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Stress (Takotsubo) Cardiomyopathy
20 Stress (Takotsubo) Cardiomyopathy Abhiram Prasad
OUTLINE Epidemiology, 204 Pathophysiology, 204 Diagnosis, 205 Electrocardiogram, 205
Cardiac Biomarkers, 206 Left Ventricular Imaging and Coronary Angiography, 206 Management, 207
Stress cardiomyopathy (SCM) is a generally reversible acute cardiac syndrome that was originally described in the Japanese population over 30 years ago.1 Hence, the Japanese term takotsubo (an octopus trap with a narrow neck and round bottom, Fig. 20.1) cardiomyopathy/syndrome has gained favor, as it describes the appearance of the left ventricle during systole. SCM is also known as apical ballooning syndrome (ABS), broken heart syndrome, and ampulla cardiomyopathy.2,3 The clinical features mimic an acute myocardial infarction (MI); therefore, patients with this syndrome frequently present to the cardiac intensive care unit (CICU). SCM should be considered in the differential diagnosis of patients presenting with an acute coronary syndrome.4 The typical patient is a postmenopausal woman presenting with symptoms of myocardial ischemia that is temporally related to a physical or emotional stressful event, with positive cardiac biomarkers and/or an electrocardiogram (ECG) that has evidence of ischemia or injury.
PATHOPHYSIOLOGY
EPIDEMIOLOGY SCM is the final diagnosis in approximately 1% to 2% of all patients initially suspected of either an acute coronary syndrome or MI.5,6 The proportion may be as high as 12% in women with ST elevation myocardial infarction.7 The incidence of SCM among patients in intensive care units has been estimated at 1.5% and 8% among those with cardiogenic shock.8 However, an accurate incidence is difficult to ascertain because of underdiagnosis. Over time, there has been increasing recognition of this entity, as highlighted by data from the Nationwide Inpatient Sample in which the mean number of patients with a discharge diagnosis of SCM from a group of community hospitals increased from 315 per year in 2006 to 6,230 per year in 2012.9 Approximately 90% of all reported cases are in postmenopausal women10 and 5% of the patients are younger than 50 years.11
204
The pathophysiology of SCM remains to be established; however, several observations suggest that the sympathetic nervous system plays an important role.12 These include the temporal relationship with preceding emotional or physical stressful triggers, hyperadrenergic states, such as pheochromocytoma and subarachnoid hemorrhage causing a transient cardiomyopathy that is similar to SCM, documentation of high levels of circulating catecholamines,13 SCM being precipitated by inadvertent administration of supratherapeutic doses of catecholamines,14 animal models of stress immobilization and exogenous catecholamine administration inducing left ventricular apical hypokinesis,15 and the presence of contraction band necrosis on endomyocardial biopsies,16 a feature of catecholamine toxicity. However, elevation in circulating catecholamines and contraction band necrosis are not always present. Early reports of cases with SCM were associated with multivessel epicardial coronary spasm, which was initially proposed as a potential mechanism for the myocardial stunning. However, this has not been supported in large case series and is unlikely to be the underlying cause of SCM in the vast majority of patients. Aborted MI due to left anterior descending artery plaque rupture and thrombosis with spontaneous thrombolysis has also been proposed but seems unlikely to be the underlying mechanism.17 Conversely, microvascular dysfunction can be detected in at least two-thirds of the patients at the time of presentation and its severity correlates with the magnitude of troponin elevation and ECG abnormalities.18 The microvascular dysfunction may be a primary mechanistic feature or an epiphenomenon. Abnormal glucose and fatty acid metabolism is frequently present, colocalizing with the wall motion abnormality.19,20 A preceding stressful trigger is present in over two-thirds of patients. The list of potential emotional triggers is extensive, but
Keywords stress cardiomyopathy apical ballooning syndrome takotsubo cardiomyopathy
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
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CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
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B
Fig. 20.1 (A) Ventriculogram. (B) An octopus pot (“tako-tsubo”). (Courtesy #FOAMed Medical Education Resources, LITFL.)
most often relates to experiences of significant grief or personal loss, fear or anxiety, anger and frustration, and interpersonal conflicts. Common physical triggers include acute medical conditions (e.g., severe exacerbation of obstructive airways disease, sepsis), neurologic conditions (e.g., subarachnoid hemorrhage, seizures), falls and other trauma, noncardiac surgery (e.g., orthopedic, major abdominal), malignancy, and experiencing severe pain.21 The absence of such triggers does not exclude the diagnosis. Patients who are conscious typically have symptoms that are similar to that associated with MI,10,22,23 the most common being angina-like chest pain, present in approximately 50% of cases. Other presenting symptoms include dyspnea and, less frequently, syncope or out-of-hospital cardiac arrest. Among patients presenting primarily with SCM, it is those with ST segment elevation and severe left ventricular dysfunction who most often are admitted to the CICU. Typically, the ejection fraction is reduced to 30% to 40%,10 which may be accompanied by significant diastolic dysfunction with elevation in left ventricular filling pressure.24 Myocardial relaxation is impaired due to the ischemia related to microvascular dysfunction and myocardial edema. Acute heart failure is a frequent complication, but major hemodynamic decompensation is uncommon, with cardiogenic shock developing in approximately 10% to 15% of patients.10 These patients should be particularly assessed for the presence of transient left ventricular outflow obstruction and clinically significant mitral regurgitation, which can be exacerbating factors,25 each being present in approximately 10% to 20% of cases. The mechanisms for regurgitation appear to be papillary muscle displacement leading to tethering and impaired coaptation of the leaflets, and/or systolic anterior motion.25,26 Outflow tract obstruction likely occurs owing to a combination of factors, including hyperdynamic basal function, systolic anterior motion of the mitral valve, and a sigmoid-shaped ventricle. Additional complications that may lead to admission to the CICU include arrhythmias. Atrial fibrillation occurs in approximately 5% of cases,27 whereas ventricular tachycardia, torsade de pointes, and ventricular fibrillation have been reported in 3% to 4% of patients and asystole in 0.5%.28 Other rare
complications of SCM include left ventricular thrombus, thromboembolism, and cardiac rupture.29 Patients who develop SCM secondary to a noncardiac illness or other physical trigger may not have the typical symptoms described earlier but instead present with ischemic changes on the ECG, elevated cardiac biomarkers of myonecrosis, pulmonary edema, and hypotension. Hypotension may due to the reduction in stroke volume and, in some cases, dynamic left ventricular outflow tract obstruction.30 The ventricular dysfunction resolves over days to weeks, with complete recovery of global systolic function by 4 to 8 weeks. The prognosis of SCM is good in the absence of significant underlying comorbid conditions. In-hospital mortality is approximately 3% to 5%. Among those who are discharged, long-term survival appears to be similar to that of the general age-matched population. The subgroup of patients in whom there is a physical trigger—such as major surgery, malignancy, and fractures—appear to have a worse prognosis, likely related to the underlying condition. The recurrence rate of SCM is approximately 1% to 2% per year.31
DIAGNOSIS There are no diagnostic ECG or biomarker findings that can differentiate SCM from an acute coronary syndrome or myocarditis; hence, it is a diagnosis of exclusion. The characteristic features of the syndrome have been incorporated into several proposed diagnostic criteria.32,33 Box 20.1 provides the Mayo Clinic criteria that can be applied at the time of presentation. All four criteria must be present.34
Electrocardiogram Between 30% to 50% of patients have ST segment elevation at presentation. The precordial leads are most commonly involved, but ST segment elevation may also occur in the limb leads. The electrocardiographic findings do not reliably distinguish SCM from an acute MI.35 Pathologic Q waves may be present transiently. Some patients present with deep T-wave inversion, nonspecific T wave abnormality, and the ECG may be normal in some cases. ST segment depression is infrequently present. Characteristic
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evolutionary changes during hospitalization include resolution of ST segment elevation and diffuse and often deep T-wave inversion associated with prolongation of the corrected QT interval (Fig. 20.2). The electrocardiographic abnormalities usually resolve gradually over weeks to months but may persist even after systolic function has recovered.
Cardiac Biomarkers Cardiac troponin levels, using contemporary assays, are invariably elevated on admission and generally peak within 24 to 48 hours. Creatine kinase MB fraction is elevated in the great majority of cases. The levels are lower compared to patients with ST segment elevation MI, but similar to that of patients with non ST elevation MI and relatively low for the extent of acute left ventricular systolic dysfunction. Blood level of brain natriuretic peptide (BNP) or N-terminal pro-BNP, markers of ventricular dysfunction, are elevated in the majority of patients and may correlate with left ventricular end-diastolic pressure.36–39
BOX 20.1 Proposed Mayo Clinic Criteria
for Apical Ballooning Syndrome
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 present, but not always.a 2. Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture.b 3. New electrocardiographic abnormalities (either ST segment elevation and/ or T-wave inversion) or modest elevation in cardiac troponin. 4. Absence of pheochromocytoma, myocarditis.
Left Ventricular Imaging and Coronary Angiography Transthoracic echocardiography can be readily performed in the intensive care setting and hence is the preferred mode of imaging to detect systolic dysfunction and potential complications that accompany SCM. In the classical form of the cardiomyopathy, basal left ventricular function is preserved and may even be hyperdynamic, but there is hypokinesis or akinesis of the midand apical segments leading to the “ballooning” appearance (Fig. 20.3, Video 20.1). The wall motion abnormality virtually always extends beyond the distribution of a single coronary artery. In a significant proportion of patients, apical contraction is preserved and the wall motion abnormality is restricted to the mid-segments (apical-sparing variant; Video 20.2).40 The least common variant is known as inverted or reverse takotsubo in which there is hypokinesis of the basal segment of the left ventricle with preserved apical function. The variant forms of SCM have similar clinical characteristics and prognosis as the typical form. The right ventricle also develops a similar pattern
From Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155:408–417. 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 apical ballooning syndrome (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. In both of the above circumstances, the diagnosis of ABS should be made with caution and a clear stressful precipitating trigger must be sought.
I
aVR
VI
V4
II
aVL
V2
V5
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aVF
V3
V6
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V5
Fig. 20.2 Twelve-lead electrocardiogram with T-wave inversion in the precordial and limb leads associated with prolongation of the QT interval.
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
Diastole
207
Systole
Fig. 20.3 Left ventriculogram in diastole and systole of a patient with stress cardiomyopathy with hyperdynamic basal contraction and akinesis of the mid- and apical segments.
of regional wall motion abnormality in approximately one-third of cases.41 Biventricular dysfunction SCM is associated with a worse hemodynamic profile and the patients are often sicker and more likely to develop acute heart failure. Cardiac magnetic resonance may be a useful imaging modality for documenting the extent of regional wall motion abnormality and differentiating SCM (virtually always characterized by the absence of delayed gadolinium hyperenhancement) from myocarditis and MI in which delayed hyperenhancement is present.42 Patients with SCM either have angiographically normal coronary arteries or mild atherosclerosis. Obstructive coronary artery disease is infrequent despite most patients being in their seventh and eighth decade of life.43 When present, the extent and distribution of obstructive plaque is generally insufficient to account for the widespread regional wall motion abnormality. Coronary angiography, either invasive or noninvasive, should be performed in patients suspected of SCM in order to exclude an acute coronary syndrome. In contemporary treatment pathways, the presence of ST segment elevation typically leads to emergency angiography to exclude coronary thrombotic occlusion that requires revascularization prior to admission to the CICU.
MANAGEMENT The recommendations for SCM management are based on expert opinion as clinical trials have not been conducted owing, in part, to the low incidence and the fact that supportive therapy leads to spontaneous recovery in the great majority of patients. The initial therapy is frequently directed toward treating myocardial ischemia with aspirin, anticoagulants, statins, and β-blockers since an acute coronary syndrome is the presumed diagnosis in the majority of cases. Aspirin, anticoagulants, and statins can be discontinued once the diagnosis of SCM has been made unless there is coexisting coronary atherosclerosis. In the absence of contraindications, a β-blocker or a combined α- and β-blocker may be initiated because excess catecholamines have been implicated in the pathogenesis. Long-term therapy should be
considered with the aim of reducing recurrence even though observational data has not supported this recommendation.10 Initiation of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy for acute ventricular dysfunction is recommended, especially as the diagnosis may not be certain at the time of discharge. Inhibitors of the renin angiotensin system may be discontinued once there is complete recovery of systolic function, though there are observational data that suggest that they may have long-term benefits.10 Mild to moderate acute heart failure responds to diuretic therapy. Severe cases with pulmonary edema may require intubation and mechanical ventilation. If present, left ventricular outflow tract obstruction may be treated with phenylephrine with the goal of increasing afterload and left ventricular cavity size. Phenylephrine use requires close monitoring due to the presence of systolic dysfunction. In the absence of heart failure, β-blockers and/or intravenous fluids may be effective. Inotropes are often used with good effect in cardiogenic shock, although there are theoretical reasons for avoiding them because of the potential role of catecholamine toxicity in precipitating the syndrome. Intraaortic balloon pump counterpulsation or other mechanical support devices may be preferable. The former has the potential to exacerbate outflow tract obstruction and should therefore be used cautiously. The acute treatment of atrial and ventricular arrhythmias is similar to other clinical situations. Although torsade de pointes is rare, patients should be on continuous ECG monitoring until the QTc is less than or equal to 500 msec. If pause-dependent torsade occurs, β-blocker therapy should be withheld and temporary pacing considered. Implantable cardioverterdefibrillator therapy is not routinely indicated for ventricular tachycardia or fibrillation as the cardiomyopathy is reversible. In cases of recurrent aborted sudden cardiac death or lifethreatening ventricular arrhythmia, the role of implantable cardioverter-defibrillator therapy is unclear. The full reference list for this chapter is available at ExpertConsult.com.
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
REFERENCES 1. Sato H, Tateishi H, Uchida T, et al. Tako-tsubo like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hori M, eds. Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure. Tokyo: Kagakuhyoronsha Publishing; 1990:56–64. 2. Tsuchihashi K, Ueshima K, Uchida T, et al. Angina PectorisMyocardial Infarction Investigations in Japan. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol. 2001;38:11–18. 3. Maron BJ, Towbin JA, Thiene G, et al. American Heart Association contemporary definitions and classification of the cardiomyopathies: American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816. 4. Prasad A. Apical ballooning syndrome: an important differential diagnosis of acute myocardial infarction. Circulation. 2007;115(5):e56–e59. 5. Bybee KA, Kara T, Prasad A, et al. Transient Left Ventricular Apical Ballooning Syndrome: A mimic of ST-segment elevation myocardial infarction. Ann Intern Med. 2004;141:858–865. 6. Prasad A, Dangas G, Srinivasan M, et al. Incidence and angiographic characteristics of patients with apical ballooning syndrome (takotsubo/stress cardiomyopathy) in the HORIZONS-AMI trial: An analysis from a multicenter, international study of ST-elevation myocardial infarction. Catheter Cardiovasc Interv. 2014;83:343–348. 7. Parodi G, Del Pace S, Carrabba N, et al. Incidence, Clinical Findings, and Outcome of Women With Left Ventricular Apical Ballooning Syndrome. Am J Cardiol. 2007;99:182–185. 8. Champion S, Belcour D, Vandroux D, et al. Stress (Tako-tsubo) cardiomyopathy in critically-ill patients. Eur Heart J Acute Cardiovasc Care. 2015;2:189–196. 9. Minhas AS, Hughey AB, Kolias TJ. Nationwide Trends in Reported Incidence of Takotsubo Cardiomyopathy from 2006 to 2012. Am J Cardiol. 2015;116:1128–1131. 10. Templin C, Ghadri JR, Diekmann J. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med. 2015;373:929–938. 11. Patel S, Chokka R, Prasad K, Prasad A. Distinctive Clinical Characteristics According to Age and Gender in Apical Ballooning Syndrome (Takotsubo/ Stress Cardiomyopathy): An Analysis Focusing on Males and Young Women. J Card Fail. 2013;19:306–310. 12. Williams R, Arri S, Prasad A. Current Concepts in the Pathogenesis of Takotsubo Syndrome. Heart Fail Clin. 2016;12:473–484. 13. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539–548. 14. Abraham J, Mudd JO, Kapur NK, et al. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol. 2009;53:1320–1325. 15. Redfors B, Shao Y, Ali A, Omerovic E. Current hypotheses regarding the pathophysiology behind the takotsubo syndrome. Int J Cardiol. 2014;177:771–779.
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16. Nef HM, Möllmann H, Kostin S, et al. Tako-Tsubo cardiomyopathy: Intraindividual structural analysis in the acute phase and after functional recovery. Eur Heart J. 2007;28:2456–2464. 17. Delgado GA, Truesdell AG, Kirchner RM, et al. An angiographic and intravascular ultrasound study of the left anterior descending coronary artery in takotsubo cardiomyopathy. Am J Cardiol. 2011;108:888–891. 18. Elesber A, Lerman A, Bybee KA, et al. Myocardial perfusion in apical ballooning syndrome correlate of myocardial injury. Am Heart J. 2006;152:469.e9–469.e13. 19. Kurisu S, Inoue I, Kawagoe T, et al. Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo like left ventricular dysfunction. J Am Coll Cardiol. 2003;41:743–748. 20. Yoshida T, Hibino T, Kako N, et al. A pathophysiologic study of takotsubo cardiomyopathy with F-18 fluorodeoxyglucose positron emission tomography. Eur Heart J. 2007;28:2598–2604. 21. Ghadri JR, Sarcon A, Diekmann J, et al. Happy heart syndrome: Role of positive emotional stress in takotsubo syndrome. Eur Heart J. 2016;37:2823–2829. 22. Abe Y, Kondo M, Matsuoka R, et al. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol. 2003;41:737–742. 23. Desmet WJ, Adriaenssens BF, Dens JA. Apical ballooning of the left ventricle: first series in white patients. Heart. 2003;89:1027–1031. 24. Medeiros K, O’Connor MJ, Baicu CF. Systolic and diastolic mechanics in stress cardiomyopathy. Circulation. 2014;129:1659–1667. 25. Parodi G, Del Pace S, Salvadori C, et al. Tuscany Registry of Tako-Tsubo Cardiomyopathy. Left ventricular apical ballooning syndrome as a novel cause of acute mitral regurgitation. J Am Coll Cardiol. 2007;50:647–649. 26. Izumo M, Nalawadi S, Shiota M, et al. Mechanisms of acute mitral regurgitation in patients with takotsubo cardiomyopathy an echocardiographic study. Circ Cardiovasc Imaging. 2011;4:392–398. 27. Syed FF, Asirvatham SJ, Francis J. Arrhythmia occurrence with takotsubo cardiomyopathy: A literature review. Europace. 2011;13:780–788. 28. Pant S, Deshmukh A, Mehta K, et al. Burden of arrhythmias in patients with Takotsubo Cardiomyopathy (apical ballooning syndrome). Int J Cardiol. 2013;170:64–68. 29. Kimura K, Tanabe-Hayashi Y, Noma S, Fukuda K. Rapid formation of left ventricular giant thrombus with Takotsubo cardiomyopathy. Circulation. 2007;115:e620–e621. 30. Ohba Y, Takemoto M, Nakano M, Yamamoto H. Takotsubo cardiomyopathy with left ventricular outflow tract obstruction. Int J Cardiol. 2006;107:120–122. 31. Elesber A, Prasad A, Lennon R, Lerman A, Rihal CS. Four-Year Recurrence Rate and Prognosis of the Apical Ballooning Syndrome. J Am Coll Cardiol. 2007;50:448–452. 32. Scantlebury DC, Prasad A. Diagnosis of Takotsubo Cardiomyopathy. Circ J. 2014;78:2129–2139. 33. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: A Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8–27. 34. Prasad A, Lerman A, Rihal CS. Apical Ballooning Syndrome (Tako-Tsubo or Stress Cardiomyopathy): A Mimic of Acute Myocardial Infarction. Am Heart J. 2008;155:408–417.
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35. Bybee K, Motiei A, Syed I, et al. Electrocardiography Cannot Reliably Differentiate Transient Left Ventricular Apical Ballooning Syndrome from Anterior ST-segment Elevation Myocardial Infarction. J Electrocardiol. 2007;40:38e1–38e6. 36. Akashi YJ, Musha H, Nakazawa K, Miyake F. Plasma brain natriuretic peptide in takotsubo cardiomyopathy. QJM. 2004;97:599–607. 37. Ahmed KA, Madhavan M, Prasad A. Brain natriuretic peptide in apical ballooning syndrome (Takotsubo/stress cardiomyopathy): Comparison with acute myocardial infarction. Coron Artery Dis. 2012;23:259–264. 38. Madhavan M, Borlaug BA, Lerman A, Rihal CS, Prasad A. Stress hormone and circulating biomarker profile of apical ballooning syndrome (Takotsubo cardiomyopathy): Insights into the clinical significance of B-type natriuretic peptide and troponin levels. Heart. 2009;95:436–1441. 39. Nguyen TH, Neil CJ, Sverdlov AL, et al. N-terminal pro-brain natriuretic protein levels in takotsubo cardiomyopathy. Am J Cardiol. 2011;108:1316–1321.
40. Hurst RT, Askew JW, Reuss CS, et al. Transient midventricular ballooning syndrome: a new variant. J Am Coll Cardiol. 2006;48:579–583. 41. Elesber A, Prasad A, Bybee KA, et al. Transient Cardiac Apical Ballooning Syndrome: Prevalence and Clinical Implications of Right Ventricular Involvement. J Am Coll Cardiol. 2006;47:1082–1083. 42. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005;111:472–479. 43. Hoyt J, Lerman A, Lennon RJ, Rihal CS, Prasad A. Left anterior descending artery length and coronary atherosclerosis in apical ballooning syndrome (Takotsubo/stress induced cardiomyopathy). Int J Cardiol. 2010;145:112–115.
OUTLINE Epidemiology, 204 Pathophysiology, 204 Diagnosis, 205 Electrocardiogram, 205
Cardiac Biomarkers, 206 Left Ventricular Imaging and Coronary Angiography, 206 Management, 207
Stress cardiomyopathy (SCM) is a generally reversible acute cardiac syndrome that was originally described in the Japanese population over 30 years ago.1 Hence, the Japanese term takotsubo (an octopus trap with a narrow neck and round bottom, Fig. 20.1) cardiomyopathy/syndrome has gained favor, as it describes the appearance of the left ventricle during systole. SCM is also known as apical ballooning syndrome (ABS), broken heart syndrome, and ampulla cardiomyopathy.2,3 The clinical features mimic an acute myocardial infarction (MI); therefore, patients with this syndrome frequently present to the cardiac intensive care unit (CICU). SCM should be considered in the differential diagnosis of patients presenting with an acute coronary syndrome.4 The typical patient is a postmenopausal woman presenting with symptoms of myocardial ischemia that is temporally related to a physical or emotional stressful event, with positive cardiac biomarkers and/or an electrocardiogram (ECG) that has evidence of ischemia or injury.
PATHOPHYSIOLOGY
EPIDEMIOLOGY SCM is the final diagnosis in approximately 1% to 2% of all patients initially suspected of either an acute coronary syndrome or MI.5,6 The proportion may be as high as 12% in women with ST elevation myocardial infarction.7 The incidence of SCM among patients in intensive care units has been estimated at 1.5% and 8% among those with cardiogenic shock.8 However, an accurate incidence is difficult to ascertain because of underdiagnosis. Over time, there has been increasing recognition of this entity, as highlighted by data from the Nationwide Inpatient Sample in which the mean number of patients with a discharge diagnosis of SCM from a group of community hospitals increased from 315 per year in 2006 to 6,230 per year in 2012.9 Approximately 90% of all reported cases are in postmenopausal women10 and 5% of the patients are younger than 50 years.11
204
The pathophysiology of SCM remains to be established; however, several observations suggest that the sympathetic nervous system plays an important role.12 These include the temporal relationship with preceding emotional or physical stressful triggers, hyperadrenergic states, such as pheochromocytoma and subarachnoid hemorrhage causing a transient cardiomyopathy that is similar to SCM, documentation of high levels of circulating catecholamines,13 SCM being precipitated by inadvertent administration of supratherapeutic doses of catecholamines,14 animal models of stress immobilization and exogenous catecholamine administration inducing left ventricular apical hypokinesis,15 and the presence of contraction band necrosis on endomyocardial biopsies,16 a feature of catecholamine toxicity. However, elevation in circulating catecholamines and contraction band necrosis are not always present. Early reports of cases with SCM were associated with multivessel epicardial coronary spasm, which was initially proposed as a potential mechanism for the myocardial stunning. However, this has not been supported in large case series and is unlikely to be the underlying cause of SCM in the vast majority of patients. Aborted MI due to left anterior descending artery plaque rupture and thrombosis with spontaneous thrombolysis has also been proposed but seems unlikely to be the underlying mechanism.17 Conversely, microvascular dysfunction can be detected in at least two-thirds of the patients at the time of presentation and its severity correlates with the magnitude of troponin elevation and ECG abnormalities.18 The microvascular dysfunction may be a primary mechanistic feature or an epiphenomenon. Abnormal glucose and fatty acid metabolism is frequently present, colocalizing with the wall motion abnormality.19,20 A preceding stressful trigger is present in over two-thirds of patients. The list of potential emotional triggers is extensive, but
Keywords stress cardiomyopathy apical ballooning syndrome takotsubo cardiomyopathy
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
204.e1
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
A
205
B
Fig. 20.1 (A) Ventriculogram. (B) An octopus pot (“tako-tsubo”). (Courtesy #FOAMed Medical Education Resources, LITFL.)
most often relates to experiences of significant grief or personal loss, fear or anxiety, anger and frustration, and interpersonal conflicts. Common physical triggers include acute medical conditions (e.g., severe exacerbation of obstructive airways disease, sepsis), neurologic conditions (e.g., subarachnoid hemorrhage, seizures), falls and other trauma, noncardiac surgery (e.g., orthopedic, major abdominal), malignancy, and experiencing severe pain.21 The absence of such triggers does not exclude the diagnosis. Patients who are conscious typically have symptoms that are similar to that associated with MI,10,22,23 the most common being angina-like chest pain, present in approximately 50% of cases. Other presenting symptoms include dyspnea and, less frequently, syncope or out-of-hospital cardiac arrest. Among patients presenting primarily with SCM, it is those with ST segment elevation and severe left ventricular dysfunction who most often are admitted to the CICU. Typically, the ejection fraction is reduced to 30% to 40%,10 which may be accompanied by significant diastolic dysfunction with elevation in left ventricular filling pressure.24 Myocardial relaxation is impaired due to the ischemia related to microvascular dysfunction and myocardial edema. Acute heart failure is a frequent complication, but major hemodynamic decompensation is uncommon, with cardiogenic shock developing in approximately 10% to 15% of patients.10 These patients should be particularly assessed for the presence of transient left ventricular outflow obstruction and clinically significant mitral regurgitation, which can be exacerbating factors,25 each being present in approximately 10% to 20% of cases. The mechanisms for regurgitation appear to be papillary muscle displacement leading to tethering and impaired coaptation of the leaflets, and/or systolic anterior motion.25,26 Outflow tract obstruction likely occurs owing to a combination of factors, including hyperdynamic basal function, systolic anterior motion of the mitral valve, and a sigmoid-shaped ventricle. Additional complications that may lead to admission to the CICU include arrhythmias. Atrial fibrillation occurs in approximately 5% of cases,27 whereas ventricular tachycardia, torsade de pointes, and ventricular fibrillation have been reported in 3% to 4% of patients and asystole in 0.5%.28 Other rare
complications of SCM include left ventricular thrombus, thromboembolism, and cardiac rupture.29 Patients who develop SCM secondary to a noncardiac illness or other physical trigger may not have the typical symptoms described earlier but instead present with ischemic changes on the ECG, elevated cardiac biomarkers of myonecrosis, pulmonary edema, and hypotension. Hypotension may due to the reduction in stroke volume and, in some cases, dynamic left ventricular outflow tract obstruction.30 The ventricular dysfunction resolves over days to weeks, with complete recovery of global systolic function by 4 to 8 weeks. The prognosis of SCM is good in the absence of significant underlying comorbid conditions. In-hospital mortality is approximately 3% to 5%. Among those who are discharged, long-term survival appears to be similar to that of the general age-matched population. The subgroup of patients in whom there is a physical trigger—such as major surgery, malignancy, and fractures—appear to have a worse prognosis, likely related to the underlying condition. The recurrence rate of SCM is approximately 1% to 2% per year.31
DIAGNOSIS There are no diagnostic ECG or biomarker findings that can differentiate SCM from an acute coronary syndrome or myocarditis; hence, it is a diagnosis of exclusion. The characteristic features of the syndrome have been incorporated into several proposed diagnostic criteria.32,33 Box 20.1 provides the Mayo Clinic criteria that can be applied at the time of presentation. All four criteria must be present.34
Electrocardiogram Between 30% to 50% of patients have ST segment elevation at presentation. The precordial leads are most commonly involved, but ST segment elevation may also occur in the limb leads. The electrocardiographic findings do not reliably distinguish SCM from an acute MI.35 Pathologic Q waves may be present transiently. Some patients present with deep T-wave inversion, nonspecific T wave abnormality, and the ECG may be normal in some cases. ST segment depression is infrequently present. Characteristic
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evolutionary changes during hospitalization include resolution of ST segment elevation and diffuse and often deep T-wave inversion associated with prolongation of the corrected QT interval (Fig. 20.2). The electrocardiographic abnormalities usually resolve gradually over weeks to months but may persist even after systolic function has recovered.
Cardiac Biomarkers Cardiac troponin levels, using contemporary assays, are invariably elevated on admission and generally peak within 24 to 48 hours. Creatine kinase MB fraction is elevated in the great majority of cases. The levels are lower compared to patients with ST segment elevation MI, but similar to that of patients with non ST elevation MI and relatively low for the extent of acute left ventricular systolic dysfunction. Blood level of brain natriuretic peptide (BNP) or N-terminal pro-BNP, markers of ventricular dysfunction, are elevated in the majority of patients and may correlate with left ventricular end-diastolic pressure.36–39
BOX 20.1 Proposed Mayo Clinic Criteria
for Apical Ballooning Syndrome
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 present, but not always.a 2. Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture.b 3. New electrocardiographic abnormalities (either ST segment elevation and/ or T-wave inversion) or modest elevation in cardiac troponin. 4. Absence of pheochromocytoma, myocarditis.
Left Ventricular Imaging and Coronary Angiography Transthoracic echocardiography can be readily performed in the intensive care setting and hence is the preferred mode of imaging to detect systolic dysfunction and potential complications that accompany SCM. In the classical form of the cardiomyopathy, basal left ventricular function is preserved and may even be hyperdynamic, but there is hypokinesis or akinesis of the midand apical segments leading to the “ballooning” appearance (Fig. 20.3, Video 20.1). The wall motion abnormality virtually always extends beyond the distribution of a single coronary artery. In a significant proportion of patients, apical contraction is preserved and the wall motion abnormality is restricted to the mid-segments (apical-sparing variant; Video 20.2).40 The least common variant is known as inverted or reverse takotsubo in which there is hypokinesis of the basal segment of the left ventricle with preserved apical function. The variant forms of SCM have similar clinical characteristics and prognosis as the typical form. The right ventricle also develops a similar pattern
From Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155:408–417. 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 apical ballooning syndrome (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. In both of the above circumstances, the diagnosis of ABS should be made with caution and a clear stressful precipitating trigger must be sought.
I
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Fig. 20.2 Twelve-lead electrocardiogram with T-wave inversion in the precordial and limb leads associated with prolongation of the QT interval.
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
Diastole
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Systole
Fig. 20.3 Left ventriculogram in diastole and systole of a patient with stress cardiomyopathy with hyperdynamic basal contraction and akinesis of the mid- and apical segments.
of regional wall motion abnormality in approximately one-third of cases.41 Biventricular dysfunction SCM is associated with a worse hemodynamic profile and the patients are often sicker and more likely to develop acute heart failure. Cardiac magnetic resonance may be a useful imaging modality for documenting the extent of regional wall motion abnormality and differentiating SCM (virtually always characterized by the absence of delayed gadolinium hyperenhancement) from myocarditis and MI in which delayed hyperenhancement is present.42 Patients with SCM either have angiographically normal coronary arteries or mild atherosclerosis. Obstructive coronary artery disease is infrequent despite most patients being in their seventh and eighth decade of life.43 When present, the extent and distribution of obstructive plaque is generally insufficient to account for the widespread regional wall motion abnormality. Coronary angiography, either invasive or noninvasive, should be performed in patients suspected of SCM in order to exclude an acute coronary syndrome. In contemporary treatment pathways, the presence of ST segment elevation typically leads to emergency angiography to exclude coronary thrombotic occlusion that requires revascularization prior to admission to the CICU.
MANAGEMENT The recommendations for SCM management are based on expert opinion as clinical trials have not been conducted owing, in part, to the low incidence and the fact that supportive therapy leads to spontaneous recovery in the great majority of patients. The initial therapy is frequently directed toward treating myocardial ischemia with aspirin, anticoagulants, statins, and β-blockers since an acute coronary syndrome is the presumed diagnosis in the majority of cases. Aspirin, anticoagulants, and statins can be discontinued once the diagnosis of SCM has been made unless there is coexisting coronary atherosclerosis. In the absence of contraindications, a β-blocker or a combined α- and β-blocker may be initiated because excess catecholamines have been implicated in the pathogenesis. Long-term therapy should be
considered with the aim of reducing recurrence even though observational data has not supported this recommendation.10 Initiation of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy for acute ventricular dysfunction is recommended, especially as the diagnosis may not be certain at the time of discharge. Inhibitors of the renin angiotensin system may be discontinued once there is complete recovery of systolic function, though there are observational data that suggest that they may have long-term benefits.10 Mild to moderate acute heart failure responds to diuretic therapy. Severe cases with pulmonary edema may require intubation and mechanical ventilation. If present, left ventricular outflow tract obstruction may be treated with phenylephrine with the goal of increasing afterload and left ventricular cavity size. Phenylephrine use requires close monitoring due to the presence of systolic dysfunction. In the absence of heart failure, β-blockers and/or intravenous fluids may be effective. Inotropes are often used with good effect in cardiogenic shock, although there are theoretical reasons for avoiding them because of the potential role of catecholamine toxicity in precipitating the syndrome. Intraaortic balloon pump counterpulsation or other mechanical support devices may be preferable. The former has the potential to exacerbate outflow tract obstruction and should therefore be used cautiously. The acute treatment of atrial and ventricular arrhythmias is similar to other clinical situations. Although torsade de pointes is rare, patients should be on continuous ECG monitoring until the QTc is less than or equal to 500 msec. If pause-dependent torsade occurs, β-blocker therapy should be withheld and temporary pacing considered. Implantable cardioverterdefibrillator therapy is not routinely indicated for ventricular tachycardia or fibrillation as the cardiomyopathy is reversible. In cases of recurrent aborted sudden cardiac death or lifethreatening ventricular arrhythmia, the role of implantable cardioverter-defibrillator therapy is unclear. The full reference list for this chapter is available at ExpertConsult.com.
CHAPTER 20 Stress (Takotsubo) Cardiomyopathy
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PART IV Noncoronary Diseases: Diagnosis and Management
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