IJCA-18142; No of Pages 3 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria John E. Madias ⁎ Icahn School of Medicine at Mount Sinai, New York, NY, United States Division of Cardiology, Elmhurst Hospital Center, Elmhurst, NY, United States
a r t i c l e
i n f o
Article history: Received 17 March 2014 Accepted 22 April 2014 Available online xxxx Keywords: Takotsubo syndrome Criteria Mayo Clinic criteria for Takotsubo syndrome
a b s t r a c t Diagnosis of Takotsubo syndrome (TTS), the reversible, acute heart failure pathological entity, precipitated by stress, is based on the fulfillment of sets of criteria, developed by careful characterization of the precipitants, symptoms, results of imaging testing, clinical course, and follow-up of many patients presented with this affliction. As understanding of TTS, increase in its awareness, and the diversion in its presentation have evolved, the various proposed diagnostic criteria, naturally have started to appear outmoded. The author argues that the initially proposed Mayo Clinic criteria, the subsequently revised Mayo Clinic criteria, the Japanese Circulation Society guidelines, the Johns Hopkins criteria, and the Gothenburg criteria for the diagnosis of TTS have been outpaced by the rapidly accumulating clinical experience, and thus need to be replaced by more realistic sets of diagnostic rules. To this effect the author proposes a set of diagnostic criteria for TTS, which include 2 plausible, albeit speculative, notions, that of the milder forms or formes frustes of TTS, and the existence of “TTS comorbidity” in patients with various other illnesses, which either precipitate TTS, or are being brought about by TTS. © 2014 Elsevier Ireland Ltd. All rights reserved.
This viewpoint will not start in the conventional fashion, i.e., providing an “Introduction”, describing in a stereotypical manner the particular characteristics of Takotsubo syndrome (TTS), since these are by now well known to all, after being elaborated in numerous short and long reviews (http://www.ncbi.nlm.nih.gov/pubmed/? term=takotsubo (accessed last on 3/17/14)). Instead this piece will delve into the adequacy of the diagnostic criteria of TTS, and whether they need to be revised. The diversity of the clinical presentation of TTS, reflected in the rapidly ever expanding vast literature on TTS, underscores the idea that the current criteria for the diagnosis of TTS are outmoded. The originally proposed Mayo Clinic criteria for TTS ([1] Table 1) have been included as item #2, the “absence of obstructive coronary disease”, and as a prerequisite for making the diagnosis of TTS; however many cases of TTS have now been described of patients with prior history of myocardial infarction, or angiographic evidence of obstructive coronary disease during the index admission for TTS [1]. Also item #4 includes again “obstructive coronary disease”, recent significant head trauma, intracranial bleeding, pheochromocytoma, myocarditis, and hypertrophic cardiomyopathy, conditions which need to be excluded, before one can make the diagnosis of TTS [1]. It is not clear by
⁎ Corresponding author at: Division of Cardiology, Elmhurst Hospital Center, 79-01 Broadway, Elmhurst, NY 11373, United States. Tel.: +1 718 334 5005; fax: +1 718 334 5990. E-mail address: [email protected].
contemporary conceptualizations why all these conditions, particularly the ones involving derangements of the central nervous system, characterized by adrenergic activity surges, and associated with classic clinical presentations of TTS should be reasons not to make the diagnosis of TTS. In reference to pheochromocytoma, this continues to be included in the Mayo Clinic criteria (Table 2), as something that needs to be excluded, when one attempts to make the diagnosis of TTS; however the authors of the revised Mayo Clinic diagnostic criteria for TTS, in the text of their article state that they “no longer exclude” the diagnosis of TTS in patients developing typical features of the condition in the setting of intracranial bleeding, including subarachnoid hemorrhage, but continue to consider simultaneous diagnoses of pheochromocytoma and TTS as incompatible (Table 2), while stating in the text of their article, that “wall motion abnormalities and depressed ejection fraction have been observed in diseases associated with high catecholamines such as pheochromocytoma and subarachnoid hemorrhage”, also citing the literature. Indeed this is a contradiction! Also, although the authors of the Mayo Clinic criteria in their revised diagnostic criteria (Table 2) continue to refer to the notion that the diagnosis of TTS should be made in the “absence of obstructive coronary disease”, at the footnote of their table, they state that TTS and “obstructive coronary atherosclerosis” may coincide, but this is “very rare in their experience and in the published literature, perhaps because such cases are misdiagnosed as an acute coronary syndrome” (Table 2) [2]. However this statement is contradictory in the sense that it implies that the coincidence of TTS and “obstructive coronary atherosclerosis” is rare according to the authors of
http://dx.doi.org/10.1016/j.ijcard.2014.04.241 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Madias JE, Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.241
2
Editorial
Table 1 Proposed Mayo Clinic criteria for the clinical diagnosis of the transient left ventricular ballooning syndrome. Reproduced from Table 3 of Ref. [1]. 1. Transient akinesis or dyskinesis of the left ventricular apical and mid-ventricular segments with regional wall-motion abnormalities extending beyond a single epicardial vascular distribution 2. Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture 3. New electrocardiographic abnormalities (either ST-segment elevation or T-wave inversion) 4. Absence of recent significant head trauma, intracranial bleeding, pheochromocytoma, obstructive epicardial coronary artery disease, myocarditis, and hypertrophic cardiomyopathy All 4 of the above statements must be met.
the revised Mayo Clinic criteria of TTS, as per their experience (a presumed fact), while at the same time it is rare because TTS is a misdiagnosed condition in the literature, as acute coronary syndrome (a fallacy). This implies that TTS is a deceptively rare, but actually common affliction. The Japanese Circulation Society has issued guidelines for TTS in 2007, based on a questionnaire sent in 2003 to 203 institutions from which scientific reports on TTS had emanated; subsequently 33 investigators who had published reports on TTS were contacted and 21 of them responded to the charge of evaluating and revising the “1st edition” of these guidelines [3]. There were disagreements about certain matters, and a surprising agreement about the noninclusion of the “inverse takotsubo” as an occasional presenting feature of the disease; midventricular involvement is not mentioned [3]. Lack of significant coronary artery stenosis was emphasized as a prerequisite to make the diagnosis of TTS. Cerebrovascular accidents with classic presentation TTS are included as “cerebrovascular disease with takotsubo-like myocardial dysfunction”, and differentiated from “idiopathic” TTS (Table 3) [3]. Conditions which need to be excluded before the diagnosis of TTS can be made are acute coronary syndrome, cerebrovascular disease, pheochromocytoma, and myocarditis (Table 3) [3]. These diagnostic guidelines appear outmoded particularly due to their strict exclusion criteria, and the disregard for atypical presentations of TTS in terms of the involvement of left ventricular segments other than the apex, all of which are contradicted by the large experience reflected in the literature. The Johns Hopkins criteria start with a set of “helpful, but not mandatory” criteria, which include the known emotional and physical stress precipitants, the electrocardiographic changes, and the release of cardiac biomarkers associated with TTS, and then proceed with a set of “mandatory criteria" (all three criteria must be met), which include the “absence of coronary thrombosis or angiographic evidence of acute plaque rupture”, and “regional ventricular wall motion abnormalities Table 2 Proposed Mayo Clinic criteria for ABS. Reproduced from Table 2 of Ref. [2]. 1. Transient hypokinesis, akinesis, or dyskinesis of the left ventricular midsegments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always presenta 2. Absence of obstructive coronary disease or angiographic evidence of acute plaque ruptureb 3. New electrocardiographic abnormalities (either ST-segment elevation and/or Twave inversion) or modest elevation in cardiac troponin 4. Absence of pheochromocytoma or myocarditis In both of the above circumstances, the diagnosis of ABS should be made with caution, and a clear stressful precipitating trigger must be sought. a There are rare exceptions to these criteria such as those patients in whom the regional wall motion abnormality is limited to a single coronary territory. b It is possible that a patient with obstructive coronary atherosclerosis may also develop ABS. However, this is very rare in our experience and in the published literature, perhaps because such cases are misdiagnosed as an acute coronary syndrome.
Table 3 Guidelines for the diagnosis of takotsubo (ampulla) cardiomyopathy. Reproduced from Table 1 of Ref. [3]. I. Definition Takotsubo (ampulla) cardiomyopathy is a disease exhibiting an acute left ventricular apical ballooning of unknown cause. In this disease, the left ventricle takes on the shape of a “takotsubo” (Japanese octopus trap). There is nearly complete resolution of the apical akinesis in the majority of the patients within a month. The contraction abnormality occurs mainly in the left ventricle, but involvement of the right ventricle is observed in some cases. A dynamic obstruction of the left ventricular outflow tract (pressure gradient difference, acceleration of blood flow, or systolic cardiac murmurs) is also observed. Note: There are patients, such as cerebrovascular patients, who have an apical systolic ballooning similar to that in takotsubo cardiomyopathy, but with a known cause. Such patients are diagnosed as “cerebrovascular disease with takotsubo-like myocardial dysfunction” and are differentiated from idiopathic cases. II. Exclusion criteria The following lesions and abnormalities from other diseases must be excluded in the diagnosis of takotsubo (ampulla) cardiomyopathy. A. Significant organic stenosis or spasm of a coronary artery. In particular, acute myocardial infarction due to a lesion of the anterior descending branch of the left coronary artery, which perfuses an extensive territory including the left ventricular apex (an urgent coronary angiogram is desirable for imaging during the acute stage, but coronary angiography is also necessary during the chronic stage to confirm the presence or absence of a significant stenotic lesion or a lesion involved in the abnormal pattern of ventricular contraction). B. Cerebrovascular disease C. Pheochromocytoma D. Viral or idiopathic myocarditis Note: For the exclusion of coronary artery lesions, coronary angiography is required. Takotsubo-like myocardial dysfunction could occur with diseases such as cerebrovascular disease and pheochromocytoma. III. References for diagnosis A. Symptoms: Chest pain and dyspnea similar to those in acute coronary syndrome. Takotsubo cardiomyopathy can occur without symptoms. B. Triggers: Emotional or physical stress may trigger takotsubo cardiomyopathy, but it can also occur without any apparent trigger. C. Age and gender difference: Known tendency to increase in the elderly, particularly females. D. Ventricular morphology: Apical ballooning and its rapid improvement in the ventriculogram and echocardiogram. E. Electrocardiogram: ST segment elevations might be observed immediately after onset. Thereafter, in a typical case, the T-wave becomes progressively more negative in multiple leads, and the QT interval is prolonged. These changes improve gradually, but a negative T-wave may continue for several months. During the acute stage, abnormal Q-waves and changes in the QRS voltage might be observed. F. Cardiac biomarkers: In a typical case, there are only modest elevations in serum levels of cardiac enzymes and troponin. G. Myocardial radionuclear study: Abnormal findings in myocardial scintigraphy are observed in some cases. H. Prognosis: The majority of the cases rapidly recover, but some cases suffer pulmonary edema and other sequelae or death.
that extend beyond a single epicardial vascular distribution” and end with the “complete recovery of regional wall motion abnormalities" (recovery is usually within days to weeks) (Table 4) [4]. These criteria are reasonable, and do not include any controversial issues that are in conflict with what is currently reported in the literature. However there is no reference to the possibilities that TTS can occasionally present as comorbidity in patients who have suffered an acute coronary syndrome, as reported lately. The Gothenburg criteria for the diagnosis of TTS were presented first in 2012, and are mainly contrasted with the revised Mayo Clinic criteria (Table 5) [5]. The authors refer to the reasons of underestimating the incidence of TTS if one applies the Mayo diagnostic criteria by citing the literature on the “considerable evidence for concomitant coronary artery disease and TTS”, the noninclusion of “any patient that dies acutely in TTS”, and exclusion of the diagnosis of TTS in patients with pheochromocytoma, for whom “there is no reason” for such an exclusion, “if TTS is indeed mediated by stress-induced catecholamine toxicity” [4]. Although diagnostic “criteria pertain to patients that survive the acute
Please cite this article as: Madias JE, Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.241
Editorial Table 4 Johns Hopkins criteria in the diagnosis of stress-induced cardiomyopathy. Reproduced and adapted from Table 1 of Ref. [4]. Helpful, but not mandatory, criteria An acute identifiable trigger (either emotional or physical) Characteristic ECG changes that may include some or all of the following: ST-segment elevation at time of admission (often ≤2 mm in magnitude, and usually not associated with reciprocal ST-segment depression) Diffuse deep T-wave inversion (may be present on admission or may evolve during the first several hospital days) QT interval prolongation (usually maximal by 24–48 h) Mildly elevated cardiac troponin (often appears disproportionately low given the degree of wall motion abnormality) Mandatory criteria (all three criteria must be met)
3
Table 6 Proposed new diagnostic criteria for Takotsubo syndrome. Transient hypokinesis/akinesis/dyskinesis of the left and/or right ventricular myocardial segments, particularly in postmenopausal women, associated frequently, but not always, with a stressful trigger (mental or physical), communicated to the physician by the patient The absence of other pathological conditions (e.g., ischemia, myocarditis, toxic damage, and tachycardia, among others) that may more credibly explain the regional dysfunctiona “Milder forms” or “formes frustes” of Takotsubo syndrome may exist, characterized by transient hypokinesis, akinesis, or dyskinesis in the left and/or right ventricular myocardial segments, and/or T-wave inversions and QTc prolongation at follow-up. Takotsubo syndrome may exist as comorbidity with a variety of illnesses (including acute coronary syndromes),b being triggered by, or triggering such illnesses. a
Reproduced from Table 2 of Ref. [4]. Although this contradicts proposition #2, the diagnosis of Takotsubo syndrome in association with an acute coronary syndrome should be made with careful consideration of all clinical, imaging, electrocardiographic, and biomarker release data, and clinical course, to ascertain the sequence of the comorbidities. b
Absence of coronary thrombosis or angiographic evidence of acute plaque rupture Regional ventricular wall motion abnormalities that extend beyond a single epicardial vascular distribution Complete recovery of regional wall motion abnormalities (recovery is usually within days to weeks)
phase of TTS” the authors of the Gothenburg criteria also emphasize the need for “additional histological criteria for diagnosing TTS in patients who do not survive the acute phase” [4], something that cannot be overemphasized. The authors go on to speculate about “milder forms of TTS”, and the possibility “that different degrees of transient TTS-like cardiac dysfunction may be rather common in the general population”, “with so many preceding events described to trigger TTS”, something this author is in full agreement with. The authors, based on their experiences at the Sahlgrenska University Hospital in Gothenburg, Sweden, discuss the higher mortality in TTS noted in their patients, than reported in the literature, the maintenance of adequate cardiac output, and the normal or almost normal left ventricular (LV) filling pressures (Table 5), even with marked “akinesis involving N 50% of the LV” [5]. They conclude that eventual recovery from such a devastating state (which is usually the case), and in contrast to what happens to patients with massive acute myocardial infarction (almost certain death), must be due to “compensatory cardiocirculatory mechanisms activated to maintain sufficient perfusion of the vital organs”, and indeed showed in patients with TTS, “decreased sympathetic tone, decreased peripheral resistance, and preserved cardiac output” [5]. This author intuitively starts from the theses that 1) all illnesses (TTS included) manifest clinically in gradations (i.e., a continuum) of severity, and consequently there must be “milder forms” of TTS escaping diagnosis, or being misdiagnosed, and 2) that there is no reason to believe that patients with TTS cannot present as comorbidities with any other illness (including acute coronary syndrome), either triggering TTS, or being triggered by it. In addition observations from the supervision of a large Cardiac Clinic (CC) of an acute tertiary hospital, accepting referrals from a large diverse community and another hospital, have identified the frequent encounter of the following disease phenotype: A woman in her 60s or 70s who presents with angina and/or dyspnea, with or without risk factors for coronary artery disease, physical or emotional inciting “triggers” (communicated), evidence of LV wall motion abnormalities (WMAs) and depressed LV ejection fraction (LVEF) on echocardiography (ECHO), who is found to have normal or
nonobstructive coronary arteries at cardiac catheterization, and at follow-up in the CC remains asymptomatic, shows resolution of the WMAs, and normalization of the LVEF at repeat ECHO, and is often discharged from the CC to the care of her primary physician. Such a patient may have normal or modestly elevated cardiac biomarkers (usually cardiac troponin I) and/or electrocardiogram (ECG) repolarization, or “near normal” ECG abnormalities on presentation or the acute phase of the illness, with subsequent normal, “near normal”, or persisting deep or shallow T-wave inversions, at follow-up in the CC. The puzzling thing is that many of such encounters are not associated with any speculation as to their pathophysiologic underpinnings in the physicians' notes in the electronic record. Based on the above, this author proposes new diagnostic criteria for TTS (Table 6) with the adoption of item #2 of the Gothenburg criteria (Table 5), and the inclusion of the speculations, that there may exist “formes frustes” of TTS, and that patients with TTS may present as a comorbidity of any other illness, either triggered by, or causing it. Data with expeditious performance of ECHO upon the patient's arrival to the hospital, with frequent repeat ECHOs during hospitalization and at outpatient follow-up, will be required to confirm or refute the above. Also what is needed is a change in the mindset, and an increased index of suspicion (perhaps it is TTS after all) among physicians called upon to evaluate patients with angina, dyspnea, palpitations, hemodynamic deterioration, or other sometimes bizarre symptom/sign complexes, as is currently reflected in the literature, and clinical practice. References [1] Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:58–65. [2] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Takotsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. [3] Kawai S, Kitabatake A, Tomoike H, Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J 2007;71:990–2. [4] Wittstein IS. Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning? Cell Mol Neurobiol 2012;32:847–57. [5] Redfors B, Shao Y, Omerovic E. Stress-induced cardiomyopathy (Takotsubo) — broken heart and mind? Vasc Health Risk Manag 2013;9:149–54.
Table 5 Gothenburg criteria in the diagnosis of stress-induced cardiomyopathy. Reproduced and adapted from Table 2 of Ref. [5]. Transient hypokinesis, akinesis, or dyskinesis in the left-ventricular segments and frequently, but not always, a stressful trigger (psychical or physical) The absence of other pathological conditions (e.g., ischemia, myocarditis, toxic damage, and tachycardia, among others) that may more credibly explain the regional dysfunction Normal or near normal filling pressure
Please cite this article as: Madias JE, Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.241
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria John E. Madias ⁎ Icahn School of Medicine at Mount Sinai, New York, NY, United States Division of Cardiology, Elmhurst Hospital Center, Elmhurst, NY, United States
a r t i c l e
i n f o
Article history: Received 17 March 2014 Accepted 22 April 2014 Available online xxxx Keywords: Takotsubo syndrome Criteria Mayo Clinic criteria for Takotsubo syndrome
a b s t r a c t Diagnosis of Takotsubo syndrome (TTS), the reversible, acute heart failure pathological entity, precipitated by stress, is based on the fulfillment of sets of criteria, developed by careful characterization of the precipitants, symptoms, results of imaging testing, clinical course, and follow-up of many patients presented with this affliction. As understanding of TTS, increase in its awareness, and the diversion in its presentation have evolved, the various proposed diagnostic criteria, naturally have started to appear outmoded. The author argues that the initially proposed Mayo Clinic criteria, the subsequently revised Mayo Clinic criteria, the Japanese Circulation Society guidelines, the Johns Hopkins criteria, and the Gothenburg criteria for the diagnosis of TTS have been outpaced by the rapidly accumulating clinical experience, and thus need to be replaced by more realistic sets of diagnostic rules. To this effect the author proposes a set of diagnostic criteria for TTS, which include 2 plausible, albeit speculative, notions, that of the milder forms or formes frustes of TTS, and the existence of “TTS comorbidity” in patients with various other illnesses, which either precipitate TTS, or are being brought about by TTS. © 2014 Elsevier Ireland Ltd. All rights reserved.
This viewpoint will not start in the conventional fashion, i.e., providing an “Introduction”, describing in a stereotypical manner the particular characteristics of Takotsubo syndrome (TTS), since these are by now well known to all, after being elaborated in numerous short and long reviews (http://www.ncbi.nlm.nih.gov/pubmed/? term=takotsubo (accessed last on 3/17/14)). Instead this piece will delve into the adequacy of the diagnostic criteria of TTS, and whether they need to be revised. The diversity of the clinical presentation of TTS, reflected in the rapidly ever expanding vast literature on TTS, underscores the idea that the current criteria for the diagnosis of TTS are outmoded. The originally proposed Mayo Clinic criteria for TTS ([1] Table 1) have been included as item #2, the “absence of obstructive coronary disease”, and as a prerequisite for making the diagnosis of TTS; however many cases of TTS have now been described of patients with prior history of myocardial infarction, or angiographic evidence of obstructive coronary disease during the index admission for TTS [1]. Also item #4 includes again “obstructive coronary disease”, recent significant head trauma, intracranial bleeding, pheochromocytoma, myocarditis, and hypertrophic cardiomyopathy, conditions which need to be excluded, before one can make the diagnosis of TTS [1]. It is not clear by
⁎ Corresponding author at: Division of Cardiology, Elmhurst Hospital Center, 79-01 Broadway, Elmhurst, NY 11373, United States. Tel.: +1 718 334 5005; fax: +1 718 334 5990. E-mail address: [email protected].
contemporary conceptualizations why all these conditions, particularly the ones involving derangements of the central nervous system, characterized by adrenergic activity surges, and associated with classic clinical presentations of TTS should be reasons not to make the diagnosis of TTS. In reference to pheochromocytoma, this continues to be included in the Mayo Clinic criteria (Table 2), as something that needs to be excluded, when one attempts to make the diagnosis of TTS; however the authors of the revised Mayo Clinic diagnostic criteria for TTS, in the text of their article state that they “no longer exclude” the diagnosis of TTS in patients developing typical features of the condition in the setting of intracranial bleeding, including subarachnoid hemorrhage, but continue to consider simultaneous diagnoses of pheochromocytoma and TTS as incompatible (Table 2), while stating in the text of their article, that “wall motion abnormalities and depressed ejection fraction have been observed in diseases associated with high catecholamines such as pheochromocytoma and subarachnoid hemorrhage”, also citing the literature. Indeed this is a contradiction! Also, although the authors of the Mayo Clinic criteria in their revised diagnostic criteria (Table 2) continue to refer to the notion that the diagnosis of TTS should be made in the “absence of obstructive coronary disease”, at the footnote of their table, they state that TTS and “obstructive coronary atherosclerosis” may coincide, but this is “very rare in their experience and in the published literature, perhaps because such cases are misdiagnosed as an acute coronary syndrome” (Table 2) [2]. However this statement is contradictory in the sense that it implies that the coincidence of TTS and “obstructive coronary atherosclerosis” is rare according to the authors of
http://dx.doi.org/10.1016/j.ijcard.2014.04.241 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Madias JE, Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.241
2
Editorial
Table 1 Proposed Mayo Clinic criteria for the clinical diagnosis of the transient left ventricular ballooning syndrome. Reproduced from Table 3 of Ref. [1]. 1. Transient akinesis or dyskinesis of the left ventricular apical and mid-ventricular segments with regional wall-motion abnormalities extending beyond a single epicardial vascular distribution 2. Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture 3. New electrocardiographic abnormalities (either ST-segment elevation or T-wave inversion) 4. Absence of recent significant head trauma, intracranial bleeding, pheochromocytoma, obstructive epicardial coronary artery disease, myocarditis, and hypertrophic cardiomyopathy All 4 of the above statements must be met.
the revised Mayo Clinic criteria of TTS, as per their experience (a presumed fact), while at the same time it is rare because TTS is a misdiagnosed condition in the literature, as acute coronary syndrome (a fallacy). This implies that TTS is a deceptively rare, but actually common affliction. The Japanese Circulation Society has issued guidelines for TTS in 2007, based on a questionnaire sent in 2003 to 203 institutions from which scientific reports on TTS had emanated; subsequently 33 investigators who had published reports on TTS were contacted and 21 of them responded to the charge of evaluating and revising the “1st edition” of these guidelines [3]. There were disagreements about certain matters, and a surprising agreement about the noninclusion of the “inverse takotsubo” as an occasional presenting feature of the disease; midventricular involvement is not mentioned [3]. Lack of significant coronary artery stenosis was emphasized as a prerequisite to make the diagnosis of TTS. Cerebrovascular accidents with classic presentation TTS are included as “cerebrovascular disease with takotsubo-like myocardial dysfunction”, and differentiated from “idiopathic” TTS (Table 3) [3]. Conditions which need to be excluded before the diagnosis of TTS can be made are acute coronary syndrome, cerebrovascular disease, pheochromocytoma, and myocarditis (Table 3) [3]. These diagnostic guidelines appear outmoded particularly due to their strict exclusion criteria, and the disregard for atypical presentations of TTS in terms of the involvement of left ventricular segments other than the apex, all of which are contradicted by the large experience reflected in the literature. The Johns Hopkins criteria start with a set of “helpful, but not mandatory” criteria, which include the known emotional and physical stress precipitants, the electrocardiographic changes, and the release of cardiac biomarkers associated with TTS, and then proceed with a set of “mandatory criteria" (all three criteria must be met), which include the “absence of coronary thrombosis or angiographic evidence of acute plaque rupture”, and “regional ventricular wall motion abnormalities Table 2 Proposed Mayo Clinic criteria for ABS. Reproduced from Table 2 of Ref. [2]. 1. Transient hypokinesis, akinesis, or dyskinesis of the left ventricular midsegments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always presenta 2. Absence of obstructive coronary disease or angiographic evidence of acute plaque ruptureb 3. New electrocardiographic abnormalities (either ST-segment elevation and/or Twave inversion) or modest elevation in cardiac troponin 4. Absence of pheochromocytoma or myocarditis In both of the above circumstances, the diagnosis of ABS should be made with caution, and a clear stressful precipitating trigger must be sought. a There are rare exceptions to these criteria such as those patients in whom the regional wall motion abnormality is limited to a single coronary territory. b It is possible that a patient with obstructive coronary atherosclerosis may also develop ABS. However, this is very rare in our experience and in the published literature, perhaps because such cases are misdiagnosed as an acute coronary syndrome.
Table 3 Guidelines for the diagnosis of takotsubo (ampulla) cardiomyopathy. Reproduced from Table 1 of Ref. [3]. I. Definition Takotsubo (ampulla) cardiomyopathy is a disease exhibiting an acute left ventricular apical ballooning of unknown cause. In this disease, the left ventricle takes on the shape of a “takotsubo” (Japanese octopus trap). There is nearly complete resolution of the apical akinesis in the majority of the patients within a month. The contraction abnormality occurs mainly in the left ventricle, but involvement of the right ventricle is observed in some cases. A dynamic obstruction of the left ventricular outflow tract (pressure gradient difference, acceleration of blood flow, or systolic cardiac murmurs) is also observed. Note: There are patients, such as cerebrovascular patients, who have an apical systolic ballooning similar to that in takotsubo cardiomyopathy, but with a known cause. Such patients are diagnosed as “cerebrovascular disease with takotsubo-like myocardial dysfunction” and are differentiated from idiopathic cases. II. Exclusion criteria The following lesions and abnormalities from other diseases must be excluded in the diagnosis of takotsubo (ampulla) cardiomyopathy. A. Significant organic stenosis or spasm of a coronary artery. In particular, acute myocardial infarction due to a lesion of the anterior descending branch of the left coronary artery, which perfuses an extensive territory including the left ventricular apex (an urgent coronary angiogram is desirable for imaging during the acute stage, but coronary angiography is also necessary during the chronic stage to confirm the presence or absence of a significant stenotic lesion or a lesion involved in the abnormal pattern of ventricular contraction). B. Cerebrovascular disease C. Pheochromocytoma D. Viral or idiopathic myocarditis Note: For the exclusion of coronary artery lesions, coronary angiography is required. Takotsubo-like myocardial dysfunction could occur with diseases such as cerebrovascular disease and pheochromocytoma. III. References for diagnosis A. Symptoms: Chest pain and dyspnea similar to those in acute coronary syndrome. Takotsubo cardiomyopathy can occur without symptoms. B. Triggers: Emotional or physical stress may trigger takotsubo cardiomyopathy, but it can also occur without any apparent trigger. C. Age and gender difference: Known tendency to increase in the elderly, particularly females. D. Ventricular morphology: Apical ballooning and its rapid improvement in the ventriculogram and echocardiogram. E. Electrocardiogram: ST segment elevations might be observed immediately after onset. Thereafter, in a typical case, the T-wave becomes progressively more negative in multiple leads, and the QT interval is prolonged. These changes improve gradually, but a negative T-wave may continue for several months. During the acute stage, abnormal Q-waves and changes in the QRS voltage might be observed. F. Cardiac biomarkers: In a typical case, there are only modest elevations in serum levels of cardiac enzymes and troponin. G. Myocardial radionuclear study: Abnormal findings in myocardial scintigraphy are observed in some cases. H. Prognosis: The majority of the cases rapidly recover, but some cases suffer pulmonary edema and other sequelae or death.
that extend beyond a single epicardial vascular distribution” and end with the “complete recovery of regional wall motion abnormalities" (recovery is usually within days to weeks) (Table 4) [4]. These criteria are reasonable, and do not include any controversial issues that are in conflict with what is currently reported in the literature. However there is no reference to the possibilities that TTS can occasionally present as comorbidity in patients who have suffered an acute coronary syndrome, as reported lately. The Gothenburg criteria for the diagnosis of TTS were presented first in 2012, and are mainly contrasted with the revised Mayo Clinic criteria (Table 5) [5]. The authors refer to the reasons of underestimating the incidence of TTS if one applies the Mayo diagnostic criteria by citing the literature on the “considerable evidence for concomitant coronary artery disease and TTS”, the noninclusion of “any patient that dies acutely in TTS”, and exclusion of the diagnosis of TTS in patients with pheochromocytoma, for whom “there is no reason” for such an exclusion, “if TTS is indeed mediated by stress-induced catecholamine toxicity” [4]. Although diagnostic “criteria pertain to patients that survive the acute
Please cite this article as: Madias JE, Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.241
Editorial Table 4 Johns Hopkins criteria in the diagnosis of stress-induced cardiomyopathy. Reproduced and adapted from Table 1 of Ref. [4]. Helpful, but not mandatory, criteria An acute identifiable trigger (either emotional or physical) Characteristic ECG changes that may include some or all of the following: ST-segment elevation at time of admission (often ≤2 mm in magnitude, and usually not associated with reciprocal ST-segment depression) Diffuse deep T-wave inversion (may be present on admission or may evolve during the first several hospital days) QT interval prolongation (usually maximal by 24–48 h) Mildly elevated cardiac troponin (often appears disproportionately low given the degree of wall motion abnormality) Mandatory criteria (all three criteria must be met)
3
Table 6 Proposed new diagnostic criteria for Takotsubo syndrome. Transient hypokinesis/akinesis/dyskinesis of the left and/or right ventricular myocardial segments, particularly in postmenopausal women, associated frequently, but not always, with a stressful trigger (mental or physical), communicated to the physician by the patient The absence of other pathological conditions (e.g., ischemia, myocarditis, toxic damage, and tachycardia, among others) that may more credibly explain the regional dysfunctiona “Milder forms” or “formes frustes” of Takotsubo syndrome may exist, characterized by transient hypokinesis, akinesis, or dyskinesis in the left and/or right ventricular myocardial segments, and/or T-wave inversions and QTc prolongation at follow-up. Takotsubo syndrome may exist as comorbidity with a variety of illnesses (including acute coronary syndromes),b being triggered by, or triggering such illnesses. a
Reproduced from Table 2 of Ref. [4]. Although this contradicts proposition #2, the diagnosis of Takotsubo syndrome in association with an acute coronary syndrome should be made with careful consideration of all clinical, imaging, electrocardiographic, and biomarker release data, and clinical course, to ascertain the sequence of the comorbidities. b
Absence of coronary thrombosis or angiographic evidence of acute plaque rupture Regional ventricular wall motion abnormalities that extend beyond a single epicardial vascular distribution Complete recovery of regional wall motion abnormalities (recovery is usually within days to weeks)
phase of TTS” the authors of the Gothenburg criteria also emphasize the need for “additional histological criteria for diagnosing TTS in patients who do not survive the acute phase” [4], something that cannot be overemphasized. The authors go on to speculate about “milder forms of TTS”, and the possibility “that different degrees of transient TTS-like cardiac dysfunction may be rather common in the general population”, “with so many preceding events described to trigger TTS”, something this author is in full agreement with. The authors, based on their experiences at the Sahlgrenska University Hospital in Gothenburg, Sweden, discuss the higher mortality in TTS noted in their patients, than reported in the literature, the maintenance of adequate cardiac output, and the normal or almost normal left ventricular (LV) filling pressures (Table 5), even with marked “akinesis involving N 50% of the LV” [5]. They conclude that eventual recovery from such a devastating state (which is usually the case), and in contrast to what happens to patients with massive acute myocardial infarction (almost certain death), must be due to “compensatory cardiocirculatory mechanisms activated to maintain sufficient perfusion of the vital organs”, and indeed showed in patients with TTS, “decreased sympathetic tone, decreased peripheral resistance, and preserved cardiac output” [5]. This author intuitively starts from the theses that 1) all illnesses (TTS included) manifest clinically in gradations (i.e., a continuum) of severity, and consequently there must be “milder forms” of TTS escaping diagnosis, or being misdiagnosed, and 2) that there is no reason to believe that patients with TTS cannot present as comorbidities with any other illness (including acute coronary syndrome), either triggering TTS, or being triggered by it. In addition observations from the supervision of a large Cardiac Clinic (CC) of an acute tertiary hospital, accepting referrals from a large diverse community and another hospital, have identified the frequent encounter of the following disease phenotype: A woman in her 60s or 70s who presents with angina and/or dyspnea, with or without risk factors for coronary artery disease, physical or emotional inciting “triggers” (communicated), evidence of LV wall motion abnormalities (WMAs) and depressed LV ejection fraction (LVEF) on echocardiography (ECHO), who is found to have normal or
nonobstructive coronary arteries at cardiac catheterization, and at follow-up in the CC remains asymptomatic, shows resolution of the WMAs, and normalization of the LVEF at repeat ECHO, and is often discharged from the CC to the care of her primary physician. Such a patient may have normal or modestly elevated cardiac biomarkers (usually cardiac troponin I) and/or electrocardiogram (ECG) repolarization, or “near normal” ECG abnormalities on presentation or the acute phase of the illness, with subsequent normal, “near normal”, or persisting deep or shallow T-wave inversions, at follow-up in the CC. The puzzling thing is that many of such encounters are not associated with any speculation as to their pathophysiologic underpinnings in the physicians' notes in the electronic record. Based on the above, this author proposes new diagnostic criteria for TTS (Table 6) with the adoption of item #2 of the Gothenburg criteria (Table 5), and the inclusion of the speculations, that there may exist “formes frustes” of TTS, and that patients with TTS may present as a comorbidity of any other illness, either triggered by, or causing it. Data with expeditious performance of ECHO upon the patient's arrival to the hospital, with frequent repeat ECHOs during hospitalization and at outpatient follow-up, will be required to confirm or refute the above. Also what is needed is a change in the mindset, and an increased index of suspicion (perhaps it is TTS after all) among physicians called upon to evaluate patients with angina, dyspnea, palpitations, hemodynamic deterioration, or other sometimes bizarre symptom/sign complexes, as is currently reflected in the literature, and clinical practice. References [1] Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:58–65. [2] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Takotsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. [3] Kawai S, Kitabatake A, Tomoike H, Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J 2007;71:990–2. [4] Wittstein IS. Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning? Cell Mol Neurobiol 2012;32:847–57. [5] Redfors B, Shao Y, Omerovic E. Stress-induced cardiomyopathy (Takotsubo) — broken heart and mind? Vasc Health Risk Manag 2013;9:149–54.
Table 5 Gothenburg criteria in the diagnosis of stress-induced cardiomyopathy. Reproduced and adapted from Table 2 of Ref. [5]. Transient hypokinesis, akinesis, or dyskinesis in the left-ventricular segments and frequently, but not always, a stressful trigger (psychical or physical) The absence of other pathological conditions (e.g., ischemia, myocarditis, toxic damage, and tachycardia, among others) that may more credibly explain the regional dysfunction Normal or near normal filling pressure
Please cite this article as: Madias JE, Why the current diagnostic criteria of Takotsubo syndrome are outmoded: A proposal for new criteria, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.241
