NIH Public Access Author Manuscript Am J Med. Author manuscript; available in PMC 2015 August 01. NIH-PA Author Manuscript Published in final edited form as: Am J Med. 2014 August ; 127(8): 691–698. doi:10.1016/j.amjmed.2014.03.009. Thyroid and the Heart Ira Martin Grais1 and James R. Sowers2,3,4,5 1Department of Medicine/Cardiology Division, Northwestern Feinberg School Medicine, Chicago, IL 2Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 3Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 4Department of Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO NIH-PA Author Manuscript 5Harry S Truman Veterans Affair Medical Center, Columbia, MO Abstract Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases. NIH-PA Author Manuscript Keywords Thyroid dysfunction; cardiac output; heart failure; peripheral vascular function; atrial fibrillation; coronary artery disease © 2014 Elsevier Inc. All rights reserved. CORRESPONDING AUTHOR: Ira Martin Grais, MD, 6611 N. Central Park Avenue, Lincolnwood, IL 60712-3701, igrais@sbcglobal.net. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Both authors had access to the data in this manuscript and both were the sole authors. Grais and Sowers Page 2 INTRODUCTION NIH-PA Author Manuscript The relationship of thyroid hormonal abnormalities and cardiovascular disease goes well beyond the risk of atherosclerosis in association with hypothyroidism and the risk of atrial fibrillation in persons with hyperthyroidism.1 The two organ systems are intimately linked by their embryological anlage, and the ubiquitous effects of thyroid hormone on the major components of the entire circulatory system: the heart, the blood vessels and the blood as defined by the flow law (Fig 1).2 Cardiac output is normally modulated by peripheral arteriolar vasoconstriction and dilatation, venous capacitance, and blood volume in response to tissue metabolic needs.3 The heart can only pump the blood that returns to it, so factors that influence venous return such as blood volume and venous capacitance are critical. Arteriolar dilatation reduces peripheral vascular resistance and thus afterload, increasing cardiac output. The four key issues to be emphasized in this review include a discussion of the normal effects of thyroid hormone on cardiovascular function, as well as therapeutic strategies designed to manage coronary artery disease, atrial fibrillation and heart failure when thyroid hormonal dysfunction is present. Before discussing these clinical issues, a brief summary of the thyroid hormone metabolic effects on the heart and vasculature will be reviewed. NIH-PA Author Manuscript CARDIOVASCULAR PHYSIOLOGY In reviewing the thyroid and the circulatory system, certain key concepts are worth restating and relating to the flow law as illustrated in Figure 1. As described4, thyroid hormone causes a myriad of hemodynamic effects and all can be related directly or indirectly to the flow law. Thyroid function influences every structure of the heart and its specialized conducting system. Moreover, thyroid hormones, in addition to their direct effects on cardiovascular function also have indirect effects mediated through the autonomic nervous system, the renin-angiotensin-aldosterone system (RAAS), vascular compliance, vasoreactivity and renal function. THYROID HORMONE EFFECTS ON THE CARDIOVASCULAR SYSTEM NIH-PA Author Manuscript The major effects of thyroid hormones on the heart are mediated by triiodothyronine (T3) (Fig 2). Indeed, T3 generally increases the force and speed of systolic contraction and the speed of diastolic relaxation.5 In addition, T3 decreases vascular resistance, including coronary vascular tone, and increases coronary arteriolar angiogenesis.5 These multiple thyroid hormone effects are largely mediated by the action of nuclear based thyroid hormone receptors (TR), specifically the TR and . TR is the predominant TR isoform in the heart, and it is the predominant subtype through which T3 binds to nuclear TRs and signals in cardiomyocytes.5–8 T3-activated TR cardiomyocyte growth and maturation is mediated by phosphorylation/activation of phosphoinositol 3-kinase (PI3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) which promotes a number of developmental processes including titan (sarcomere protein) transition.9–13 These T3-activated TR growth effects are modulated by increases in atrial natriuretic peptide (ANP) and decreases in protein kinase C (PKC), especially PKCe.11,12 T3 mediated activation of these signaling pathways initiates changes in gene expression which are compatible with the physiological cardiac hypertrophy phenotype. T3-activated TR regulates myosin heavy chain (MHC) Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 3 NIH-PA Author Manuscript genes which encode for the two contractile protein isoforms of the thick filament of the cardiomyocyte.5–10 T3 exerts a positive effect on the transcription of the myosin heavy chain(MHC) gene and a negative effect on the MHC gene expression (Fig 2).5–10 MHC expression is modulated by T3 regulation of micro (m)-RNAs which influence MHC mRNA turnover and translation. NIH-PA Author Manuscript Thyroid hormones can promote both physiological and pathological myocardial hypertrophy. In this regard cardiac hypertrophy, in its initial phases, presents a physiological process with includes increased adenosine triphosphatase (ATP) and gene expression of the sarcoplasmic reticulum Ca2+ (SERCa2+) and decreased expression of MHC (Fig 2). T3activated TR cardiac effects also include the regulation of cation transport (Fig 2). Regulation of intracellular Ca2+ ([Ca2+]i) is important for both normal systolic and diastolic function. For example, T3 promotes increases in SERCa2+ ATPase and the ryanodine channel, and decreases phosphorylation/activation of phospholamban which functions to inhibit the SERCa2+ pump.14–18 Diastolic function of the heart is substantially influenced by the thyroid status. The speed of diastolic relaxation in the heart is markedly influenced by lowering of the [Ca2+]i levels. In cardiomyocytes, most [Ca2+]i lowering is achieved by pumping [Ca2+]i into the sarcoplasmic reticulum by the SERCa2+ pump. Experimental results in animal models of hypothyroidism indicate that the level and activity of the SERCa2+ pump is markedly decreased and that of inhibitory phospholamban increased.5 These SERCa2+ and phospholamban changes can be linked to a decrease in the rate of diastolic relaxation. The ryanodine receptor is also decreased in hypothyroid hearts.5 Finally, the 1 adrenergic and the TR receptors are positively and negatively regulated by T3, respectively, which promotes optimal modulation of T3-activated TR inotrophic and chronotrophic cardiac effects.5 MECHANISMS OF THYROID HORMONE EFFECTS ON THE VASCULATURE NIH-PA Author Manuscript Thyroid hormones exert effects on the vasculature that generally lead to reduced vascular tone and maintenance of normal arteriolar remodeling.5 It has been known for two decades that T3 exerts direct effects on vascular smooth muscle cells to promote relaxation.5 Several mechanisms for this T3 mediated vascular relaxation have been reported. For example, it has been demonstrated that T3 dose-dependently reduces expression of the angiotensin (Ang) II type 1 receptor and reduces the increased [Ca2+]i and contractile response to Ang II.19. Further, T3 stimulates nitric oxide (NO) production via activation of the PI3-K/Akt mediated endothelial NO synthase (eNOS) signaling pathway.20, 21 The resulting increase in bioavailable NO is associated with decreased myosin light chain (MLC) phosphorylation in response to Ang II and phenylephrine.21 Collectively, these data suggest that T3 reduces VSMC contraction by decreasing [Ca2+]i as well as Ca2+ sensitization. Studies have shown that T3 also promotes angiogenesis and increases the density of small arterioles, including coronary arterioles.5, 22, 23 This T3-activated TR effect on coronary arterioles may be especially important following myocardial ischemia and in the process of myocardial ischemic reconditioning. Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 4 THYROID HORMONES AND HEART FAILURE NIH-PA Author Manuscript NIH-PA Author Manuscript The role of low thyroid hormone function in promoting heart failure and the potential benefits of thyroid hormone replacement, have been reviewed extensively.5, 24 In this regard, heart failure can lead to the down-regulation of the thyroid hormone signaling system in the heart.5 In the failing heart, decreases of nuclear TR levels occur. In addition, serum levels of T4 and T3 are decreased with heart failure in the context of the nonthyroidal illness syndrome. In animal models, it can be shown that in pressure overloadinduced cardiac hypertrophy, a decrease of TR levels occurs. Heart failure is an increasing medical problem in our aging population. There is increasing evidence that decreased thyroid function may contribute to systolic and diastolic dysfunction.5,22,25 Data from clinical studies indicate that thyroid hormone replacement in patients with heart failure has beneficial effects on cardiac contractile function.25–28 Overall, it appears that in heart failure, a hypothyroid cardiac state may occur due to decreased TR levels in failing hearts.5, 25–28 Animal studies and a limited number of human trials indicate that increasing thyroid hormone action, either by increasing T3 receptor levels or serum levels of T3 hormone itself, can improve cardiac function without significant detrimental effects.24, 29,30 It is currently unclear if long term administration of thyroid hormone to patients in heart failure will be well tolerated and will lead to increased survival. This can only be determined by long term randomized controlled clinical trials. NIH-PA Author Manuscript While atherosclerosis and atrial fibrillation are most commonly related to abnormal thyroid function, numerous other cardiac conditions have also been related to thyroid dysfunction. These include pericarditis, pericardial effusion,31 cardiac tamponade, sinus bradycardia and tachycardia, atrioventricular block,32–34 Torsade de pontes ventricular tachycardia typically with a long QTc, left ventricular systolic and diastolic dysfunction, heart failure, high output congestive state, cardiomyopathy,35 mitral valve prolapse (in particular with autoimmune thyroid gland disorders),36,37 endothelial dysfunction, dyslipidemia, and both systolic and diastolic hypertension.38 Thyroid hormones exert effects on both the heart and the vascular system as discussed above. Hypothyroidism decreases endothelial mediated vasorelaxation and vascular compliance and thus elevated diastolic blood pressure (BP).39 Lowered peripheral vascular resistance in hyperthyroidism increases blood volume and venous return.40 This can lead to what is called “ high output failure” when a more accurate term is a congestive state. Clinically relevant heart failure implies that despite adequate venous return the heart cannot pump all the blood that returns to it. However, this is not the case in uncomplicated hyperthyroidism where there is a high output state not unlike that which may occur with a peripheral arteriovenous fistula, severe anemia, pregnancy, or severe liver disease. While these cardiovascular disease abnormalities have been described with overt thyroid dysfunction, some are increasingly recognized as being associated with subclinical hypothyroidism and subclinical hyperthyroidism. Even high normal thyroid hormone function is associated with a slightly increased risk for developing atrial fibrillation.35 HYPOTHYROIDISM Hypothyroidism is characterized by depressed levels of T4 and T3 with compensatory high levels of thyroid stimulating hormone. In seeking the classic clinical manifestations of this condition such as fatigue, sluggishness, hoarse voice, constipation, delayed distal tendon Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 5 NIH-PA Author Manuscript reflexes, and skin changes, the clinician should also evaluate patients for cardiovascular manifestations of hypothyroidism. The most common are diastolic hypertension, sinus bradycardia, due to sinus node dysfunction, and failure of the sinus node to accelerate normally under conditions of stress such as caused by fever, infection or heart failure.41 Other cardiac manifestations may include heart block, pericarditis, pericardial effusion, rare cardiac tamponade.42 Additionally, in chronic hypothyroid states there is increased risk of atherosclerosis often associated with dyslipidemia (hypercholesterolemia) and hypertension. Less common are cardiomyopathy, endocardial fibrosis, and myxomatous valvular changes. NIH-PA Author Manuscript The coronary artery disease accompanying hypothyroidism may be pre-existent or be aggravated by the thyroid dysfunction especially as peripheral vascular resistance increases. The hypertension associated with hypothyroidism may be asymptomatic or attended by overt myocardial ischemia including angina pectoris or myocardial infarction. Great caution is needed in treating such patients with thyroid hormone replacement. The key with replacement therapy is to “ go low and go slow.” The apt caveat is to start with the lowest imaginable dose of thyroid hormone and cut that in half. Important exceptions are patients who are young and without coronary risk factors or patients immediately after total thyroidectomy. There are, of course, many causes of hypothyroidism and these will influence the judgments made about therapy. These are addressed elsewhere in this supplement; however, it is important to identify autoimmune thyroid disorders such as Hashimoto’ s thyroiditis and Graves’ disease since these require special therapeutic considerations. NIH-PA Author Manuscript Typical electrocardiographic changes that can be seen in hypothyroidism include sinus bradycardia, a prolonged QTc (which can result in Torsade de Ponte ventricular tachycardia), low voltage, and the rare instance of atrioventricular block. Some of the salient cardiovascular changes that can occur when hypothyroidism is present are sinus bradycardia, decreased cardiac output, diastolic hypertension, increased myocardial oxygen demand due to increased afterload, long QTc with increased risk of Torsade, increased risk of atherosclerosis due to dyslipidemia (increased total cholesterol, increased low density lipoprotein cholesterol, decreased low density lipoprotein receptors, hypertension and elevated homocysteine levels), some evidence for increased abdominal aortic atherosclerosis and increased intimal-medial carotid thickening, and decreased myocardial perfusion which can resolve with thyroid replacement therapy. Some of these changes are risk factors for coronary artery disease, some relate to the flow law, and some are prime determinants of left ventricular function and myocardial oxygen demand. When coronary artery disease is known or suspected to be present, treating hypothyroidism is a challenge for the clinician. Key questions include 1) What dose of thyroid replacement is best if coronary artery disease is known, 2) What dose if coronary artery disease is suspected, and 3) Does the patient need risk stratification for revascularization before thyroid replacement therapy is initiated? Some of the predominant pathophysiologic and therapeutic considerations with thyroid hormone replacement include the fact that there is increased maximum oxygen consumption (M O2) in the setting of increased peripheral vascular resistance. Secondly, in hypothyroid patients with unstable angina, main left anterior descending coronary disease, triple vessel disease with impaired left ventricle Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 6 NIH-PA Author Manuscript function and with overt hypothyroidism, angioplasty or coronary artery bypass grafting, merit consideration before thyroid hormone replacement therapy. For hypothyroid patients with stable CAD, one should use lower doses of L-thyroxin and increase the dose slowly. For example one may consider starting at 12.5 μg orally daily and increasing the dose every six weeks. The lowering of peripheral vascular resistance with thyroid hormone replacement can also ameliorate the myocardial ischemia in patients with hypothyroidism. The goal of therapy is a euthyroid state with normal TSH and, of course, improvement in myocardial ischemia and cardiac function. NIH-PA Author Manuscript NIH-PA Author Manuscript Approximately 4% of patients with hypothyroidism develop pericarditis so that the finding of pericarditis warrants checking a TSH level even if there is another obvious cause of any non-traumatic pericarditis. Patients with pericarditis require observation for effusion or tamponade although these can occur without pericarditis. The cause of pericardial effusion in hypothyroidism is not certain but likely due to volume retention. The fluid is extruded from the surface of the heart43 and may be golden in color due to cholesterol crystals.44 Subclinical hypothyroidism is defined as a state with high TSH with normal blood levels of T4 and T3. Here the thyroid dysfunction is compensated by the greater stimulation of the elevated TSH level. Despite normal levels of thyroid hormone, such patients are at somewhat increased risk of atherosclerosis. The clinical decision about starting thyroid supplement therapy will be influenced by the age of the patient, the cause of the hypothyroidism and the presence of other atherosclerotic risk factors including hypertension and dyslipidemia. These risk factors for atherosclerosis require appropriate medical management along with thyroid supplementation. With the aging of our population and the ease of getting a TSH level, we can expect to see an increased incidence of subclinical hypothyroidism.45 Endothelial dysfunction is a known early progenitor of hypertension and atherosclerosis. There is evidence of decreased nitric oxide (NO) mediated vascular relaxation in patients with subclinical hypothyroidism as demonstrated by abnormal flow mediated vasodilatation.46 Flow mediated vasodilatation depends on the presence of adequate bioavailable NO in the endothelium. Evaluation of endothelial mediated vascular relaxation has revealed reduced flow mediated vasodilatation in persons with subclinical hypothyroidism. Baseline and flow mediated (NO dependent) vasodilatation values were significantly higher in persons with subclinical hypothyroidism after treatment with Lthyroxin. This study and another in a young cohort47 support the notion that thyroid replacement therapy is beneficial in patients with subclinical hypothyroidism. Left and right ventricular systolic and diastolic dysfunction have also been described in subclinical hypothyroidism and there is evidence for improvement in ventricular function with thyroid replacement therapy.48–50 HYPERTHYROIDISM Hyperthyroidism is characterized biochemically by a low TSH level and elevated T4, T3 or both. The causes include Graves’ disease, nodular thyroid disease, and factitious or iatrogenic over dosage with thyroid hormone.51 Patients with hyperthyroidism can develop a life threatening complication called thyroid storm or crisis, requiring urgent therapy with beta blockers, antithyroid medication and iodine. This complication can be precipitated by an acute illness such as a myocardial infarction, infection or other stress.52 Timely treatment Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 7 of this condition is especially critical in patients with underlying coronary disease or heart failure. NIH-PA Author Manuscript The clinical symptoms and signs of hyperthyroidism include systolic hypertension, increased left ventricular mass,53 exercise intolerance, angina pectoris and systolic murmurs.53, Complications include atrial fibrillation with its risk of stroke, and high output and heart failure.54, 55 A serum TSH level should be measured in any patient with paroxysmal or sustained atrial fibrillation. If the TSH level is low, further thyroid evaluation is needed. Atrial fibrillation, especially in the presence of pre-existent heart disease can result in clinical heart failure. This heart failure may be due to an associated rapid ventricular response which when sustained can lead to tachycardia-mediated cardiomyopathy. The loss of atrial contractile function and decreased diastolic filling time due to the tachycardia may cause increased filling pressures further contributing to this cardiomyopathy. NIH-PA Author Manuscript Atrial fibrillation and atrial flutter management presents unique challenges in patients with associated hyperthyroidism. The usual guidelines should be followed except that efforts to restore sinus rhythm are ordinarily delayed until the patient is euthyroid. This reduces the likelihood of the rhythm reverting to atrial fibrillation. In the absence of evidence based studies to support anticoagulation in such patients, careful clinical judgment is required.56 With novel anticoagulants such as the direct thrombin antagonist dabigatran and the factor Xa inhibitors rivaroxaban and apixaban for nonvalvular atrial fibrillation, such a decision for anticoagulant therapy is likely to be easier in the future, especially in patients who are not good candidates for warfarin. NIH-PA Author Manuscript While sinus tachycardia is the most common arrhythmia seen in hyperthyroidism, the incidence of atrial fibrillation ranges from 2–20%, with prevalence increasing with age. Of all cases of atrial fibrillation, only 1% are due to overt hyperthyroidism. Yet available therapy justifies checking the TSH level in any patient with atrial fibrillation. The principle objectives in treating atrial fibrillation associated with hyperthyroidism are rate control, prevention of thromboembolism, and restoration of sinus rhythm. The following list is the 2011 guidelines of the joint committee of the American College of Cardiology and the American Heart Association57: 1. Beta blockers to control the heart rate unless specifically contraindicated; 2. When a beta blocker cannot be used, a nondihydropyridine calcium channel antagonist is recommended; 3. oral anticoagulation (INR 2.0 to 3.0); 4. Once euthyroid state is achieved, antithrombotic prophylaxis is the same as for patients without hyperthyroidism. In patients with atrial fibrillation/flutter, if digitalis is used for rate control, higher doses are typically needed. Two thirds of patients return to sinus rhythm with radioiodine or antithyroid drugs within 2–3 months. Despite its significant iodine content, amiodarone can be used safely in these patients for rate control and cardioversion while checking the TSH level at least every six months. The role of new anticoagulants such as dabigatran, rivaroxaban and apixaban remain to be determined in the patient with both atrial fibrillation and hyperthyroidism. Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 8 NIH-PA Author Manuscript Using the CHADS2 risk score provides useful guidelines for determining prophylactic anticoagulation and compelling considerations in the management of atrial fibrillation with regard to stroke prevention. For patients with borderline risk based on the CHADS2 score, the newer CHA2DS2-VASc score assigns points for female gender, age 65–75, and vascular disease. This latter score seems to fill an important gap. The most evidence-based study available reached variant conclusions from that discussed above59 regarding stroke in thyrotoxic atrial fibrillation.60 This evidence based study involved a retrospective of 610 patients with untreated thyrotoxicosis, 91 or 14.9% of whom had atrial fibrillation, the highest frequency being in elderly patients.60 The risk of cerebrovascular events was calculated using logistic regression methods. Only age was an important independent risk factor. The authors concluded that the indication for prophylactic treatment with anticoagulants for prevention of stroke in thyrotoxic atrial fibrillation seemed doubtful in the absence of controlled trials. Aspirin seems a good alternative in younger patients without organic heart disease. Meanwhile the new novel anticoagulants may help resolve the issues.61 NIH-PA Author Manuscript Heart failure in hyperthyroidism is another complex problem with many facets. It is essential to distinguish a congestive state from clinical heart failure. If heart failure exists, a number of conditions can precipitate it. Adding a Doppler echocardiogram to a careful history and physical will usually clarify if structural heart disease or dysfunction is present. The differential diagnosis of heart failure, with which the Doppler echocardiogram can assist, includes high output failure (congestive state), tachycardia induced cardiomyopathy, precipitation by atrial fibrillation, precipitation by coexistent organic heart disease including coronary heart disease, hypertension, valvular disease including mitral valve prolapse, left ventricular dilatation leading to mitral regurgitation and ruling out cardiac tamponade. NIH-PA Author Manuscript The presence of hyperthyroidism does not exclude other common causes of heart failure. Moreover, there is an essential basic principle that applies: whenever an organ or organ system fails, look for a precipitating cause. Common causes of heart failure include onset of atrial fibrillation, uncontrolled ventricular response with atrial fibrillation, uncontrolled hypertension, excessive salt intake, failure to adhere to medical therapy, myocardial ischemia or infarction, papillary muscle dysfunction, ruptured chordae, endocarditis, other infections, renal failure, and, of course, hyperthyroidism. In 2009 the FDA approved the Thyretain™ TSI Reporter Bioassay, the first test specifically detecting thyroid stimulating immunoglobulin (TSI), the causative agent for Graves’ disease. Initial testing includes a TSH, T3 and FT4 in asymptomatic or symptomatic patients at clinically increased risk of hyperthyroidism. If the TSH is low or even borderline low, step two is to repeat the TSH to confirm accuracy, and obtain TSI and thyroid peroxidase (TPO) antibody tests. If the TSI test is negative, but TSH, T3 and/or FT4 are abnormal, the clinician should pursue further cardiovascular workup and consider consultation with an endocrinologist. When hyperthyroidism is suspected in a patient with atrial fibrillation, the TSI test should be obtained and attempts to restore sinus rhythm should be deferred until the patient is rendered euthyroid in order to reduce the risk of failure to convert or of recurrent atrial fibrillation. Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 9 Beta blockers have a pre-eminent role in the management of heart failure in hyperthyroidism although the ultimate treatment is restoration of a euthyroid state. NIH-PA Author Manuscript Subclinical hyperthyroidism is defined as normal T4 and T3 levels with a low TSH level. As with subclinical hypothyroidism, the ease of getting TSH levels results in an increased recognition of subclinical hyperthyroidism, especially in the elderly. Such patients also have an increased risk of developing atrial fibrillation. Indeed, the Rotterdam study showed that even individuals with high normal thyroid function (high range of normal TSH levels) have an increased such risk as well as for atherosclerosis and myocardial infarction in elderly women.64,65,66 Such patients require periodic monitoring to search for evidence of overt hyperthyroidism. A decision to treat subclinical hyperthyroidism depends on its cause, evidence of cardiac disease, and comorbidities. NIH-PA Author Manuscript While controversy remains for the management of both subclinical hyperthyroidism and hypothyroidism, it was concluded in a recent review51 that a clinical decision regarding initiating therapy requires consideration of the cause of the thyroid disease, the degree of thyroid function tests abnormality, associated comorbidities, risk of progression, age of the patient, and coexistent conditions such as pregnancy. The authors recommend the urgent need for large-scale randomized trials. Meanwhile investigators,67 using data from 10 prospective cohort studies totaling 52,674 patients assessed the risks of coronary heart disease mortality and events and atrial fibrillation in patients with subclinical hyperthyroidism and concluded that risks were increased when the TSH level was lower than 0.10 mU/L. In this regard, most patients with both primary hypothyroidism and Grave’ s disease will have positive antibodies as iterated in two review articles.68, 69 SUMMARY NIH-PA Author Manuscript Thyroid hormone affects virtually every anatomic and physiologic component of the cardiovascular system. In the presence of heart disease, pericardial disease, heart failure and/or arrhythmias, overt or subclinical thyroid dysfunction merits a high level of clinical suspicion. The ease of obtaining a screening TSH level especially in our aging population means many more patients will need assessment, risk stratification, and treatment in the future. By understanding pertinent cardiovascular physiology and pathophysiology, physicians will have a firmer basis for making the often complicated recommendations for patient care even when evidence-based studies are not yet available. Meanwhile for subclinical thyroid disease, while routine treatment remains controversial, routine screening with TSH levels merits implementation especially in pregnant women, women over 60 years of age, and anyone whose risk of thyroid dysfunction is high.70 Acknowledgments IRA MARTIN GRAIS: Funding related to this manuscript: None Conflict of interest: None JAMES R. SOWERS: Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 10 Funding related to this manuscript: Work conducted in our laboratory is supported by NIH (R01 HL73101-08 and R01 HL107910-03) (JRS) and Veterans Affairs Merit System 0018 (JRS). NIH-PA Author Manuscript Conflict of interest: None References NIH-PA Author Manuscript NIH-PA Author Manuscript 1. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007; 116:1725–1735. [PubMed: 17923583] 2. Klein, I. Chapter 86: Endocrine disorders and cardiovascular disease In Braunwald’ s. In: Bonow, RO.; Mann, DL.; Zipes, DP.; Libby, P., editors. Heart Disease. Ninth. Vol. 2. Elsevier; Saunders: 2012. p. 1833-1841. 3. Guyton’ s, Arthur C. Circulatory Physiology: Cardiac output and its regulation. W. B. Saunders Company; Philadelphia: 1963. 4. Fazio S, Palmieri EA, Lombardi G, Biondi B. Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res. 2004; 59:31–50. [PubMed: 14749496] 5. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001; 344(7): 501–509. [PubMed: 11172193] 6. Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart. Endocr Rev. 2005; 26(5):704–728. [PubMed: 15632316] 7. Yen PM, Ando S, Feng X, et al. Thyroid hormone action at the cellular, genomic and target gene levels. Mol Cell Endocrinol. 2006; 246(1–2):121–127. [PubMed: 16442701] 8. Bassett JH, Harvey CB, Williams GR. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol. 2003; 213(1):1–11. [PubMed: 15062569] 9. Kuzman JA, Gerdes AM, Kobayashi S, Liang Q. Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 2005; 39(5):841–844. [PubMed: 16171808] 10. Kenessey A, Ojamaa K. Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt- mTOR and p70S6K pathways. J Biol Chem. 2006; 281:20666–20672. [PubMed: 16717100] 11. Kruger M, Sachse C, Zimmermann WH, et al. Thyroid hormone regulates developmental titan isoform transitions via the phosphatidylinositol-3-kinase/Akt pathway. Circ Res. 2008; 102:439– 447. [PubMed: 18096819] 12. Dillman W. Cardiac hypertrophy and thyroid hormone signaling. Heart Fail Rev. 2010; 15:125– 132. [PubMed: 19125327] 13. Chattergoon NN, Giraud GD, Loney S, et al. Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J. 2012; 26:397–408. [PubMed: 21974928] 14. Rohrer DK, Hartong R, Dillmann WH. Influence of thyroid hormone and retinoic acid on slow sarcoplasmic reticulum Ca2+ATPase and myosin heavy chain alpha gene expression in cardiac myocytes. Delineation of cis-active DNA elements that confer responsiveness to thyroid hormone but not to retinoic acid. J Biol Chem. 1991; 266(13):8638–8646. [PubMed: 1827123] 15. Reed TD, Babu GJ, Ji Y, et al. The expression of calcium SR transport ATPase and the Na(+)/ Ca(2+)Exchanger are antithetically regulated during mouse cardiac development and in hypo/ hyperthyroidism. J Mol Cell Cardiol. 2000; 32(3):453–464. [PubMed: 10731444] 16. Gloss B, Trost S, Bluhm W, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid receptor alpha or beta. Endocrinology. 2001; 142(2):544–550. [PubMed: 11159823] 17. Ojamaa K, Kenessey A, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology. 2000; 141(6):2139–2144. [PubMed: 10830301] 18. Davis PJ, Leonard JL, Davis FB. Mechanisms of nongenomic actions of thyroid hormone. Front Neuroendocrinol. 2008; 29(2):211–218. [PubMed: 17983645] 19. Fukuyama K, Ichiki T, Takeda K, et al. Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone. Hypertension. 2003; 41:598–603. [PubMed: 12623965] Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 11 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 20. Bussemaker E, Popp R, Fisslthaler B, et al. Hyperthyroidism enhances endothelium-dependent relaxation in the rat renal artery. Cardiovasc Res. 2003; 59(1):181–189. [PubMed: 12829189] 21. Carrillo-Sepúlveda MA, Ceravolo GS, Fortes ZB, et al. Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes. Cardiovasc Res. 2010; 85(3):560–570. [PubMed: 19734167] 22. Tang YD, Kuzman JA, Said S, et al. Low thyroid function leads to cardiac atrophy and chamber dilatation, impaired myocardial blood flow, loss of arterioles, and severe systolic dysfunction. Circulation. 2005; 112(20):3122–3130. [PubMed: 16275864] 23. Savinova OV, Liu Y, Aasen GA, et al. Thyroid hormone promotes remodeling of coronary resistance vessels. PLoS One. 2011; 6(9):e25054. [PubMed: 21966411] 24. Gerdes AM, Iervasi G. Thyroid replacement therapy and heart failure. Circulation. 2010; 122(4): 385–393. [PubMed: 20660814] 25. Kinugawa K, Minobe WA, Wood WM, et al. Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression. Circulation. 2001; 103(8):1089–1094. [PubMed: 11222471] 26. Pantos C, Dritsas A, Mourouzis I, et al. Thyroid hormone is a critical determinant of myocardial performance in patients with heart failure: potential therapeutic implications. Eur J Endocrinol. 2007; 157(4):515–520. [PubMed: 17893267] 27. Olivares EL, Marassi MP, Fortunato RS, et al. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology. 2007; 148(10):4786–4792. [PubMed: 17628010] 28. Iervasi G, Pingitore A, Landi P, et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003; 107(5):708–713. [PubMed: 12578873] 29. Trivieri MG, Oudit GY, Sah R, et al. Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction. Proc Natl Acad Sci USA. 2006; 103(15):6043–6048. [PubMed: 16595628] 30. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2008; 93(4):1351–1358. [PubMed: 18171701] 31. Ovadia S, Lysyy L, Zubkov T. Pericardial effusion as an expression of thyrotoxicosis. Tex Heart Inst J. 2007; 34(1):88–90. [PubMed: 17420800] 32. Schoenmakers N, de Graaff WE, Peters RHJ. Hypothyroidism as a cause of atrioventricular block in an elderly patient. Neth Heart J. 2008; 16(2):57–59. [PubMed: 18335023] 33. Mangiari L, Gaita F, Brun S, et al. Atrioventricular block complicating amiodarone-induced hypothyroidism in a patient with pre-excitation and rate-dependent bilateral bundle branch block. J Am Coll Cardiol. 1986; 7(1):180–184. [PubMed: 3941210] 34. Eraker SA, Wickamasekaran R, Goldman S. Complete heart block with hyperthyroidism. JAMA. 1978; 239(16):1644–1646. [PubMed: 580298] 35. Ladenson PW. Recognition and management of cardiovascular disease related to thyroid dysfunction. Am J Med. 1990; 88(6):638–641. [PubMed: 2189308] 36. Zullo MA, Devereux RB, Kramer-Fox R, et al. Mitral valve prolapse and hyperthyroidism: effect of patient selection. Am Heart J. 1985; 110(5):977–980. [PubMed: 4061273] 37. Brauman A, Rosenberg T, Gilboa Y, et al. Prevalence of mitral valve prolapse in chronic lymphocytic thyroiditis and nongoitrous hypothyroidism. Cardiology. 1988; 75(4):269–273. [PubMed: 3167916] 38. Klein M, Pascal V, Aubert V, et al. Heart and thyroid [article in French]. Ann Endocrinol (Paris). 1995; 56(5):473–86. [PubMed: 8597489] 39. Prisant LM, Gujral JS, Mulloy AL. Hyperthyroidism: a secondary cause of isolated systolic hypertension. J Clin Hypertens (Greenwich). 2006; 8(8):596–599. [PubMed: 16896276] 40. Chang H-C. The blood volume in hyperthyroidism. J Clin Invest. 1931; 10(3):475–487. [PubMed: 16693993] 41. Grais IM. Bedside skills: A 50-year personal retrospective. Texas Heart Institute J. 2010; 37(6): 629–632. Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 12 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 42. Patil VC, Patil HV, Agrawal V, Patil S. Cardiac tamponade in a patient with primary hypothyroidism. Indian J Endocrinol Metab. 2011; 15(Suppl2):S144–S146. [PubMed: 21966654] 43. Miller, AJ. Chaper 9: The lymph drainage of the heart. In: Johnson, editor. Experimental Biology of the lymphatic circulation. Elsevier Science Publishers, B.V.; 1985. 44. Alexander JS. Pericardial effusion of “ Gold Paint” appearance due to presence of cholesterin. Brit Med J. 1919; 2:463. [PubMed: 20769656] 45. Asvold BO, Bjøro T, Nilsen TL, et al. Thyrotropin levels and risk of fatal coronary heart disease: The HUNT Study. Arch Intern Med. 2008; 168(8):855–860. [PubMed: 18443261] 46. Alibaz OF, Yurdakul S, Oner E, et al. Evaluation of the effect of L thyroxin therapy on endothelial functions in patients with subclinical hypothyroidism. Endocrine. 2011; 40(2):280–284. [PubMed: 21505892] 47. Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events and mortality. Arch Intern Med. 2012; 172(10):811–817. [PubMed: 22529180] 48. Turhan S, Tulunay C, Ozduman CM, et al. Effects of thyroxin therapy on right ventricular systolic and diastolic function in patients with subclinical hypothyroidism: a study by pulsed wave tissue Doppler imaging. J Clin Endocrinol Metab. 2006; 91(9):3490–3493. [PubMed: 16822817] 49. Niafar M, Toufan M, Ghafoori S, Aghamohammadzadeh N. Subclinical hypothyroidism effects on cardiac function. Pak J Biol Sci. 2009; 12(15):1056–1062. [PubMed: 19943461] 50. Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid. 2000; 10(8):665–679. [PubMed: 11014311] 51. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012; 379:1142–1154. [PubMed: 22273398] 52. Grais IM. Internal medicine problems as they present to the cardiologist. Tex Heart Inst J. 2011; 38(4):330–332. [PubMed: 21841853] 53. Marcisz C, Jonderko G, Wróblewski T, et al. Left ventricular mass in patients with hyperthyroidism. Med Sci Monit. 2006; 12(11):CR481–486. [PubMed: 17072274] 54. Fadel BM, Ellahham S, Ringel MD, et al. Hyperthyroid heart disease. Clin Cardiol. 2000; 23:402– 408. [PubMed: 10875028] 55. Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012; 379:1155–1166. [PubMed: 22394559] 56. Traube E, Coplan NL. Embolic risk in atrial fibrillation that arises from hyperthyroidism. Tex Heart Inst J. 2011; 38(3):225–228. [PubMed: 21720457] 57. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS Focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011; 57:223–242. [PubMed: 21177058] 58. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011; 365(24):2268–2276. [PubMed: 22082198] 59. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke. Results from the national registry of atrial fibrillation. JAMA. 2001; 285(22): 2864–2870. [PubMed: 11401607] 60. Peterson P, Hansen JM. Stroke in thyrotoxicosis with atrial fibrillation. Stroke. 1988; 19:15–18. [PubMed: 3336898] 61. De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC working group on thrombosis— task force on anticoagulation in heart disease position paper. J Am Coll Cardiol. 2012; 59:1413–1425. [PubMed: 22497820] 62. Zullp MA, Devereux RB, Kramer-Fox R, et al. Am Heart J. 1985; 110(5):977–980. [PubMed: 4061273] 63. McKee A, Peyerl F. TSI assay utilization: impact on costs of graves’ hyperthyroidism diagnosis. Am J Manag Care. 2012; 18(1):e1–e14. [PubMed: 22435785] 64. Heeringa J, Hoogendoorn EH, van der Deure WM, et al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam study. Arch Intern Med. 2008; 168(20):2219–2224. [PubMed: 19001198] Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 13 NIH-PA Author Manuscript 65. Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med. 2000; 132:270–278. [PubMed: 10681281] 66. Völzke H, Alte D, Dorr M, et al. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertes. 2006; 24(10):1947–1953. 67. Collet TH, Gussekloo Bauer DC, et al. for the Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. Published online April 23, 2012. 10.1001/archinternmed.2012.402 68. Surks MI, Ortiz E, Daniels GH. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004; 291(2):228–238. [PubMed: 14722150] 69. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med. 1996; 335:99–107. [PubMed: 8649497] 70. Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National Health and Nutrition Examination Survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol Metab. 2007; 92:4236–4240. [PubMed: 17684054] NIH-PA Author Manuscript NIH-PA Author Manuscript Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 14 CLINCIAL SIGNIFICANCE NIH-PA Author Manuscript • Thyroid and cardiovascular function are intimately linked. • When thyroid dysfunction is known or suspected, cardiovascular disease or risk should be assessed. • When certain cardiovascular diseases, such as atrial fibrillation or sinus bradycardia occur, thyroid function should be assessed. • Cardiac and peripheral vascular function, including cardiac and endothelial mediated vasorelaxation, is partly dependent on thyroid hormone signaling. • Subclinical thyroid dysfunction can also be associated with cardiac disorders and merits clinical screening. NIH-PA Author Manuscript NIH-PA Author Manuscript Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 15 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. Each component of the flow law is influenced by thyroid hormone MAP = mean arterial pressure, RAP = right atrial pressure, = Cardiac Output, TPR = total peripheral resistance. The Poiseuille-Hagan Law demonstrates how small changes in arteriolar radius lead to geometric changes in arteriolar resistance. R= resistance; r = radius; # = (η = dynamic fluid viscosity; Δ = change; X = distance in direction of flow; ∏ = mathematical constant Pi). NIH-PA Author Manuscript Am J Med. Author manuscript; available in PMC 2015 August 01. Grais and Sowers Page 16 NIH-PA Author Manuscript Figure 2. Thyroid hormone effects on the heart NIH-PA Author Manuscript T3 = triiodothyronine; TR = thyroid hormone receptors; cAMP = cyclic AMP, PKC = protein kinase C; PI3-K = phosphoinositol 3-kinase; Akt = protein kinase B; (p) mTOR = phosphorylation of mammalian target of rapamycin; (p)ERK = phosphorylation of extracellular-signal-regulated kinases; SERCa2+= sarcoplasmic reticulum Ca2+; Na = sodium; K-ATPase = potassium adenosine triphosphatase; MHC = myosin heavy chain alpha; MHC = myosin heavy chain alpha beta; ANP = atrial natriuretic peptide NIH-PA Author Manuscript Am J Med. Author manuscript; available in PMC 2015 August 01.