, while number of receptors and their affinity for their ligand, while hypothyroidism induces the opposite effect.hypothyroidism induces the opposite effect.

TH also increases mRNA levels for the beta1-adrenergic TH also increases mRNA levels for the beta1-adrenergic receptor.receptor.


Changes in receptor number and affinity then lead to Changes in receptor number and affinity then lead to changes in sensitivity of the myocardium to beta changes in sensitivity of the myocardium to beta adrenoceptor agonists. For example, stimulation of adrenoceptor agonists. For example, stimulation of adenylate cyclase activity by isoproterenol is increased in adenylate cyclase activity by isoproterenol is increased in hyperthyroidism and reduced in hypothyroidism. hyperthyroidism and reduced in hypothyroidism. Changes are also seen in the force of contraction. Changes are also seen in the force of contraction. These effects were also observed in vivo in dogs, in which These effects were also observed in vivo in dogs, in which propranolol-induced reductions in heart rate and myocardial propranolol-induced reductions in heart rate and myocardial contractility were greater in hyperthyroid than euthyroid contractility were greater in hyperthyroid than euthyroid animals.animals.

Effect of Thyroid Hormone on the HeartEffect of Thyroid Hormone on the Heart T4 enhances the rate of contraction of cardiac T4 enhances the rate of contraction of cardiac

muscle, even in the presence of adrenergic muscle, even in the presence of adrenergic blockade. blockade.

The major actions of T4 on the left ventricle are The major actions of T4 on the left ventricle are (1) a direct (+) inotropic effect and (2) an (1) a direct (+) inotropic effect and (2) an increase in the size of the ventricular cavity increase in the size of the ventricular cavity without a change in end-diastolic pressure or without a change in end-diastolic pressure or length of the sarcomere in diastole.length of the sarcomere in diastole.

Effect of Thyroid Hormone on the HeartEffect of Thyroid Hormone on the Heart

The direct effect of thyroid The direct effect of thyroid hormone on the heart is primarily hormone on the heart is primarily mediated via a change in protein mediated via a change in protein synthesis. synthesis.

Specifically, synthesis of myosin Specifically, synthesis of myosin heavy chains is changed from the heavy chains is changed from the beta to the alpha form.beta to the alpha form.


TH increases expression of Na-Ca-ATPase, which augments TH increases expression of Na-Ca-ATPase, which augments trans-sarcolemmal Ca influx in cultured ventricular cells. trans-sarcolemmal Ca influx in cultured ventricular cells. TH modifies the electrical activity of the heart by several TH modifies the electrical activity of the heart by several mechanisms.mechanisms.It increases recruitment of slower inactivating Na channels. It increases recruitment of slower inactivating Na channels. It modifies the expression and/or composition and thereby the It modifies the expression and/or composition and thereby the activity of one or more K channels and several Ca channels. activity of one or more K channels and several Ca channels. These effects probably result from altered gene transcription These effects probably result from altered gene transcription because of TH. because of TH.


The tachycardia in hyperthyroidism appears to be The tachycardia in hyperthyroidism appears to be due to an increased rate of diastolic depolarization due to an increased rate of diastolic depolarization and a decreased duration of the action potential in and a decreased duration of the action potential in the SA node cells. the SA node cells.

The propensity for the development of AF may be The propensity for the development of AF may be due to the shortened refractory period of atrial cells. due to the shortened refractory period of atrial cells.

HyperthyroidismHyperthyroidismHyperthyroidism is a relatively common disease that occurs more often in Hyperthyroidism is a relatively common disease that occurs more often in women than men, with a peak incidence in the third and fourth decades. women than men, with a peak incidence in the third and fourth decades. Signs and symptoms : fatigue, hyperactivity, insomnia, heat intolerance, Signs and symptoms : fatigue, hyperactivity, insomnia, heat intolerance, palpitations, dyspnea, increased appetite with weight loss, nocturia, palpitations, dyspnea, increased appetite with weight loss, nocturia, diarrhea, oligomenorrhea, muscle weakness, tremor, emotional lability, diarrhea, oligomenorrhea, muscle weakness, tremor, emotional lability, increased heart rate, systolic hypertension, hyperthermia, warm moist skin. increased heart rate, systolic hypertension, hyperthermia, warm moist skin. Hyperthyroidism is the clinical state resulting from excess production of T4, Hyperthyroidism is the clinical state resulting from excess production of T4, T3 or both. T3 or both. The most common cause is a diffuse toxic goiter The most common cause is a diffuse toxic goiter The second most common form of hyperthyroidism is nodular toxic goiterThe second most common form of hyperthyroidism is nodular toxic goiterSerum T4 levels are increased and serum TSH is suppressed.Serum T4 levels are increased and serum TSH is suppressed.

CARDIOVASCULAR MANIFESTATIONSCARDIOVASCULAR MANIFESTATIONS

Cardiovascular signs and symptoms are therefore Cardiovascular signs and symptoms are therefore important clinical features of hyperthyroidism.important clinical features of hyperthyroidism.Palpitations, dyspnea, tachycardia, and systolic Palpitations, dyspnea, tachycardia, and systolic hypertension are common findings. hypertension are common findings. Diastolic hypertension can also occur. Typically noted are a Diastolic hypertension can also occur. Typically noted are a hyperactive precordium with a loud first heart sound, a third hyperactive precordium with a loud first heart sound, a third heart sound; occasionally, a systolic ejection click is heard. heart sound; occasionally, a systolic ejection click is heard.


Coronary blood flow are increased, systolic ejection Coronary blood flow are increased, systolic ejection and preejection period are abbreviated, pulse and preejection period are abbreviated, pulse pressure is widened, systemic vascular resistance pressure is widened, systemic vascular resistance is reduced. is reduced.


The changes in cardiac function are secondary to the The changes in cardiac function are secondary to the increased metabolic demands of peripheral tissue. increased metabolic demands of peripheral tissue. TH exerts a direct cardiac stimulant action independent of TH exerts a direct cardiac stimulant action independent of its effect on general tissue metabolism.its effect on general tissue metabolism.Normalization of the myocardial contractile may not occur Normalization of the myocardial contractile may not occur until several months after normalization of thyroid function. until several months after normalization of thyroid function. The overall pathological consequences associated with The overall pathological consequences associated with thyrotoxicosis result from an interaction between the effect thyrotoxicosis result from an interaction between the effect of TH on the heart and its effect on the peripheral of TH on the heart and its effect on the peripheral circulation. circulation.


Cardiovascular effects of hyperthyroidism.


C-XR and ECG changes are common, but nonspecific in C-XR and ECG changes are common, but nonspecific in hyperthyroidism.hyperthyroidism.On chest x-ray the left ventricle, aorta, and pulmonary On chest x-ray the left ventricle, aorta, and pulmonary artery are prominent, and generalized cardiac enlargement artery are prominent, and generalized cardiac enlargement can be noted. can be noted. In Px sinus rhythm, the magnitude of the tachycardia in In Px sinus rhythm, the magnitude of the tachycardia in general parallels the severity of the disease. general parallels the severity of the disease. Sinus tachycardia is present in 40 % of patients with Sinus tachycardia is present in 40 % of patients with hyperthyroidism and occurs most frequently. hyperthyroidism and occurs most frequently. Ten to 15 percent of patients with hyperthyroidism have Ten to 15 percent of patients with hyperthyroidism have persistent AF. persistent AF.


Intraatrial conduction disturbances, manifested by Intraatrial conduction disturbances, manifested by prolongation or notching of the P wave and prolongation or notching of the P wave and prolongation of the PR interval in patients with prolongation of the PR interval in patients with hyperthyroidism. hyperthyroidism. Second - or third-degree heart block may result. Second - or third-degree heart block may result. The cause of the AV conduction disturbance is not The cause of the AV conduction disturbance is not clear. clear.


Intraventricular conduction disturbances, commonly Intraventricular conduction disturbances, commonly RBBB, occur in 15 % of patients with hyperthyroidism RBBB, occur in 15 % of patients with hyperthyroidism without associated heart disease of other etiology. without associated heart disease of other etiology.

Paroxysmal SVTand flutter are rare in Paroxysmal SVTand flutter are rare in hyperthyroidism. hyperthyroidism.

Occult thyrotoxicosis may underlie either chronic or Occult thyrotoxicosis may underlie either chronic or paroxysmal isolated AF paroxysmal isolated AF


Angina and CHF occur in patients with hyperthyroidism.Angina and CHF occur in patients with hyperthyroidism. Five lines of evidence have suggested: Five lines of evidence have suggested: (1) CHF has been produced in animals by administering T4. (1) CHF has been produced in animals by administering T4. (2) CHF in children with thyrotoxicosis and no underlying cardiac (2) CHF in children with thyrotoxicosis and no underlying cardiac

disease. disease. (3) Angina reported in a hyperthyroid Px with normal coronary arteries, (3) Angina reported in a hyperthyroid Px with normal coronary arteries,

presumably secondary to thyroid-induced coronary artery spasm. presumably secondary to thyroid-induced coronary artery spasm. (4) The abnormal left ventricular function observed in hyperthyroid Px is (4) The abnormal left ventricular function observed in hyperthyroid Px is

not reversed by beta blockade but is reversed by treating the not reversed by beta blockade but is reversed by treating the hyperthyroidism. hyperthyroidism.

(5) The cardiomyopathy in patients with thyrotoxicosis may be (5) The cardiomyopathy in patients with thyrotoxicosis may be irreversible. irreversible.

DIAGNOSIS OF HYPERTHYROIDISMDIAGNOSIS OF HYPERTHYROIDISM

Hyperthyroidism in most patients is clinically Hyperthyroidism in most patients is clinically manifested as described above. manifested as described above.

The diagnosis is confirmed with a low TSH level, The diagnosis is confirmed with a low TSH level, which reflects an elevated level of TH in the blood. which reflects an elevated level of TH in the blood.

In elderly patients with apathetic hyperthyroidism, In elderly patients with apathetic hyperthyroidism, cardiovascular manifestations predominate, cardiovascular manifestations predominate, specifically, AF and/or CHF.specifically, AF and/or CHF.

TREATMENT OF HYPERTHYROIDISMTREATMENT OF HYPERTHYROIDISM

The mainstay of Tx is beta-adrenergic blocking The mainstay of Tx is beta-adrenergic blocking agents pending initiation of more definite treatment.agents pending initiation of more definite treatment.Definitive treatment of hyperthyroidism is surgical Definitive treatment of hyperthyroidism is surgical and or irradiation with radioactive iodide. and or irradiation with radioactive iodide. In severely ill patients, medical therapy is directed In severely ill patients, medical therapy is directed at reducing both the production and the biological at reducing both the production and the biological effect of TH with thionamides and beta blockers.effect of TH with thionamides and beta blockers.

TREATMENT OF CARDIOVASCULAR TREATMENT OF CARDIOVASCULAR MANIFESTATIONS OF HYPERTHYROIDISMMANIFESTATIONS OF HYPERTHYROIDISM

50 % of patients with concurrent onset of 50 % of patients with concurrent onset of hyperthyroidism and angina pectoris experience hyperthyroidism and angina pectoris experience complete remission of this symptom after Tx of complete remission of this symptom after Tx of hyperthyroidism.hyperthyroidism.

30 to 40 % of thyrotoxic patients with AF sustained 30 to 40 % of thyrotoxic patients with AF sustained for 1 week or longer, spontaneous reversion to for 1 week or longer, spontaneous reversion to sinus rhythm occurs when they become euthyroid.sinus rhythm occurs when they become euthyroid.

TREATMENT OF CARDIOVASCULAR TREATMENT OF CARDIOVASCULAR MANIFESTATIONS OF HYPERTHYROIDISMMANIFESTATIONS OF HYPERTHYROIDISMBeta blockers can be administered, with caution in patients Beta blockers can be administered, with caution in patients with CHF. with CHF. The heart failure with tachycardia, beta blockade may be The heart failure with tachycardia, beta blockade may be beneficial. Beta-blocking drugs also slow the ventricular beneficial. Beta-blocking drugs also slow the ventricular rate in AF. rate in AF. The agents for correcting the fundamental defect are The agents for correcting the fundamental defect are thionamides.thionamides.Iodine inhibits the release of TH from the thyrotoxic gland. It Iodine inhibits the release of TH from the thyrotoxic gland. It is therefore useful for rapid amelioration of the hyperthyroid is therefore useful for rapid amelioration of the hyperthyroid state in patients with thyroid heart disease. state in patients with thyroid heart disease.

Amiodarone and the ThyroidAmiodarone and the Thyroid The amiodarone for arrhythmias is now one of the most The amiodarone for arrhythmias is now one of the most common causes of thyroid abnormalities in patients with common causes of thyroid abnormalities in patients with cardiovascular disease. cardiovascular disease. Amiodarone has structural similarity to T4 and T3. Amiodarone has structural similarity to T4 and T3. Amiodarone decreases the peripheral conversion of T4 to Amiodarone decreases the peripheral conversion of T4 to T3, which leads to elevated levels of circulating T4 and T3, which leads to elevated levels of circulating T4 and lower levels of circulating T3. lower levels of circulating T3. Since this inhibition occurs in the pituitary gland as well, a Since this inhibition occurs in the pituitary gland as well, a transient increase in TSH is seen early in treatment but transient increase in TSH is seen early in treatment but usually resolves over the next 3 months.usually resolves over the next 3 months.

Amiodarone and the ThyroidAmiodarone and the Thyroid Amiodarone-induced hyperthyroidism most commonly Amiodarone-induced hyperthyroidism most commonly occurs in areas of the world with iodine deficiency . occurs in areas of the world with iodine deficiency . Dx is made by the history, clinical examination, and thyroid Dx is made by the history, clinical examination, and thyroid function testing (low TSH and elevated T4). function testing (low TSH and elevated T4). Low TSH and elevated T4 levels can also be commonly in Low TSH and elevated T4 levels can also be commonly in the early phase of amiodarone Tx without symptoms, the early phase of amiodarone Tx without symptoms, measurement of total T3 may be helpful in distinguishing measurement of total T3 may be helpful in distinguishing these conditions. these conditions. In the early phase of Tx with amiodarone, T3 levels are In the early phase of Tx with amiodarone, T3 levels are decreased, whereas in hyperthyroidism, the T3 level is decreased, whereas in hyperthyroidism, the T3 level is increased.increased.

Algorithm for evaluating thyroid status in patients taking amiodarone.Algorithm for evaluating thyroid status in patients taking amiodarone.

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Zainal Thyroid DISEASE

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