- Email: [email protected]
The broken heart syndrome: Takotsubo cardiomyopathy
Author's Accepted Manuscript
The Broken Heart Syndrome: Takotsubo Cardiomyopathy Matthew N. Peters MD, Praveen George MD, Anand M. Irimpen MD
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(14)00210-2 http://dx.doi.org/10.1016/j.tcm.2014.11.005 TCM6073
To appear in: trends in cardiovascular medicine
Cite this article as: Matthew N. Peters MD, Praveen George MD, Anand M. Irimpen MD, The Broken Heart Syndrome: Takotsubo Cardiomyopathy, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j.tcm.2014.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Broken Heart Syndrome: Takotsubo Cardiomyopathy
Matthew N. Peters, MD*,€; Praveen George, MD†; Anand M. Irimpen, MD‡,□
*
Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD † Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD ‡ Tulane University Heart and Vascular Institute, Tulane University of School of Medicine, New Orleans, LA □ Department of Cardiology, Southeast Louisiana Veterans Affairs Hospital, New Orleans, LA
€
Corresponding Author: Matthew N. Peters, MD Department of Cardiovascular Medicine 110 South Paca St, 7th Floor Baltimore, MD 21201 Phone: 443-286-2729 Fax: 410-328-3292 Email: [email protected]
All authors are responsible for the content and have read and approved the manuscript. This manuscript conforms to the Uniform Requirements for Manuscripts submitted to biomedical journals published in Annals in Internal Medicine. None of the authors have any conflicts of interest to disclose.
1
Abstract First described in 1990, Takotsubo cardiomyopathy consists of a transient systolic dysfunction of localized segments of the left ventricle. Commonly occurring in postmenopausal women, Takotsubo is often associated with intense physical and/or emotional stress. It is traditionally identified by distinctive wall motion patterns on transthoracic echocardiogram and left ventriculography. Further understanding of disease mechanisms and recognition of at-risk populations has potentially tremendous therapeutic benefit. Key Words Takotsubo cardiomyopathy; stress; echocardiography; left ventriculography
Introduction Also known as “broken heart syndrome”, “apical ballooning syndrome” and “stress induced cardiomyopathy”, Takotsubo cardiomyopathy (TCM) was first described in Japan in 1990 (1). The condition is characterized by transient systolic dysfunction of the apical and middle segments of the left ventricle (with preserved contraction of the left ventricular base), an appearance which, on left ventriculogram (in cases of apical dysfunction) mimics a Japanese octopus trap, or “tako tsubo.” TCM most commonly occurs in postmenopausal women and is often brought on by intense emotional stress. TCM was first recognized by the American Heart Association as a type of acquired cardiomyopathy in 2006 (2).
2
Mechanisms While the exact mechanism of TCM remains controversial, it has become clear that the disease process is mediated by an excess in circulating catecholamines. Initial epidemiologic evidence supporting this mechanism was provided in a 2005 study which compared 13 patients with TCM to 7 patients with Killip class III acute myocardial infarctions (AMI); TCM patients demonstrated both higher serum epinephrine levels (376 compared to 164 pg/ml) as well as norepinephrine levels (2284 compared to 1100 pg/mL) in comparison to the AMI group (3). Additional evidence for the catecholamine-mediated hypothesis is provided by studies demonstrating transient TCM-like wall motion abnormalities with administration of exogenous catecholamines (4) and in individuals with pheochromocytoma (5). Less clear is whether the catecholamine mediated effects seen in TCM exert their primary effect upon the coronary arterial vasculature or directly on the myocardium. Toxic effects on the coronary vasculature may include abnormalities in endotheliumdependent vasodilation as well as excessive vasoconstriction and subsequent impairment in myocardial perfusion (6). These effects have been described in studies that have demonstrated multifocal coronary arterial vasospasm on angiography (7,8), transient myocardial perfusion abnormalities (9) and the presence of abnormal TIMI frame counts (total number of cine frames required for the injected dye to reach standardized distal coronary landmarks) (10). Catecholamine-mediated histopathologic myocardial toxicity has been reported to include increased interstitial fibrosis, band necrosis and reversible intracellular accumulation of glycogen associated with disorganized cytoskeletal and contractile
3
structure (3,4,15). Additional support for the catecholamine mediated myocardial inflammation theory is provided by increased levels of C-reactive protein and white blood cells in TCM, suggesting an increase in concentrations of inflammatory cytokines such as tumor necrosis factor alpha and interleukin 6 (16) Evidence of catecholamine mediated myocardial inflammation is not only limited to biochemical and histopathologic levels but also has been seen to be associated with structural abnormalities on cardiac magnetic resonance (CMR) imaging, such as myocardial edema, in the presence of normal coronary perfusion (17,18). An additional possible mechanism, which has been studied within a mouse model, may provide an explanation for the localized distribution of myocardial dysfunction in TCM. It has been shown that the presence of epinephrine mediates a switch from the beta-2 adrenoreceptor (B2AR) mediated stimulatory G protein (Gs) (which is a positive inotrope and occurs at low serum epinephrine levels) to an inhibitory G protein ( Gi) (which is negatively intotropic and occurs at higher serum epinephrine levels)(19,20) This effect known as epinephrine “biased agonism” appears to protect myocytes from excess stimulation and ultimately decrease apoptosis (suggested by small or slow increases in troponin levels) (19,21). The subsequent disproportionate regional effects can then be explained by the presence of a higher density of beta-2 adrenoreceptors at the left ventricular apex as compared to the base (22,23). Any discussion of TCM should also provide mention of a previouslyhypothesized mechanism in which a transient clot forms in a left anterior descending (LAD) coronary artery, wraps around the apex, and subsequently lyses prior to angiography, thereby creating residual myocardial stunning in the absence of
4
angiographically significant coronary artery disease (24). Evidence for this theory is supported by a recent comparison of TCM and control patients which demonstrated a 20% higher occurrence of LAD reaching the left ventricular apex among the TCM group. (25) While this process may certainly occur in some cases of apical TCM, a study demonstrating occurrence of apical “wrap around” LAD in only 27% of TCM patients suggests that this mechanism is not responsible for the majority of cases of TCM.
Risk Factors Emotional stress is a documented risk factor for the development of TCM and it has been reported that stressful events precede the development of TCM in nearly two thirds of patients (17). Physical stress, related to critical illness is also associated with a high incidence of TCM. A 2005 study of TCM in a medical intensive care unit of 92 patients with no active or prior cardiac disease demonstrated that 28% of these patients had the appearance of left ventricular apical ballooning within 7 days of admission (26). Post-menopausal females are at increased risk of TCM. It is estimated that 90% of all cases occur in post-menopausal females (27,28). Interestingly, in a 2010 study, it was found that none of the 31 enrolled patients with TCM were receiving estrogen replacement therapy at the time of presentation (29). It should also be noted that ovariectomized rats that had been subjected to stress by means of restraints demonstrated a greater decrease in LV function compared to rats receiving estradiol supplementation (30). The protective property of estrogen is likely due to enhanced transcription of heat shock protein and atrial natriuretic peptide that protects against toxic effects of catecholamines and calcium overload as well as decreasing oxidative stress (31).
5
An additional subgroup that may also be predisposed to occurrence of TCM is the population with psychiatric disorders. It has been previously shown that when patients with depression experience a stressful event, vagal tone decreases while the response to adrenal medullary hormone increases (32). It has also been previously demonstrated that some patients with depression have very high rates of noradrenaline release that may lead to higher circulating levels of catecholamines (33). It is unclear whether patients may be genetically predisposed to TCM. In support of potential genetic predisposition are two case reports of TCM occurrence in two sisters (34) and a mother and daughter (35). While attempts to identify specific genetic polymorphisms have generally been generally unsuccessful, a 2010 study identified an L41Q polymorphism of G-protein coupled receptor kinase (GRK5) to occur more frequently in TCM compared to controls (36). In the L4Q10 polymorphism, GRK5 may have an altered response to catecholamine stimulation and attenuate the response to beta adrenergic receptors, leading to a potentially negative inotropic effect via either beta receptor decoupling or an imbalance between alpha-1 adrenergic coronary arterial vasoconstriction and beta adrenergic vasodilation (36).
Detection and Diagnosis It is important to consider TCM in the differential diagnosis of any patient with chest pain. Four small series of consecutive patients presenting with suspected acute coronary syndrome (ACS) (each consisting of at least 10 patients with TCM) demonstrated a TCM prevalence of 1.7-2.2% (12). An additional registry of 3265 patients with positive troponin and ACS symptoms demonstrated a TCM incidence of 1.2% (37).
6
Typical symptoms of TCM are similar to that of ACS and consist of chest pain, dyspnea and occasionally syncope. ST segment elevation has been reported to occur in 34-56% and is most common in the anterior precordial leads (4) (Figure 1). Other reported ECG abnormalities include deep T-wave inversions (Figure 1, Figure 2), QT interval prolongation (Figure 2) and appearance of abnormal Q waves (3,7). These abnormal electrocardiographic (ECG) findings usually mirror the clinical course of TCM and generally resolve within days to weeks (3). Troponin elevations have been reported in 74-86% percent of patients with TCM (12) and are usually relatively mild as evidenced by a review of 136 patients in which reported levels ranged from 0.01 to 5.2 ng/mL (4). It should be pointed out that in addition to chest pain, troponin elevations, ECG and wall motion abnormalities, complications of TCM may also mimic those of ACS and include congestive heart failure, ventricular rupture, left ventricular thrombus, dyna mic left ventricular outflow tract gradients and torsades de pointes (20,38) Traditionally TCM imaging consists of identification of hypokinesis of the apical one half to two thirds of the left ventricle (8,10). While apical hypokinesis is the most commonly reported wall motion abnormality (82%) (Figure 3) other variants include isolated mid-ventricular (17%) and basal (1%) (Figure 4) involvement (17). An additional 34% of patients have been shown to have RV involvement as well (17). While wall motion abnormalities are often detected on trans-thoracic echocardiography (TTE) left ventriculography (Figure 5) is often utilized prior to TTE given the fact that coronary angiography is frequently performed to rule out AMI in suspected TCM patients. An evolving method with which to evaluate TCM is cardiac magnetic resonance (CMR), which not only shows wall motion but also provides assessment of the amount of
7
inflammation and fibrosis. (21). Additionally, confirmation of the absence of delayed gadolinium enhancement helps to separate TCM from conditions with similar clinical presentations such as AMI and myocarditis. (17) The current standard diagnostic criteria were established by the Mayo clinic in 2004 and include each of the following: 1) suspicion of AMI based on precordial pain and ST elevation observed on the acute-phase ECG; 2) transient hypokinesis or akinesia of the middle and apical regions of the LV and functional hyperkinesia of the basal region, observed on ventriculography or echocardiography; 3) normal coronary arteries confirmed by arteriography (luminal narrowing of less than 50% in all the coronary arteries) in the first 24 hours after the onset of symptoms and 4) absence of recent significant head injury, intracranial hemorrhage, suspicion of pheochromocytoma, myocarditis, or hypertrophic cardiomyopathy (10. While these criteria may be useful in clinical practice, it is important to recognize TCM as a clinical diagnosis and that these criteria are not a diagnostic standard.
Management Options and Prognosis TCM is a transient disorder with resolution corresponding to alleviation of physical or emotional stress. Interim supportive therapy can include traditional medications for left ventricular systolic dysfunction including angiotensin converting enzyme inhibitors (ACE-I), beta blockers (BB) and diuretics (in the presence of volume overload) plus anticoagulants to prevent thrombus formation. Patients with hemodynamic instability may derive benefit from mechanical circulatory support (39,40) While evidence is currently insufficient for official recommendation, consideration for
8
fitting with wearable cardiac defibrillators may be considered in patients with left ventricular ejection fractions less than 35% until their ejection fraction recovers. Once patients survive their initial presentation (in-hospital mortality has been reported to range from 0-8% and is typically reported in the 1-2% range) (4,8,10,41), recovery of systolic function is typically seen within 1-4 weeks (3,41). It has been suggested that in the absence of any contraindications that an ACE-I or BB can be continued indefinitely (even past the recovery phase) although there are currently no data demonstrating that continued use of these drugs prevents TCM recurrence or improves overall survival (20). Bradycardia and QT interval prolongation should also be considered a relative contraindication to the use of BB given the increased risk for torsades de pointes in TCM (38). To date, the longest current follow-up study consists of 100 patients with followup of 4.4 + 4.6 years; of these, 10% had recurrent apical ballooning syndrome and 17 patients died; however the mortality rate was not significantly different in comparison to age and gender matched controls (42). It is also important to recognize that no prognostic indicators including ECG findings, troponin levels (3) NT-proBNP levels or any other biochemical markers have been found to have any type of prognostic implications in terms of ultimate recovery (20). However, it should be pointed out that TCM has a nearly 6-fold higher BMP/troponin ratio compared to AMI which may serve as a useful diagnostic tool. (43)
9
Conclusions Discovered less than 25 years ago and officially recognized as a cardiomyopathy for less than 10 years, the field of TCM is rapidly evolving. Further elucidation of underlying mechanisms and potential recognition of genetic predisposition will aid in prompt recognition of TCM and facilitate differentiation from conditions such as AMI and myocarditis that have similar presentations. The potential for early identification of high risk patient groups may lead to a decrease in both morbidity and mortality.
References 1. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M.[Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991; 21:20314, 2. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an 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: 1807-16. 3. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al.. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005; 352:539-48.
10
4. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010; 55:333-41. 5. Kassim TA, Clarke DD, Mai VQ, Clyde PW, Mohamed Shakir KM. Catecholamineinduced cardiomyopathy. Endocr Pract 2008; 14:1137-49. 6. Martin EA, Prasad A, Rihal CS, Lerman LO, Lerman A.Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome.J Am Coll Cardiol 2010; 56: 1840-6. 7. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M. 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. 8. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J, Longe TF, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005; 111:472-9. 9. Ito K, Sugihara H, Katoh S, Azuma A, Nakagawa M. Assessment of Takotsubo (ampulla) cardiomyopathy using 99m-Tc-tetrofosmin myocardial SPECT-comparison with acute coronary syndrome. Ann Nucl Med 2003;17:115-22. 10. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:858-65. 11. Angelini P. Transient left ventricular apical ballooning: A unifying pathophysiologic theory at the edge of Prinzmetal angina. Catheter Cardiovasc Interv 2008;71:342-52. 12. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27:152329. 13. Kurisu S, Sato H, Kawagoe T, Ishihara M, Shimatani Y, Nishioka K, et al. Takotsubolike left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction. Am Heart J 2002; 143: 448-455
11
14. Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:737-42. 15. Nef HM, Möllmann H, Kostin S, Troidl C,Voss S, Weber M, et al. Tako-Tsubo cardiomyopathy: intraindividual structural analysis in the acute phase and after functional recovery. Eur Heart J 2007; 28:2456-64. 16. Morel O, Sauer F, Imperiale A, Cimarelli S, Blondet C, Jesel L, et al. Importance inflammation and neurohumoral activation in Takotsubo cardiomyopathy. J Card Fail 2009; 15: 206-13 17. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011; 306:27-86. 18. Avegliano G, Huguet M, Costabel JP, Ronderos R, Bijnens B, Kuschnir P, et al. Morphologic pattern of late gadolinium enhancement in Takotsubo cardiomyopathy detected by early cardiovascular magnetic resonance. Clin Cardiol 2011;34:178-82. 19. Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O'Gara P, et al. High levels of circulating epinephrine trigger apical cardio depression in a2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012 Aug 7;126:697-706. 20. Heubach JF, Ravens U, Kaumann AJ. Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart. Mol Pharmacol 2004; 65:1313-22 21. Komamura K, Fukui M, Iwasaku T, Hirotani S, Masuyama T. Taskotsubo cardiomyopathy: Pathophysiology, diagnosis and treatment. World Journal of Cardiology2014;6:602-9. 22. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE.. Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamineinduced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008; 5:22-9. 23. Mori H, Ishikawa S, Kojima S, Hayashi J, Watanabe Y, Hoffman JI, et al. Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli. Cardiovasc Res 1993;27:192-98. 24. Ibanez B, Navarro F, Cordoba M, M-Alberca P, Farre J. Tako-tsubo transient left ventricular apical ballooning: is intravascular ultrasound the key to resolve the enigma? Heart 2005; 91:102-4. 25. Stiermaier T, Desch S, Blazek S, Schuler G, Thiele H, Eitel I. Frequency and significance of myocardial bridging and recurrent segment of the left anterior descending coronary artery in patients with takotsubo cardiomyopathy. Am J Cardiol. 2014 Oct 15;114:1204-9
12
26. Park JH, Kang SJ, Song JK, Kim HK, Lim CM, Kang DH, et al. Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest 2005; 128:296-302. 27. Parodi G, Del Pace S, Carrabba N, Salvadori C, Memisha G, Simonetti I, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol 2007; 99: 182-5 28. Eshtehardi P, Koestner SC, Adorjan P, Windecker S, Meier B,Hess OM, Wahl A, Cook S. Transient apical ballooning syndrome-clinical characteristics, ballooning pattern, and longterm follow-up in a Swiss population. Int J Cardiol 2009; 135:370-375 29. Kuo BT, Choubey R, Novaro GM. Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy. Gen Med 2010; 7: 71-77. 30. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y,Nishio I. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (Ampulla) cardiomyopathy. J Cardiovasc Pharmacol 2003; 42 Suppl1: S117-S119 31. Migliore F, Bilato C, Isabella G, Iliceto S, Tarantini G. Haemondyamic effects of acute intravenous metoprolol in apical ballooning syndrome with dynamic left ventricular outflow tract obstruction. Eur J Heart Fail 2010;12:305-8. 32. Cevik C, Nugent K. The role of cardiac autonomic control in the pathogenesis of takotsubo cardiomyopathy. Am Heart J 2008;156:31. 33. Barton DA, Dawood T, Lambert EA, Esler MD, Haikerwal D, Brenchley C, et al. Sympathetic activity in major depressive disorder: identifying those at increased cardiac risk? J Hypertens 2007;25: 2117-24 34. Pison L, De Vusser P, Mullens W. Apical ballooning in relatives. Heart 2004;90:67 35. Kumar G, Holmes DR Jr, Prasad A. "Familial" apical ballooning syndrome (Takotsubo cardiomyopathy). Int J Cardiol 2010; 144:444-5. 36. Spinelli L, Trimarco V, Di Marino S, Marino M, Iaccarino G, Trimarco B. L41Q polymorphism of the G protein coupled mreceptor kinase 5 is associated with left ventricular apical ballooning syndrome. Eur J Heart Fail 2010; 12: 13-16 37. Kurowski K, Kaiser A, Von Hof K, Killermann DP, Mayer B, Hartmann F, et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132:809-16. 38. Madias C, Fitzgibbons TP, Alsheikh-Ali AA, Bouchard JL, Kalsmith B, GarlitskiAC, et al. Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes. Heart Rhythm. 2011 Apr;8:555-61
13
39. Patel HM, Kantharia BK, Morris DL, Yazdanfar S. Takotsubo syndrome in AfricanAmerican women with atypical presentations: a single-center experience. Clin Cardiol 2007;30:14-8. 40. Cangella F, Medolla A, De Fazio G, Iuliano C, Curcio N, Salemme L, et al. Stress induced cardiomyopathy presenting as acute coronary syndrome: Tako-Tsubo in Mercogliano, Southern Italy. Cardiovasc Ultrasound 2007;5:36. 41. Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 2008;118:2754-62. 42. Elesber AA, Prasad A, Lennon RJ, Wright Rs, Lerman A, Rihal CS. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol 2007; 50:44852. 43. Randhawa MS, Dhillon AS, Taylor HC, Sun Z, Desai MY. Diagnostic utility of cardiac biomarkers in discriminating Takotsubo cardiomyopathy from acute myocardial infarction. J Card Fail. 2014;20:377.e25-31.
14
Figure Legends Figure 1. Electrocardiogram (ECG) demonstrating anterior precordial ST segment elevation and diffuse T wave inversions in a 53 year old woman with Takotsubo cardiomyopathy (TCM). Figure 2. Electrocardiogram (ECG) demonstrating QT segment prolongation and diffuse, deep T wave inversions in a 42 year old woman with Takotsubo cardiomyopathy (TCM). Figure 3. Transthoracic echocardiogram (TTE) during diastole (left) and systole (right) demonstrating apical and mid left ventricular hypokinesis with preserved basal contraction creating pathognomonic apical ballooning appearance in 53 year old woman with Takotsubo cardiomyopathy. Figure 4. Transthoracic echocardiogram (TTE) during diastole (left) and systole (right) demonstrating basal and mid left ventricular hypokinesis with preserved apical contraction in a 53 year old woman with an unusual variant of Takotsubo cardiomyopathy (TCM).. Figure 5. Left venticulogram during diastole (left) and systole (right) demonstrating apical and mid hypokinesis with preserved basal contraction creating pathognomonic apical balooning appearance in a 42 year old woman with Takotsubo cardiomyopathy (TCM).
15
Fig 1
16
Fig 2
17
Fig 3
18
Fig 4
19
Fig 5
20
The Broken Heart Syndrome: Takotsubo Cardiomyopathy Matthew N. Peters MD, Praveen George MD, Anand M. Irimpen MD
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(14)00210-2 http://dx.doi.org/10.1016/j.tcm.2014.11.005 TCM6073
To appear in: trends in cardiovascular medicine
Cite this article as: Matthew N. Peters MD, Praveen George MD, Anand M. Irimpen MD, The Broken Heart Syndrome: Takotsubo Cardiomyopathy, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j.tcm.2014.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Broken Heart Syndrome: Takotsubo Cardiomyopathy
Matthew N. Peters, MD*,€; Praveen George, MD†; Anand M. Irimpen, MD‡,□
*
Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD † Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD ‡ Tulane University Heart and Vascular Institute, Tulane University of School of Medicine, New Orleans, LA □ Department of Cardiology, Southeast Louisiana Veterans Affairs Hospital, New Orleans, LA
€
Corresponding Author: Matthew N. Peters, MD Department of Cardiovascular Medicine 110 South Paca St, 7th Floor Baltimore, MD 21201 Phone: 443-286-2729 Fax: 410-328-3292 Email: [email protected]
All authors are responsible for the content and have read and approved the manuscript. This manuscript conforms to the Uniform Requirements for Manuscripts submitted to biomedical journals published in Annals in Internal Medicine. None of the authors have any conflicts of interest to disclose.
1
Abstract First described in 1990, Takotsubo cardiomyopathy consists of a transient systolic dysfunction of localized segments of the left ventricle. Commonly occurring in postmenopausal women, Takotsubo is often associated with intense physical and/or emotional stress. It is traditionally identified by distinctive wall motion patterns on transthoracic echocardiogram and left ventriculography. Further understanding of disease mechanisms and recognition of at-risk populations has potentially tremendous therapeutic benefit. Key Words Takotsubo cardiomyopathy; stress; echocardiography; left ventriculography
Introduction Also known as “broken heart syndrome”, “apical ballooning syndrome” and “stress induced cardiomyopathy”, Takotsubo cardiomyopathy (TCM) was first described in Japan in 1990 (1). The condition is characterized by transient systolic dysfunction of the apical and middle segments of the left ventricle (with preserved contraction of the left ventricular base), an appearance which, on left ventriculogram (in cases of apical dysfunction) mimics a Japanese octopus trap, or “tako tsubo.” TCM most commonly occurs in postmenopausal women and is often brought on by intense emotional stress. TCM was first recognized by the American Heart Association as a type of acquired cardiomyopathy in 2006 (2).
2
Mechanisms While the exact mechanism of TCM remains controversial, it has become clear that the disease process is mediated by an excess in circulating catecholamines. Initial epidemiologic evidence supporting this mechanism was provided in a 2005 study which compared 13 patients with TCM to 7 patients with Killip class III acute myocardial infarctions (AMI); TCM patients demonstrated both higher serum epinephrine levels (376 compared to 164 pg/ml) as well as norepinephrine levels (2284 compared to 1100 pg/mL) in comparison to the AMI group (3). Additional evidence for the catecholamine-mediated hypothesis is provided by studies demonstrating transient TCM-like wall motion abnormalities with administration of exogenous catecholamines (4) and in individuals with pheochromocytoma (5). Less clear is whether the catecholamine mediated effects seen in TCM exert their primary effect upon the coronary arterial vasculature or directly on the myocardium. Toxic effects on the coronary vasculature may include abnormalities in endotheliumdependent vasodilation as well as excessive vasoconstriction and subsequent impairment in myocardial perfusion (6). These effects have been described in studies that have demonstrated multifocal coronary arterial vasospasm on angiography (7,8), transient myocardial perfusion abnormalities (9) and the presence of abnormal TIMI frame counts (total number of cine frames required for the injected dye to reach standardized distal coronary landmarks) (10). Catecholamine-mediated histopathologic myocardial toxicity has been reported to include increased interstitial fibrosis, band necrosis and reversible intracellular accumulation of glycogen associated with disorganized cytoskeletal and contractile
3
structure (3,4,15). Additional support for the catecholamine mediated myocardial inflammation theory is provided by increased levels of C-reactive protein and white blood cells in TCM, suggesting an increase in concentrations of inflammatory cytokines such as tumor necrosis factor alpha and interleukin 6 (16) Evidence of catecholamine mediated myocardial inflammation is not only limited to biochemical and histopathologic levels but also has been seen to be associated with structural abnormalities on cardiac magnetic resonance (CMR) imaging, such as myocardial edema, in the presence of normal coronary perfusion (17,18). An additional possible mechanism, which has been studied within a mouse model, may provide an explanation for the localized distribution of myocardial dysfunction in TCM. It has been shown that the presence of epinephrine mediates a switch from the beta-2 adrenoreceptor (B2AR) mediated stimulatory G protein (Gs) (which is a positive inotrope and occurs at low serum epinephrine levels) to an inhibitory G protein ( Gi) (which is negatively intotropic and occurs at higher serum epinephrine levels)(19,20) This effect known as epinephrine “biased agonism” appears to protect myocytes from excess stimulation and ultimately decrease apoptosis (suggested by small or slow increases in troponin levels) (19,21). The subsequent disproportionate regional effects can then be explained by the presence of a higher density of beta-2 adrenoreceptors at the left ventricular apex as compared to the base (22,23). Any discussion of TCM should also provide mention of a previouslyhypothesized mechanism in which a transient clot forms in a left anterior descending (LAD) coronary artery, wraps around the apex, and subsequently lyses prior to angiography, thereby creating residual myocardial stunning in the absence of
4
angiographically significant coronary artery disease (24). Evidence for this theory is supported by a recent comparison of TCM and control patients which demonstrated a 20% higher occurrence of LAD reaching the left ventricular apex among the TCM group. (25) While this process may certainly occur in some cases of apical TCM, a study demonstrating occurrence of apical “wrap around” LAD in only 27% of TCM patients suggests that this mechanism is not responsible for the majority of cases of TCM.
Risk Factors Emotional stress is a documented risk factor for the development of TCM and it has been reported that stressful events precede the development of TCM in nearly two thirds of patients (17). Physical stress, related to critical illness is also associated with a high incidence of TCM. A 2005 study of TCM in a medical intensive care unit of 92 patients with no active or prior cardiac disease demonstrated that 28% of these patients had the appearance of left ventricular apical ballooning within 7 days of admission (26). Post-menopausal females are at increased risk of TCM. It is estimated that 90% of all cases occur in post-menopausal females (27,28). Interestingly, in a 2010 study, it was found that none of the 31 enrolled patients with TCM were receiving estrogen replacement therapy at the time of presentation (29). It should also be noted that ovariectomized rats that had been subjected to stress by means of restraints demonstrated a greater decrease in LV function compared to rats receiving estradiol supplementation (30). The protective property of estrogen is likely due to enhanced transcription of heat shock protein and atrial natriuretic peptide that protects against toxic effects of catecholamines and calcium overload as well as decreasing oxidative stress (31).
5
An additional subgroup that may also be predisposed to occurrence of TCM is the population with psychiatric disorders. It has been previously shown that when patients with depression experience a stressful event, vagal tone decreases while the response to adrenal medullary hormone increases (32). It has also been previously demonstrated that some patients with depression have very high rates of noradrenaline release that may lead to higher circulating levels of catecholamines (33). It is unclear whether patients may be genetically predisposed to TCM. In support of potential genetic predisposition are two case reports of TCM occurrence in two sisters (34) and a mother and daughter (35). While attempts to identify specific genetic polymorphisms have generally been generally unsuccessful, a 2010 study identified an L41Q polymorphism of G-protein coupled receptor kinase (GRK5) to occur more frequently in TCM compared to controls (36). In the L4Q10 polymorphism, GRK5 may have an altered response to catecholamine stimulation and attenuate the response to beta adrenergic receptors, leading to a potentially negative inotropic effect via either beta receptor decoupling or an imbalance between alpha-1 adrenergic coronary arterial vasoconstriction and beta adrenergic vasodilation (36).
Detection and Diagnosis It is important to consider TCM in the differential diagnosis of any patient with chest pain. Four small series of consecutive patients presenting with suspected acute coronary syndrome (ACS) (each consisting of at least 10 patients with TCM) demonstrated a TCM prevalence of 1.7-2.2% (12). An additional registry of 3265 patients with positive troponin and ACS symptoms demonstrated a TCM incidence of 1.2% (37).
6
Typical symptoms of TCM are similar to that of ACS and consist of chest pain, dyspnea and occasionally syncope. ST segment elevation has been reported to occur in 34-56% and is most common in the anterior precordial leads (4) (Figure 1). Other reported ECG abnormalities include deep T-wave inversions (Figure 1, Figure 2), QT interval prolongation (Figure 2) and appearance of abnormal Q waves (3,7). These abnormal electrocardiographic (ECG) findings usually mirror the clinical course of TCM and generally resolve within days to weeks (3). Troponin elevations have been reported in 74-86% percent of patients with TCM (12) and are usually relatively mild as evidenced by a review of 136 patients in which reported levels ranged from 0.01 to 5.2 ng/mL (4). It should be pointed out that in addition to chest pain, troponin elevations, ECG and wall motion abnormalities, complications of TCM may also mimic those of ACS and include congestive heart failure, ventricular rupture, left ventricular thrombus, dyna mic left ventricular outflow tract gradients and torsades de pointes (20,38) Traditionally TCM imaging consists of identification of hypokinesis of the apical one half to two thirds of the left ventricle (8,10). While apical hypokinesis is the most commonly reported wall motion abnormality (82%) (Figure 3) other variants include isolated mid-ventricular (17%) and basal (1%) (Figure 4) involvement (17). An additional 34% of patients have been shown to have RV involvement as well (17). While wall motion abnormalities are often detected on trans-thoracic echocardiography (TTE) left ventriculography (Figure 5) is often utilized prior to TTE given the fact that coronary angiography is frequently performed to rule out AMI in suspected TCM patients. An evolving method with which to evaluate TCM is cardiac magnetic resonance (CMR), which not only shows wall motion but also provides assessment of the amount of
7
inflammation and fibrosis. (21). Additionally, confirmation of the absence of delayed gadolinium enhancement helps to separate TCM from conditions with similar clinical presentations such as AMI and myocarditis. (17) The current standard diagnostic criteria were established by the Mayo clinic in 2004 and include each of the following: 1) suspicion of AMI based on precordial pain and ST elevation observed on the acute-phase ECG; 2) transient hypokinesis or akinesia of the middle and apical regions of the LV and functional hyperkinesia of the basal region, observed on ventriculography or echocardiography; 3) normal coronary arteries confirmed by arteriography (luminal narrowing of less than 50% in all the coronary arteries) in the first 24 hours after the onset of symptoms and 4) absence of recent significant head injury, intracranial hemorrhage, suspicion of pheochromocytoma, myocarditis, or hypertrophic cardiomyopathy (10. While these criteria may be useful in clinical practice, it is important to recognize TCM as a clinical diagnosis and that these criteria are not a diagnostic standard.
Management Options and Prognosis TCM is a transient disorder with resolution corresponding to alleviation of physical or emotional stress. Interim supportive therapy can include traditional medications for left ventricular systolic dysfunction including angiotensin converting enzyme inhibitors (ACE-I), beta blockers (BB) and diuretics (in the presence of volume overload) plus anticoagulants to prevent thrombus formation. Patients with hemodynamic instability may derive benefit from mechanical circulatory support (39,40) While evidence is currently insufficient for official recommendation, consideration for
8
fitting with wearable cardiac defibrillators may be considered in patients with left ventricular ejection fractions less than 35% until their ejection fraction recovers. Once patients survive their initial presentation (in-hospital mortality has been reported to range from 0-8% and is typically reported in the 1-2% range) (4,8,10,41), recovery of systolic function is typically seen within 1-4 weeks (3,41). It has been suggested that in the absence of any contraindications that an ACE-I or BB can be continued indefinitely (even past the recovery phase) although there are currently no data demonstrating that continued use of these drugs prevents TCM recurrence or improves overall survival (20). Bradycardia and QT interval prolongation should also be considered a relative contraindication to the use of BB given the increased risk for torsades de pointes in TCM (38). To date, the longest current follow-up study consists of 100 patients with followup of 4.4 + 4.6 years; of these, 10% had recurrent apical ballooning syndrome and 17 patients died; however the mortality rate was not significantly different in comparison to age and gender matched controls (42). It is also important to recognize that no prognostic indicators including ECG findings, troponin levels (3) NT-proBNP levels or any other biochemical markers have been found to have any type of prognostic implications in terms of ultimate recovery (20). However, it should be pointed out that TCM has a nearly 6-fold higher BMP/troponin ratio compared to AMI which may serve as a useful diagnostic tool. (43)
9
Conclusions Discovered less than 25 years ago and officially recognized as a cardiomyopathy for less than 10 years, the field of TCM is rapidly evolving. Further elucidation of underlying mechanisms and potential recognition of genetic predisposition will aid in prompt recognition of TCM and facilitate differentiation from conditions such as AMI and myocarditis that have similar presentations. The potential for early identification of high risk patient groups may lead to a decrease in both morbidity and mortality.
References 1. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M.[Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991; 21:20314, 2. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an 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: 1807-16. 3. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al.. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005; 352:539-48.
10
4. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010; 55:333-41. 5. Kassim TA, Clarke DD, Mai VQ, Clyde PW, Mohamed Shakir KM. Catecholamineinduced cardiomyopathy. Endocr Pract 2008; 14:1137-49. 6. Martin EA, Prasad A, Rihal CS, Lerman LO, Lerman A.Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome.J Am Coll Cardiol 2010; 56: 1840-6. 7. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M. 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. 8. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J, Longe TF, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005; 111:472-9. 9. Ito K, Sugihara H, Katoh S, Azuma A, Nakagawa M. Assessment of Takotsubo (ampulla) cardiomyopathy using 99m-Tc-tetrofosmin myocardial SPECT-comparison with acute coronary syndrome. Ann Nucl Med 2003;17:115-22. 10. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:858-65. 11. Angelini P. Transient left ventricular apical ballooning: A unifying pathophysiologic theory at the edge of Prinzmetal angina. Catheter Cardiovasc Interv 2008;71:342-52. 12. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27:152329. 13. Kurisu S, Sato H, Kawagoe T, Ishihara M, Shimatani Y, Nishioka K, et al. Takotsubolike left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction. Am Heart J 2002; 143: 448-455
11
14. Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:737-42. 15. Nef HM, Möllmann H, Kostin S, Troidl C,Voss S, Weber M, et al. Tako-Tsubo cardiomyopathy: intraindividual structural analysis in the acute phase and after functional recovery. Eur Heart J 2007; 28:2456-64. 16. Morel O, Sauer F, Imperiale A, Cimarelli S, Blondet C, Jesel L, et al. Importance inflammation and neurohumoral activation in Takotsubo cardiomyopathy. J Card Fail 2009; 15: 206-13 17. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011; 306:27-86. 18. Avegliano G, Huguet M, Costabel JP, Ronderos R, Bijnens B, Kuschnir P, et al. Morphologic pattern of late gadolinium enhancement in Takotsubo cardiomyopathy detected by early cardiovascular magnetic resonance. Clin Cardiol 2011;34:178-82. 19. Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O'Gara P, et al. High levels of circulating epinephrine trigger apical cardio depression in a
12
26. Park JH, Kang SJ, Song JK, Kim HK, Lim CM, Kang DH, et al. Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest 2005; 128:296-302. 27. Parodi G, Del Pace S, Carrabba N, Salvadori C, Memisha G, Simonetti I, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol 2007; 99: 182-5 28. Eshtehardi P, Koestner SC, Adorjan P, Windecker S, Meier B,Hess OM, Wahl A, Cook S. Transient apical ballooning syndrome-clinical characteristics, ballooning pattern, and longterm follow-up in a Swiss population. Int J Cardiol 2009; 135:370-375 29. Kuo BT, Choubey R, Novaro GM. Reduced estrogen in menopause may predispose women to takotsubo cardiomyopathy. Gen Med 2010; 7: 71-77. 30. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y,Nishio I. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (Ampulla) cardiomyopathy. J Cardiovasc Pharmacol 2003; 42 Suppl1: S117-S119 31. Migliore F, Bilato C, Isabella G, Iliceto S, Tarantini G. Haemondyamic effects of acute intravenous metoprolol in apical ballooning syndrome with dynamic left ventricular outflow tract obstruction. Eur J Heart Fail 2010;12:305-8. 32. Cevik C, Nugent K. The role of cardiac autonomic control in the pathogenesis of takotsubo cardiomyopathy. Am Heart J 2008;156:31. 33. Barton DA, Dawood T, Lambert EA, Esler MD, Haikerwal D, Brenchley C, et al. Sympathetic activity in major depressive disorder: identifying those at increased cardiac risk? J Hypertens 2007;25: 2117-24 34. Pison L, De Vusser P, Mullens W. Apical ballooning in relatives. Heart 2004;90:67 35. Kumar G, Holmes DR Jr, Prasad A. "Familial" apical ballooning syndrome (Takotsubo cardiomyopathy). Int J Cardiol 2010; 144:444-5. 36. Spinelli L, Trimarco V, Di Marino S, Marino M, Iaccarino G, Trimarco B. L41Q polymorphism of the G protein coupled mreceptor kinase 5 is associated with left ventricular apical ballooning syndrome. Eur J Heart Fail 2010; 12: 13-16 37. Kurowski K, Kaiser A, Von Hof K, Killermann DP, Mayer B, Hartmann F, et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132:809-16. 38. Madias C, Fitzgibbons TP, Alsheikh-Ali AA, Bouchard JL, Kalsmith B, GarlitskiAC, et al. Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes. Heart Rhythm. 2011 Apr;8:555-61
13
39. Patel HM, Kantharia BK, Morris DL, Yazdanfar S. Takotsubo syndrome in AfricanAmerican women with atypical presentations: a single-center experience. Clin Cardiol 2007;30:14-8. 40. Cangella F, Medolla A, De Fazio G, Iuliano C, Curcio N, Salemme L, et al. Stress induced cardiomyopathy presenting as acute coronary syndrome: Tako-Tsubo in Mercogliano, Southern Italy. Cardiovasc Ultrasound 2007;5:36. 41. Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation 2008;118:2754-62. 42. Elesber AA, Prasad A, Lennon RJ, Wright Rs, Lerman A, Rihal CS. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol 2007; 50:44852. 43. Randhawa MS, Dhillon AS, Taylor HC, Sun Z, Desai MY. Diagnostic utility of cardiac biomarkers in discriminating Takotsubo cardiomyopathy from acute myocardial infarction. J Card Fail. 2014;20:377.e25-31.
14
Figure Legends Figure 1. Electrocardiogram (ECG) demonstrating anterior precordial ST segment elevation and diffuse T wave inversions in a 53 year old woman with Takotsubo cardiomyopathy (TCM). Figure 2. Electrocardiogram (ECG) demonstrating QT segment prolongation and diffuse, deep T wave inversions in a 42 year old woman with Takotsubo cardiomyopathy (TCM). Figure 3. Transthoracic echocardiogram (TTE) during diastole (left) and systole (right) demonstrating apical and mid left ventricular hypokinesis with preserved basal contraction creating pathognomonic apical ballooning appearance in 53 year old woman with Takotsubo cardiomyopathy. Figure 4. Transthoracic echocardiogram (TTE) during diastole (left) and systole (right) demonstrating basal and mid left ventricular hypokinesis with preserved apical contraction in a 53 year old woman with an unusual variant of Takotsubo cardiomyopathy (TCM).. Figure 5. Left venticulogram during diastole (left) and systole (right) demonstrating apical and mid hypokinesis with preserved basal contraction creating pathognomonic apical balooning appearance in a 42 year old woman with Takotsubo cardiomyopathy (TCM).
15
Fig 1
16
Fig 2
17
Fig 3
18
Fig 4
19
Fig 5
20