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Thyroid hormone and the heart
u
EDITORIAL
Thyroid
Hormone
and the Heart
Irwin Klein, MD and Kaie Ojamaa, PhD, Manhasseti, New York
T
hyroid hormone has profound effects on the heart and circulation. For over 200 years it has been recorded that some of the most prominent signs and symptoms of hyperthyroidism are those involving the cardiovascular system.’ These include palpitations, tachycardia, widened pulse pressure, a hyperdynamic precordium, and marked increases in cardiac output (Table I) .’ All measures of ventricular contractility in both humans and experimental animals have demonstrated supranormal systolic and diastolic function.” These changes arise from multiple factors including alterations in systemic hemodynamics” and thyroid hormone-mediated effects on cardiac myocyte-specific gene expression.’ In contrast, the hypothyroid heart is characterized by subnormal resting contractile performance. With this as a rationale, investigators have attempted to apply thyroid hormone therapy to the treatment of various forms of heart disease.” The tiding that patients with congestive heart failure have low serum TG3levels, which is a poor prognostic indicator for survival, gives further theoretic support for these studies.” The search for novel hormonal therapies for dilated cardiomyopathies7 has been stimulated by recent reports that immunocyte production of tumor necrosis factor and nitric oxide can mediate myocyte damage in this disease.8 In the present issue of the Jownal, Moruzzi and colleagues have studied the effectiveness of 12 weeks of l-thyroxine (T,) treatment on the physiologic and functional parameters of patients with dialated cardiomyopathy.” They have previously observed that 7 days of T4 treatment improved cardiac performance lo and now report significant increases in ejection fraction, ventricular contractility, resting cardiac output, and a decline in systemic vascular resistance. Most impressive was the improvement in exercise capacity and the apparent lack of hyperthyroid signs and symptoms consistent with the normal levels of thyroid function tests. The dose of T1 used (100 pg/day) corresponds to a standard replace-
From the Division of Endocrinology, Department of Medicine, North Shore Unlverslty Hospital, Manhassett, New York and NYU School of Medicine. New York Citv. New York. Requests for reprintszshould be addressed to Irwin Klein, MD, Dlvislon of Endocrinoloav. North Shore University Hospital, 300 Community Drive, Manhasset. New York 11030. Manuscript submltted September 16, 1996 and accepted in revised form September 24, 1996.
aD1996 by Excerpta All rights reserved.
Medica.
Inc.
ment dose of T4 for this patient age group and did not alter oxygen consumption or suppress serum TSH as would occur with iatrogenic hyperthyroidism. Biondi and colleagues’ have previously reported that subclinical hyperthyroidism, which occurs with TSH suppressive doses of l-thyroxine (- 150 &day), did increase cardiac contractility in patients with no prior history of heart disease.” In a recent study, parenteral TiI treatment increased cardiac output in postoperative patients with impaired left ventricular function.” To understand the potential mechanisms for these beneficial cardiac effects, it is necessary to focus on both the heart and systemic vasculature. The ability of thyroid hormone to act as a positive cardiac inotropic agent derives in part from increased gene transcription of important myocyte regulatory proteins (Table II) .4 These include the myosin heavy chain contractile proteins and the calcium transport proteins, the sarcoplasmic reticulum calcium ATPase and phospholamban, which modulates the activity of this calcium translocator.‘” The net effect of thyroid hormone on these genes is to enhance calcium uptake into the sarcoplasmic reticulum during diastole and increase the rate of diastolic relaxatilon.‘3 In addition, thyroid hormone may act directly on the myocyte plasma membrane to alter the activity of specific sodium or potassium ion channells. Such a mechanism would account for both chronotropic and inotropic effects.” A reduction in systemic vascular resistance (SVR), as occurs with exercise, is characteristic of hyperthyroidism and can produce increased cardiac output and left ventricular ejection fraction. Moruzzi et al observed that T1 treatment for 1 or 4 weeks significantly lowered SVR”.“’ as did Klemperer et al” when T3 was administered acutely to patient.s undergoing coronary artery bypass surgery. IXPierro et al” showed that bolus administration of TG3improved cardiac function at no cost in oxygen co:nsumption by primarily reducing afterload through vasodilation. These data suggest that thyroid hormone is an effective vasodilator that modulates vascular tone potentially by acting directly on the vascular smooth muscle cell.‘” Many of the signs and symptoms of hyperthyroidism are similar to those of a hyperadrenergic state. This is exemplified by the resting tachycardia, episodes of atria1 fibrillation, and positive inotropy. An interaction between thyroid hormone and endogePII
0002-9343/96/$15.00 SOOO2-9343(96)00310-5
459
EDITORIAL
TABLE
I Cardiovascular
If systemic hemodynamic benefits can be obtained with a dose of T, that does not suppress TSH or, alternatively, if a modified thyroid hormone molecule can be formulated to act specifically as a vasodilator and a cardiac inotropic agent, then cardiovascular therapeutics will have been advanced.
Actions of Thyroid Hormone
Parameter
Effect
Cardiac output Systemic vascular resistance Heart rate Cardiac contractility Systolic Diastolic
t 1 t
References
t t
1. Parry CH. Collections from the unpublished Parry. Dis Heart. 1825;2:111. 2. Klein
I. Thyroid
hormone
and
the
papers
of the late Caleb
cardiovascular
system.
Hillrel
Am J Med.
1990;88:631. 3. Mintz G, Pizzarello R, Klein I. Enhanced hyperthyroidism: noninvasive assessment
TABLE II Thyroid Hormone Responsive Genes in the Heart Myosin heavy chain (isoforms) Sarcoplasmic reticulum calcium activated ATPase Phospholamban Sodium/Potassium ATPase Beta-adrenergic receptor Thyroid hormone nuclear receptors
November
1996
The American
Journal
of Medicine@
diastolic function in to treatment. J Clan
Endocnnol Metab. 1991;73:146. 4. Dillmann WH. Biochemical basis of thyroid hormone actton In the heart. Am J Med. 1990;88:626. 5. Klemperer JD, Ojamaa K, Klein I. Thyroid hormone therapy In cardiovascular disease. Prog Cardiovasc Dis. 1996;38:329. 6. Hamilton MA, Stevenson LW, Luu M, et al. Altered thyroid hormone metabolism in advanced heart failure. JAm Coil Cardiol. 1990;16:91. 7. Fazio S, Sabatini D. Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. NEJM. 1996;334:811.
nous or exogenous catecholamines to augment cardiac function has long been postulated.16 The finding that heart failure and coronary artery surgery are associated with decreases in beta-adrenergic responsiveness,17,18 and that thyroid hormone might attenuate this response by increasing beta-receptors, lg suggests a therapeutically desirable effect.” In the setting of hyperthyroidism, physicians are well aware of the risk of atria1 arrhythmias. Sawin et al have documented this in older patients.‘l The unwanted occurrence of sinus tachycardia or episodes of atrial fibrillation, which were observed by Biondi et al” following long-term T4 treatment, were not seen in the current study. Although Moruzzi et al9 reported an increase in frequency of premature ventricular contractions suggestive of enhanced ventricular irritability, these were not of sufficient duration to warrant treatment. What then would preclude the routine application of T4 therapy to patients with dilated cardiomyopathy? Certainly not the poor prognosis of this disease, the low cost of the medication, or the ease of administration. However, just as bariatricians have been unable to harness the weight loss properties of thyroid hormone and the lipidologist’s have so far failed to extract the cholesterol lowering effects, cardiologists must be vigil that thyroid hormone treatment does not lead to undesirable long-term effects on arrhythmias, bone, skeletal muscle, or behavior.
460
left ventricular and response
Volume
8. Tracey
KJ. RepaIring
the broken
heart
of dilated
cardiomyopathy.
Lancet
1996;347:1129. 9. Moruzzi treatment
P, Dona
467. 10. Moruzzi cardiac
E, Agostoni
in idiopathic P, Doria and exercise
dilated
PG. Medium
term effectiveness
of l-thyroxine
cardiomyopathy.
Am J Med.
1996;101:461-
E, Agostini PG, et al. Usefulness of l-thyroxine to improve performance in idiopathic dilated cardiomyopathy. Am J
Cardiol. 1994;73:374. 11. Biondi B, Fazro S, Carella
C, et al. Cardiac
effects
of long term thyrotropin
suppressive therapy with levothyroxine. J C/in Endocrinol Metab. 1993;77:334. 12. Klemperer JD, Klein I, Ojamaa K, et al. Effects of thyroid hormone supplementation in cardiac surgery. NEJM. 1995;333:1522. 13. Arat M, Masur H, Perisamy M. Sarcoplasmic rebculum gene expression in cardiac hypertrophy and heart failure. Circ Res. 1994;74:555. 14. DlPierro FV, Bavaria sheep ventrrculoarterial
JE, Lankford coupling for
EB, et al. Tmodothyronine opbmizes work efficiency. Ann Thorac Surg.
1996;62:662. 15. Ojamaa K, Balkman
C, Klein I. Acute effects of tmodothyronine on arterjal smooth muscle cells. Ann Thorac Surg. 1993;56:S61. 16. Levey GS, Klein I, Catecholamine-thyroid hormone interactions and the cardiovascular manifestations of hyperthyroidism. Am J Med. 1990;88:642.
17. White downregulation to idiopathic 18. Schwinn beta-adrenergic
M, Yanowitz F, GIlbert EM, et al. Role of beta-adrenergic receptor in the peak exercise response in patients with heart failure due dilated cardiomyopathy. Am J Cardiol. 1995;76: 1271. DA, Leone BJ, Chestnut LC, et al. Desensitization of myocardlal receptors during cardiopulmonary bypass: evidence for early
uncoupling and late downregulation. Circulation. 1991;84:2559. 19. Levine MA, Feldman AM, Robishaw JD. Influence of thyrolcl hormone on expression of genes encoding G protein subunits in the rat heart. Chem. 1990;25:3553. 20. Koch WJ, Rockman HA, Samama expressing the beta-adrenergic receptor
status J Biol
P, et al. Cardiac function in mice overkinase or a beta ARK inhibitor. Science.
1995;268:1350. 21. Sawrn CT, Geller A, Wolf PA, et al. Low serum thyrotropin levels as a risk factor for atrial fibrillation in older persons. NEJM. 1994;33:1249.
101
EDITORIAL
Thyroid
Hormone
and the Heart
Irwin Klein, MD and Kaie Ojamaa, PhD, Manhasseti, New York
T
hyroid hormone has profound effects on the heart and circulation. For over 200 years it has been recorded that some of the most prominent signs and symptoms of hyperthyroidism are those involving the cardiovascular system.’ These include palpitations, tachycardia, widened pulse pressure, a hyperdynamic precordium, and marked increases in cardiac output (Table I) .’ All measures of ventricular contractility in both humans and experimental animals have demonstrated supranormal systolic and diastolic function.” These changes arise from multiple factors including alterations in systemic hemodynamics” and thyroid hormone-mediated effects on cardiac myocyte-specific gene expression.’ In contrast, the hypothyroid heart is characterized by subnormal resting contractile performance. With this as a rationale, investigators have attempted to apply thyroid hormone therapy to the treatment of various forms of heart disease.” The tiding that patients with congestive heart failure have low serum TG3levels, which is a poor prognostic indicator for survival, gives further theoretic support for these studies.” The search for novel hormonal therapies for dilated cardiomyopathies7 has been stimulated by recent reports that immunocyte production of tumor necrosis factor and nitric oxide can mediate myocyte damage in this disease.8 In the present issue of the Jownal, Moruzzi and colleagues have studied the effectiveness of 12 weeks of l-thyroxine (T,) treatment on the physiologic and functional parameters of patients with dialated cardiomyopathy.” They have previously observed that 7 days of T4 treatment improved cardiac performance lo and now report significant increases in ejection fraction, ventricular contractility, resting cardiac output, and a decline in systemic vascular resistance. Most impressive was the improvement in exercise capacity and the apparent lack of hyperthyroid signs and symptoms consistent with the normal levels of thyroid function tests. The dose of T1 used (100 pg/day) corresponds to a standard replace-
From the Division of Endocrinology, Department of Medicine, North Shore Unlverslty Hospital, Manhassett, New York and NYU School of Medicine. New York Citv. New York. Requests for reprintszshould be addressed to Irwin Klein, MD, Dlvislon of Endocrinoloav. North Shore University Hospital, 300 Community Drive, Manhasset. New York 11030. Manuscript submltted September 16, 1996 and accepted in revised form September 24, 1996.
aD1996 by Excerpta All rights reserved.
Medica.
Inc.
ment dose of T4 for this patient age group and did not alter oxygen consumption or suppress serum TSH as would occur with iatrogenic hyperthyroidism. Biondi and colleagues’ have previously reported that subclinical hyperthyroidism, which occurs with TSH suppressive doses of l-thyroxine (- 150 &day), did increase cardiac contractility in patients with no prior history of heart disease.” In a recent study, parenteral TiI treatment increased cardiac output in postoperative patients with impaired left ventricular function.” To understand the potential mechanisms for these beneficial cardiac effects, it is necessary to focus on both the heart and systemic vasculature. The ability of thyroid hormone to act as a positive cardiac inotropic agent derives in part from increased gene transcription of important myocyte regulatory proteins (Table II) .4 These include the myosin heavy chain contractile proteins and the calcium transport proteins, the sarcoplasmic reticulum calcium ATPase and phospholamban, which modulates the activity of this calcium translocator.‘” The net effect of thyroid hormone on these genes is to enhance calcium uptake into the sarcoplasmic reticulum during diastole and increase the rate of diastolic relaxatilon.‘3 In addition, thyroid hormone may act directly on the myocyte plasma membrane to alter the activity of specific sodium or potassium ion channells. Such a mechanism would account for both chronotropic and inotropic effects.” A reduction in systemic vascular resistance (SVR), as occurs with exercise, is characteristic of hyperthyroidism and can produce increased cardiac output and left ventricular ejection fraction. Moruzzi et al observed that T1 treatment for 1 or 4 weeks significantly lowered SVR”.“’ as did Klemperer et al” when T3 was administered acutely to patient.s undergoing coronary artery bypass surgery. IXPierro et al” showed that bolus administration of TG3improved cardiac function at no cost in oxygen co:nsumption by primarily reducing afterload through vasodilation. These data suggest that thyroid hormone is an effective vasodilator that modulates vascular tone potentially by acting directly on the vascular smooth muscle cell.‘” Many of the signs and symptoms of hyperthyroidism are similar to those of a hyperadrenergic state. This is exemplified by the resting tachycardia, episodes of atria1 fibrillation, and positive inotropy. An interaction between thyroid hormone and endogePII
0002-9343/96/$15.00 SOOO2-9343(96)00310-5
459
EDITORIAL
TABLE
I Cardiovascular
If systemic hemodynamic benefits can be obtained with a dose of T, that does not suppress TSH or, alternatively, if a modified thyroid hormone molecule can be formulated to act specifically as a vasodilator and a cardiac inotropic agent, then cardiovascular therapeutics will have been advanced.
Actions of Thyroid Hormone
Parameter
Effect
Cardiac output Systemic vascular resistance Heart rate Cardiac contractility Systolic Diastolic
t 1 t
References
t t
1. Parry CH. Collections from the unpublished Parry. Dis Heart. 1825;2:111. 2. Klein
I. Thyroid
hormone
and
the
papers
of the late Caleb
cardiovascular
system.
Hillrel
Am J Med.
1990;88:631. 3. Mintz G, Pizzarello R, Klein I. Enhanced hyperthyroidism: noninvasive assessment
TABLE II Thyroid Hormone Responsive Genes in the Heart Myosin heavy chain (isoforms) Sarcoplasmic reticulum calcium activated ATPase Phospholamban Sodium/Potassium ATPase Beta-adrenergic receptor Thyroid hormone nuclear receptors
November
1996
The American
Journal
of Medicine@
diastolic function in to treatment. J Clan
Endocnnol Metab. 1991;73:146. 4. Dillmann WH. Biochemical basis of thyroid hormone actton In the heart. Am J Med. 1990;88:626. 5. Klemperer JD, Ojamaa K, Klein I. Thyroid hormone therapy In cardiovascular disease. Prog Cardiovasc Dis. 1996;38:329. 6. Hamilton MA, Stevenson LW, Luu M, et al. Altered thyroid hormone metabolism in advanced heart failure. JAm Coil Cardiol. 1990;16:91. 7. Fazio S, Sabatini D. Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. NEJM. 1996;334:811.
nous or exogenous catecholamines to augment cardiac function has long been postulated.16 The finding that heart failure and coronary artery surgery are associated with decreases in beta-adrenergic responsiveness,17,18 and that thyroid hormone might attenuate this response by increasing beta-receptors, lg suggests a therapeutically desirable effect.” In the setting of hyperthyroidism, physicians are well aware of the risk of atria1 arrhythmias. Sawin et al have documented this in older patients.‘l The unwanted occurrence of sinus tachycardia or episodes of atrial fibrillation, which were observed by Biondi et al” following long-term T4 treatment, were not seen in the current study. Although Moruzzi et al9 reported an increase in frequency of premature ventricular contractions suggestive of enhanced ventricular irritability, these were not of sufficient duration to warrant treatment. What then would preclude the routine application of T4 therapy to patients with dilated cardiomyopathy? Certainly not the poor prognosis of this disease, the low cost of the medication, or the ease of administration. However, just as bariatricians have been unable to harness the weight loss properties of thyroid hormone and the lipidologist’s have so far failed to extract the cholesterol lowering effects, cardiologists must be vigil that thyroid hormone treatment does not lead to undesirable long-term effects on arrhythmias, bone, skeletal muscle, or behavior.
460
left ventricular and response
Volume
8. Tracey
KJ. RepaIring
the broken
heart
of dilated
cardiomyopathy.
Lancet
1996;347:1129. 9. Moruzzi treatment
P, Dona
467. 10. Moruzzi cardiac
E, Agostoni
in idiopathic P, Doria and exercise
dilated
PG. Medium
term effectiveness
of l-thyroxine
cardiomyopathy.
Am J Med.
1996;101:461-
E, Agostini PG, et al. Usefulness of l-thyroxine to improve performance in idiopathic dilated cardiomyopathy. Am J
Cardiol. 1994;73:374. 11. Biondi B, Fazro S, Carella
C, et al. Cardiac
effects
of long term thyrotropin
suppressive therapy with levothyroxine. J C/in Endocrinol Metab. 1993;77:334. 12. Klemperer JD, Klein I, Ojamaa K, et al. Effects of thyroid hormone supplementation in cardiac surgery. NEJM. 1995;333:1522. 13. Arat M, Masur H, Perisamy M. Sarcoplasmic rebculum gene expression in cardiac hypertrophy and heart failure. Circ Res. 1994;74:555. 14. DlPierro FV, Bavaria sheep ventrrculoarterial
JE, Lankford coupling for
EB, et al. Tmodothyronine opbmizes work efficiency. Ann Thorac Surg.
1996;62:662. 15. Ojamaa K, Balkman
C, Klein I. Acute effects of tmodothyronine on arterjal smooth muscle cells. Ann Thorac Surg. 1993;56:S61. 16. Levey GS, Klein I, Catecholamine-thyroid hormone interactions and the cardiovascular manifestations of hyperthyroidism. Am J Med. 1990;88:642.
17. White downregulation to idiopathic 18. Schwinn beta-adrenergic
M, Yanowitz F, GIlbert EM, et al. Role of beta-adrenergic receptor in the peak exercise response in patients with heart failure due dilated cardiomyopathy. Am J Cardiol. 1995;76: 1271. DA, Leone BJ, Chestnut LC, et al. Desensitization of myocardlal receptors during cardiopulmonary bypass: evidence for early
uncoupling and late downregulation. Circulation. 1991;84:2559. 19. Levine MA, Feldman AM, Robishaw JD. Influence of thyrolcl hormone on expression of genes encoding G protein subunits in the rat heart. Chem. 1990;25:3553. 20. Koch WJ, Rockman HA, Samama expressing the beta-adrenergic receptor
status J Biol
P, et al. Cardiac function in mice overkinase or a beta ARK inhibitor. Science.
1995;268:1350. 21. Sawrn CT, Geller A, Wolf PA, et al. Low serum thyrotropin levels as a risk factor for atrial fibrillation in older persons. NEJM. 1994;33:1249.
101