- Email: [email protected]
Relation of Triiodothyronine to Subclinical Myocardial Injury in Patients With Chest Pain
Readers’ Comments
infarction according to the universal definition of myocardial infarction and 19 (5.9%) met the criteria for TTS. Three more patients who also had TTS were separately mentioned because they had TTS in conjunction with a neurologic primary diagnosis. However, the investigators presented them separately hesitating implicitly to include them in the group of 19 with TTS, presumably because the original Mayo Clinic diagnostic criteria for TTS excluded such a diagnosis in the presence of neurologic illnesses,3 and the current revised criteria2 still include diagnosis of pheochromocytoma as a reason to exclude a diagnosis of TTS. The investigators concluded that TTS may be more common (5.7%) than previously reported (1% to 2.2%) in postmenopausal women presenting with a clinical picture of an acute coronary syndrome (ACS), although their patient study population denominator (SPD) included patients with an acute myocardial infarction, and not ACS. The study has some limitations, which the investigators recognize, particularly the lack of a repeat imaging evaluation proving the improvement or restoration to normal of the initially impaired left ventricular function, which is a sine qua nonelement in the diagnosis of TTS in published works (http://www.ncbi.nlm.nih.gov/ pubmed/?term¼takotsubo). The investigators could not do better considering the current prevailing diagnostic constrains,2 considering that they had to start by using the diagnostic TTS model employing the “filter” of an SPD with suspected ACS on the basis of clinical presentation of chest pain, dyspnea, electrocardiographic changes, and elevated troponin I levels. Of course this is not what should be the case, and ideally all the patients who presented with chest pain or dyspnea or palpitations, including those who died or were discharged, should be the right denominator from whom the case of TTS should have been drawn. Because this is impractical, one should go to the next best SPD, which is the cohort of patients who presented with chest pain or dyspnea or palpitations, irrespective of the results of the troponin I test. Probably, such a study population will not be more revealing, and the authors anticipated this and commented that such patients would be expected to have a very low frequency of TTS. Because patients with eventually proved TTS may present without troponin I increase, and even with a normal or
“near normal” electrocardiogram, one wonders whether the appropriate SPD should be patients with suggestive symptomatology, with an expeditiously performed echocardiography in the emergency department showing cardiac wall motion abnormalities with depressed left ventricular function. Such SPD should be reevaluated before hospital discharge and at the outpatient follow-up with repeat echocardiography, and diagnosis of TTS should be based on the proof that cardiac wall motion abnormalities have been markedly ameliorated or disappeared and that left ventricular function has improved or restored to normal. Thus, this notion forwards the thesis that TTS diagnosis should be based on serial echocardiography and not on the negative results of a coronary arteriogram, which is the current model according to Mayo Clinic TTS diagnostic criteria.2 Indeed, we should start entertaining the notion that TTS can overlap with obstructive coronary artery disease or even ACS because the authors commented that “any illness has the potential to trigger TTS and the diagnosis should be considered in all hospitalized patients with medical or surgical conditions who develop unexplained heart failure or left ventricular (LV) dysfunction.” John E. Madias, MD Elmhurst, New York 23 May 2013
1. Sy F, Basraon J, Zheng H, Singh M, Richina J, Ambrose JA. Frequency of Takotsubo cardiomyopathy in postmenopausal women presenting with an acute coronary syndrome. Am J Cardiol 2013 May 16. pii:S0002-9149(13)00983-1. http://dx. doi.org/10.1016/j.amjcard.2013.04.010. [Epub ahead of print]. 2. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408e417. 3. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, Rihal CS. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141: 858e865.
http://dx.doi.org/10.1016/j.amjcard.2013.05.046
Relation of Triiodothyronine to Subclinical Myocardial Injury in Patients With Chest Pain Growing evidence suggests that reductions in circulating thyroid hormone
465
(TH) levels, in particular reductions in biologically active T3, are commonly observed in patients with various acute and chronic cardiac etiologies, which may negatively influence prognosis.1e4 Therefore, the recently published report by Kim et al5 is of great interest. In their study, the investigators identified an independent association between subclinical myocardial injury, as assessed by elevated high-sensitivity cardiac troponin T, and low serum T3 levels in patients with chest pain and without clinically apparent coronary heart disease (CHD). We commend the investigators for their study and certainly recognize the potential clinical importance of characterizing serum thyroid alterations in cardiac patients.1e4 In fact, we believe that the aforementioned study nicely complements a previous report from our laboratory that demonstrated that serum T3 levels add prognostic information to conventional clinical and functional cardiac parameters in patients with both postischemic and nonischemic dilated cardiomyopathies.2 However, in its present form, we find that it is challenging to adequately draw independent conclusions from this report without further clarification. First, the population examined in this study remains largely undefined from a cardiac perspective as the investigators did not elaborate on the diagnostic screening criteria used to identify the presence or absence of CHD in patients presenting with chest pain. No information was provided regarding electrocardiographic changes (ST elevation or downsloping, T-wave inversion, and Q-wave abnormalities), characteristics of the chest pain (typical vs atypical, acute vs chronic), regional and global left ventricular function, or cardiac event history. It would be enlightening if the investigators clarify whether criteria used to identify CHD was solely on the basis of cardiac enzyme elevations or if more accurate and validated techniques such as invasive coronary angiography or coronary computed tomography angiography were used to confirm the true absence of CHD in patients. Considering that angina is clinically a transitory and completely reversible phenomenon that can occur without myocardial damage or tissue necrosis, it would be invalid to assume that all patients presenting with chest pain symptoms but without elevated cardiac enzymes are truly free from CHD.
466
The American Journal of Cardiology (www.ajconline.org)
A second key clarification is needed as to why the investigators chose to exclude only patients with overt hyperthyroidism from their study population. We find it puzzling that this study did not account for (1) overt or subclinical hypothyroidism, (2) concomitant treatment with synthetic THs or antithyroid medications, or (3) drugs that alter thyroid metabolism (amiodarone, corticosteroids, glucocorticoids, dopamine, dobutamine) and worry that patients with pharmacologic thyroid alterations or severe TH abnormalities may provide disproportionate influence on the study findings and conclusions (selection bias). By only screening for hyperthyroidism, the investigators have likely created an artificial study population characterized by mean serum thyroid-stimulating hormone (TSH) levels greater than those typically observed in the general population and already meeting the diagnostic criteria for subclinical hypothyroidism (TSH 5.97 15.0 mIU/L, median 1.92, interquartile range 1.02 to 3.31).6 The likelihood of far outlying patients skewing the findings of this investigation becomes even more apparent after the investigators categorize patients according to serum T3 levels (low T3 group: TSH 10.1 20.9 mIU/L). These significant TSH elevations, coupled with concomitantly reduced serum T3 levels in this subgroup are strongly suggestive of a patient population composed of both mixed (overt and subclinical hypothyroidism, low T3 syndrome, exogenous thyroid alterations) and coexistent (primary hypothy-
roidism and low T3 syndrome) thyroid abnormalities. Moreover, the prognostic importance of the observed TSH elevations should not be overlooked considering the well-demonstrated relationship between elevated TSH values, especially those >10 mIU/L and risk for CHD events and mortality that occur irrespective of serum T3 or T4 alterations.1 Subsequently, we find it highly unlikely that the investigators can truly elucidate the relative diagnostic value of T3, as an isolated predictor of subclinical myocardial injury, considering the “mixed” and coexistent nature of TH abnormalities in this patient population. It is essential to recognize that distinct peripheral pathophysiologic mechanisms and processes contribute to the altered serum thyroid profile observed in the low T3 syndrome (reduced T3, normal TSH, and FT4), as are commonly observed in cardiac patients, compared with other forms of primary thyroid illness (overt hypothyroidism: elevated TSH, reduced FT4; subclinical hypothyroidism: elevated TSH, normal FT4).1e4,6 This key distinction is especially important considering that the low T3 syndrome carries a separate and distinct relative risk for cardiac and all-cause mortality compared with other forms of altered serum thyroid homeostasis.1e4 Although we certainly recognize the merits and clinic importance of this investigation, it is our belief that more meaningful clinical insight could be drawn from the present study if the investigators comment on and/or reevaluated their data and findings after better
controlling for the characteristics of their study population. Nathan Y. Weltman, MEd Sioux Falls, South Dakota Alessandro Pingitore, MD, PhD Giorgio Iervasi, MD Pisa, Italy 8 May 2013
1. Rodondi N, den Elzen W, Bauer D, Cappola A, Razvi S, Walsh J, Asvold B, Iervasi G, Imaizumi M, Collet T, Bremner A, Maisonneuve P, Sgarbi J, Khaw K, Vanderpump M, Newman A, Cornuz J, Franklyn J, Westendorp R, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304: 1365e1374. 2. Pingitore A, Landi P, Taddei MC, Ripoli A, L’Abbate A, Iervasi G. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118:132e136. 3. Iervasi G, Landi P, Raciti M, Ripoli A, Scarlattini M, L’Abbate A, Donato L. Low-T3 syndrome—a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:708e713. 4. Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L’Abbate A, Pingitore A. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526e1532. 5. Kim BB, Ku YH, Han JY, Ha JM, Park G, Choi DH, Song H. Relation of triiodothyronine to subclinical myocardial injury in patients with chest pain. Am J Cardiol 2013;111: 1087e1091. 6. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease— scientific review and guidelines for diagnosis and management. JAMA 2004;291:228e238. http://dx.doi.org/10.1016/j.amjcard.2013.05.047
infarction according to the universal definition of myocardial infarction and 19 (5.9%) met the criteria for TTS. Three more patients who also had TTS were separately mentioned because they had TTS in conjunction with a neurologic primary diagnosis. However, the investigators presented them separately hesitating implicitly to include them in the group of 19 with TTS, presumably because the original Mayo Clinic diagnostic criteria for TTS excluded such a diagnosis in the presence of neurologic illnesses,3 and the current revised criteria2 still include diagnosis of pheochromocytoma as a reason to exclude a diagnosis of TTS. The investigators concluded that TTS may be more common (5.7%) than previously reported (1% to 2.2%) in postmenopausal women presenting with a clinical picture of an acute coronary syndrome (ACS), although their patient study population denominator (SPD) included patients with an acute myocardial infarction, and not ACS. The study has some limitations, which the investigators recognize, particularly the lack of a repeat imaging evaluation proving the improvement or restoration to normal of the initially impaired left ventricular function, which is a sine qua nonelement in the diagnosis of TTS in published works (http://www.ncbi.nlm.nih.gov/ pubmed/?term¼takotsubo). The investigators could not do better considering the current prevailing diagnostic constrains,2 considering that they had to start by using the diagnostic TTS model employing the “filter” of an SPD with suspected ACS on the basis of clinical presentation of chest pain, dyspnea, electrocardiographic changes, and elevated troponin I levels. Of course this is not what should be the case, and ideally all the patients who presented with chest pain or dyspnea or palpitations, including those who died or were discharged, should be the right denominator from whom the case of TTS should have been drawn. Because this is impractical, one should go to the next best SPD, which is the cohort of patients who presented with chest pain or dyspnea or palpitations, irrespective of the results of the troponin I test. Probably, such a study population will not be more revealing, and the authors anticipated this and commented that such patients would be expected to have a very low frequency of TTS. Because patients with eventually proved TTS may present without troponin I increase, and even with a normal or
“near normal” electrocardiogram, one wonders whether the appropriate SPD should be patients with suggestive symptomatology, with an expeditiously performed echocardiography in the emergency department showing cardiac wall motion abnormalities with depressed left ventricular function. Such SPD should be reevaluated before hospital discharge and at the outpatient follow-up with repeat echocardiography, and diagnosis of TTS should be based on the proof that cardiac wall motion abnormalities have been markedly ameliorated or disappeared and that left ventricular function has improved or restored to normal. Thus, this notion forwards the thesis that TTS diagnosis should be based on serial echocardiography and not on the negative results of a coronary arteriogram, which is the current model according to Mayo Clinic TTS diagnostic criteria.2 Indeed, we should start entertaining the notion that TTS can overlap with obstructive coronary artery disease or even ACS because the authors commented that “any illness has the potential to trigger TTS and the diagnosis should be considered in all hospitalized patients with medical or surgical conditions who develop unexplained heart failure or left ventricular (LV) dysfunction.” John E. Madias, MD Elmhurst, New York 23 May 2013
1. Sy F, Basraon J, Zheng H, Singh M, Richina J, Ambrose JA. Frequency of Takotsubo cardiomyopathy in postmenopausal women presenting with an acute coronary syndrome. Am J Cardiol 2013 May 16. pii:S0002-9149(13)00983-1. http://dx. doi.org/10.1016/j.amjcard.2013.04.010. [Epub ahead of print]. 2. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408e417. 3. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, Rihal CS. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141: 858e865.
http://dx.doi.org/10.1016/j.amjcard.2013.05.046
Relation of Triiodothyronine to Subclinical Myocardial Injury in Patients With Chest Pain Growing evidence suggests that reductions in circulating thyroid hormone
465
(TH) levels, in particular reductions in biologically active T3, are commonly observed in patients with various acute and chronic cardiac etiologies, which may negatively influence prognosis.1e4 Therefore, the recently published report by Kim et al5 is of great interest. In their study, the investigators identified an independent association between subclinical myocardial injury, as assessed by elevated high-sensitivity cardiac troponin T, and low serum T3 levels in patients with chest pain and without clinically apparent coronary heart disease (CHD). We commend the investigators for their study and certainly recognize the potential clinical importance of characterizing serum thyroid alterations in cardiac patients.1e4 In fact, we believe that the aforementioned study nicely complements a previous report from our laboratory that demonstrated that serum T3 levels add prognostic information to conventional clinical and functional cardiac parameters in patients with both postischemic and nonischemic dilated cardiomyopathies.2 However, in its present form, we find that it is challenging to adequately draw independent conclusions from this report without further clarification. First, the population examined in this study remains largely undefined from a cardiac perspective as the investigators did not elaborate on the diagnostic screening criteria used to identify the presence or absence of CHD in patients presenting with chest pain. No information was provided regarding electrocardiographic changes (ST elevation or downsloping, T-wave inversion, and Q-wave abnormalities), characteristics of the chest pain (typical vs atypical, acute vs chronic), regional and global left ventricular function, or cardiac event history. It would be enlightening if the investigators clarify whether criteria used to identify CHD was solely on the basis of cardiac enzyme elevations or if more accurate and validated techniques such as invasive coronary angiography or coronary computed tomography angiography were used to confirm the true absence of CHD in patients. Considering that angina is clinically a transitory and completely reversible phenomenon that can occur without myocardial damage or tissue necrosis, it would be invalid to assume that all patients presenting with chest pain symptoms but without elevated cardiac enzymes are truly free from CHD.
466
The American Journal of Cardiology (www.ajconline.org)
A second key clarification is needed as to why the investigators chose to exclude only patients with overt hyperthyroidism from their study population. We find it puzzling that this study did not account for (1) overt or subclinical hypothyroidism, (2) concomitant treatment with synthetic THs or antithyroid medications, or (3) drugs that alter thyroid metabolism (amiodarone, corticosteroids, glucocorticoids, dopamine, dobutamine) and worry that patients with pharmacologic thyroid alterations or severe TH abnormalities may provide disproportionate influence on the study findings and conclusions (selection bias). By only screening for hyperthyroidism, the investigators have likely created an artificial study population characterized by mean serum thyroid-stimulating hormone (TSH) levels greater than those typically observed in the general population and already meeting the diagnostic criteria for subclinical hypothyroidism (TSH 5.97 15.0 mIU/L, median 1.92, interquartile range 1.02 to 3.31).6 The likelihood of far outlying patients skewing the findings of this investigation becomes even more apparent after the investigators categorize patients according to serum T3 levels (low T3 group: TSH 10.1 20.9 mIU/L). These significant TSH elevations, coupled with concomitantly reduced serum T3 levels in this subgroup are strongly suggestive of a patient population composed of both mixed (overt and subclinical hypothyroidism, low T3 syndrome, exogenous thyroid alterations) and coexistent (primary hypothy-
roidism and low T3 syndrome) thyroid abnormalities. Moreover, the prognostic importance of the observed TSH elevations should not be overlooked considering the well-demonstrated relationship between elevated TSH values, especially those >10 mIU/L and risk for CHD events and mortality that occur irrespective of serum T3 or T4 alterations.1 Subsequently, we find it highly unlikely that the investigators can truly elucidate the relative diagnostic value of T3, as an isolated predictor of subclinical myocardial injury, considering the “mixed” and coexistent nature of TH abnormalities in this patient population. It is essential to recognize that distinct peripheral pathophysiologic mechanisms and processes contribute to the altered serum thyroid profile observed in the low T3 syndrome (reduced T3, normal TSH, and FT4), as are commonly observed in cardiac patients, compared with other forms of primary thyroid illness (overt hypothyroidism: elevated TSH, reduced FT4; subclinical hypothyroidism: elevated TSH, normal FT4).1e4,6 This key distinction is especially important considering that the low T3 syndrome carries a separate and distinct relative risk for cardiac and all-cause mortality compared with other forms of altered serum thyroid homeostasis.1e4 Although we certainly recognize the merits and clinic importance of this investigation, it is our belief that more meaningful clinical insight could be drawn from the present study if the investigators comment on and/or reevaluated their data and findings after better
controlling for the characteristics of their study population. Nathan Y. Weltman, MEd Sioux Falls, South Dakota Alessandro Pingitore, MD, PhD Giorgio Iervasi, MD Pisa, Italy 8 May 2013
1. Rodondi N, den Elzen W, Bauer D, Cappola A, Razvi S, Walsh J, Asvold B, Iervasi G, Imaizumi M, Collet T, Bremner A, Maisonneuve P, Sgarbi J, Khaw K, Vanderpump M, Newman A, Cornuz J, Franklyn J, Westendorp R, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304: 1365e1374. 2. Pingitore A, Landi P, Taddei MC, Ripoli A, L’Abbate A, Iervasi G. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118:132e136. 3. Iervasi G, Landi P, Raciti M, Ripoli A, Scarlattini M, L’Abbate A, Donato L. Low-T3 syndrome—a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:708e713. 4. Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L’Abbate A, Pingitore A. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526e1532. 5. Kim BB, Ku YH, Han JY, Ha JM, Park G, Choi DH, Song H. Relation of triiodothyronine to subclinical myocardial injury in patients with chest pain. Am J Cardiol 2013;111: 1087e1091. 6. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease— scientific review and guidelines for diagnosis and management. JAMA 2004;291:228e238. http://dx.doi.org/10.1016/j.amjcard.2013.05.047