Circulation Oe Association. ‘Takotsubo Cardiomyopathy : A New Form of Acute, Reversible Heart Failure Yoshihiro J. Akashi, David 8. Goldstein, Giuseppe Barbaro and Takashi Ueyama Circulation, 2008;118:2754-2762 doi: 10.1161/CIRCULATIONAHA.108,767012 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2008 American Heart Association, Inc. All rights reserved Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http:/cire-abajoumnals.orgicontent/118/25/2754 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services, Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online a: bttp:/Awww.lww com/reprints ‘Subscriptions: Information about subscribing to Circulation is online at: [tip:/eite-ahajournals.org//subscriptions Downloaded from hrtp ere ahajournals. orp! by guest on October 30,2012po Cardiomyopathy A New Form of Acute, Reversible Heart Failure Yoshihiro J. Akashi, MD, PhD; David S. Goldstein, MD, PhD; Giuseppe Barbaro, MD; Takashi Ueyama, MD, PhD everal relatively recent case reports and series have described a condition featuring symptoms and signs of acute myocardial infarction without demonstrable coronary artery stenosis or spasm in which the heart takes on the appearance of a Japanese octopus fishing pot called a takot- subo (Figure 1). Tn takotsubo cardiomyopathy (also called ‘wansient apical ballooning and stress cardiomyopathy), left ventricular dysfunction, which can be remarkably depressed, recovers within a few weeks Takoisubo cardiomyopathy occurs predominantly in post- menopausal women soon after exposure to sudden, unexpected emotional or physical stess. For instance, the incidence of takotsubo cardiomyopathy increased substantially in elderly ‘women living near the epicenter of the Niigata earthquake." Although the left ventricular dysfunction is wansient and there is no evidence of obstructive epicardial coronary disease, an increasing number of angioplasty procedures have been performed for presumed acute coronary syndromes. Concepts about the demographics, clinical features, pro gnosis, and management of this reversible form of left venric= alr failure are still evolving. In this brief review, we summarize recent clinical reports and discuss an animal model that may clarify the pathogenesis of this condition, History of the Condition Many case reports and series have demonstrated acute, severe, reversible left ventricular dysfunction that coronary ischemia, aortic valvular lesions, or myocarditis cannot ex- Iga ct al? reported a ease of reversible left ysfunction associated with pheochromocytoma in which the akolsubo appeasance was fist described, although they did not use the term takotsubo, The authors also inferred that high 1g concentzations of catecholamines could disectly damage the myocardium. In 1990, Sato etal? fst described this reversible cardiomyopathy as tako-tsubo-like left ventric- ular dysfunction; outside Japan, this phenomenon was called apical ballooning? or stress cardiomyopathy.* After 2000, many case reports cited associations with emotional stress, 2 icular ‘normal coronaty angiography. and minimally increased se~ rum levels of cardiac enzymes. Diagnostic Criteri ‘There is as yet no consensus on the diagnostic criteria for Cakotsubo cardiomyopathy. Researchers at the Mayo Clinic proposed diagnostic criteria in 2004, which have been mod- ified recently”: (1) transient bypokinesis, akinesis, or dyski- resis in the left ventricular mid segments with or without apical involvement; regional wall motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful vigger; (2) the absence of obstructive coronary disease or angiographic evidence of acute plague rupture; (3) new ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) the absence of pheochromocytoma and myocarditis Patients were assigned this diagnosis when they satisfied all shese criteria, Japanese investigators have recently pre- sented diagnostic guidelines: however, the modified Mayo criteria are commonly used, It is necessary to establish worldwide consensus on diagnostic ctiteria for takotsuvo cardiomyopathy Epidemiology Computer-assisted SCOPUS or MEDLINE searches of the literature forthe tems apical ballooning, ampulla cardiomy, pathy, tako-tsubo cardiomyopathy, and takotsubo cardiomy- ‘pathy between 1989 and December 2007 demonstrated an exponentially increasing frequency of publications, Until 2000, afew case reports were published, but the presentation of takotsubo cardiomyopatiay has increased gradually since 2001. ‘The number of publications has increased rapidly: Cakotsubo cardiomyopathy has probably gained broad atten- tion in the field of eadiclogy among US and European physicians. On the basis of recent analyses reported from several counties, this condition probably accounts for = 1% 0 2% ofall cases of suspected acute myocardial infarction.” Trom the Division of Cardiology, Deparimen' of Ineral Medicine Si Mananna University School of Medicine Kawa, Kanagawa Tapan (PTV aie uocandiology Secion. Cincal Newosciences Program. Division of Invamural Research, Naonal Insutute of Neurological Disorees and ‘Suoke, NaonlIstites of Heals, Bethesda, Mad (D 5.) Cardology Unit Depurent of Medial Paophysiology Univesity "La Sapetza” Rome aly (GB), and Department of Asatomy and Cell Biology, Wakayama Medical Univerity School of Modine, Kimidera, Wakayams, Japan (I) CCorespondence (© Yorhihro J Akash, MD, PAD, Divison of Cardiology, Deparment of Inlernl Meine, St Marianna Univernty School of (Circulation. 2008:118:27842762) (© 2008 Amevican Hea Atsorision Ine Circulation is aallable at ip:ldecahajournalorg Medicine, 2-16-1 Sugao Miyamae su Kawasai City, Kanagawa Prefecture, 216-8511. Japan. Ell Johany@maranaeu.aejp DOK: 10.161/CIRCULATIONAHA.108.767012 Downloaded from hrtp ere ahajoiBR6H.orp! by guest on October 30,2012A B Clinical Features ‘The Table shows clinical features hased on the available literature “046-4 Most reports have noted a clear gender iscrepancy, with te syndrome much more common in women than men, Takotsubo cardiomyopathy typically is preceded by exposure to emotional or physical stressors such as an unex pected death in the family, abuse, a quartel, of exhausting Table, Patient Clinical and Laboratory Characteristics Akashi ct al Takotsubo Cardiomyopathy 2755 Figure 1. Let venticulogram (A, end-di- stoic phase; B,end-aystole phase) n ‘the right anterior eblque projection. The extensive area sound the apex shows akinesis, andthe basal sogmants display hypercantracton, especially Inthe end- dlastolc phase. C, A picture of a real ‘akotsubo, which has a round bottom and narrow neck to capture octopuses Sand has Deen used fora ong time in Japan Cc work, although in some cases, precipitant stressors have not been identified, The most frequent clinical symptoms of {akotsubo cardiomyopathy on admission are chest pain and dyspnea, resembling acute myocardial infarction. Moreover, the ECG findings on admission often include ST elevation in precordial leads. Subsequent T-wave inversion and Q-wave formation also are frequently found. The ECG findings Tea Kaos ——Staay With Pacn je Yah eel lera eta etal etal ata ear eal” Spee w @ = » Zz 7 * 6 ce Jun cemasy apn SUS pan gan US pan sie Fatocpecie gece fatepecve Prapacthe Pressey Retrzeche epee Ppecve Poseive wey wie mss eset at Tk MS Ta TRET Preasegenstoral sane 20 2 7 sw ” “ ” Presa sts, 8 a ” “ » 100 a 4 6 Caspar a o 1s 2 100 " s Span leain. % ° o 100 so 0 6 8 a 2 STaupnar clots npocrel a5 a 2 10 8 tet Oe 7 som set ” 7 use, we sss sor ‘ete nee eye ss se 0 s Il oneage Lee casos asses asss012 o2es0a8 00 eMssomt 9d 94as08e aA2s0%0 Foteap er os12010 ost2012 oss=o08 osm" ceseonn 06 a7és001 Tins a 18 es 177 ‘ ta Fart sent agephaly rtm caraney ° sms 10 100 8 00 Spores mules ° ° 0 ° ° ° a Q ° Proeslemuthosel spzm, SI 1) onan ase won an vais ree Iressa meray 9 1 a ° oe . ° Q 0 : Decanrindecurece, nh} 2020) 2) oe oo ns.) ° EF nats verviody zen (aten, Vatns Ae expressed a men==SD wien apprprat, Ts le daped and modtieg fom Reorance 1 with parison. “aesian ‘th prcoria eaes. Downloaded from hrtp ere ahajournals. orp! by guest on October 30,2012Your complimentary - c ; tse period has ended. # Complete —™ryovorusng DF Complete —_ P Se ween ream arecc 20 ti 2nd Expanded Features ihe best |rsiomy- NDEI Too! to diayaose THIS TORGATON—MIOsTTases: lack significant coronaty stenoses (Table). Patients with takotsubo cardiomyopathy on admission have high levels of serum calecholamines and of plasma brain nalriucetic peptide (BNP), The secretion pattern of BNP in takotsubo patients is quite similar to that in myocardial infarction patients. and 1 report presented the precise time course of [BNP secretion in patients with takotsubo cardiomyopathy." Basal hyperkinesia might be related with left vi end-diastolic pressure and BNP release.” Cardiac enzyme levels (eg, creatinine Kinase, woponin T) are slightly Several patients with takotsubo cardiomyopathy have been evaluated by cardiac magoetic resonance imaging to assess subendocardial necrosis with delayed contrast enhancement techniques. Although the findings are still a matter of debate lack of delayed enhancement may prediet wall motion recov- ery (Figute 2). Histological changes have been identified by myocardial biopsy in some studies, Further evidence is re ‘quired, however, to clarify the actual structural findings. Both magnetic resonance imaging and histopathological findings ean differentiate patients with takotsubo cardiomyopathy from those with acute myocardial infarction resulting from coronary arterial occlusion. cular Concepts About Pathophysiology ‘Most patents with takotsubo cardiomyopathy who underwent myocardial biopsy have shown the same results: interstitial infiltrates consisting primarily of mononuclear lymphocytes. leukocytes, and macrophages; myocardial fibrosis; and con- action bands with or without overt myocyte necrosis. The inflammatory changes ané contraction bands distinguish t Kotsubo cardiomyopathy’ from coagulation necrosis, as seen in myocardial infarction resulting from coronary attery 0¢- clusion. The exact pathophysiological basis of the distinctive contractile patter in takotsubo cardiomyopathy remains to be clucidated. A few concepts are discussed below. ‘Multivessel Epicardial Coronary Artery Spasm Reversible ventricular dysfunction might result from epicar- Gial coronary artery spasm and consequently regionally stunned myocardium.* When no spontancous coronary spasm has actually been observed, impaired coronary blood flow caused by vulnerable plaque rupture has been proposed as a cause of takotsubo cardiomyopathy. Mulivessel epicardial spasm and regionally stunned myocardium would not explain the discrepancy between severe apical ventricular dysfunc- tion and only slightly increased levels of cardiac enzymes and after plaque rupture in a single coronary artery, the area of abnormal leRt ventricular wall motion would not be expected to extend beyond the perfusion teritory normally supplied by the artery. Moreover, ECG findings seem to differ between patients with acute coronary syndrome and those with takot- subo cardiomyopathy." The latter do not evince reciprocal changes, although ECG findings do not have sufficient Downloaded from 5 i , Figure 2. Cine sequences of cardiac magnetic resonance imag- ing during systole A) and diastole (Bn the acute phase. Nor- tal function could be docursented aftr 2 weeks (C, systle D, tlastole), Convas-enhanced cardiovascular magnetic re20- ance image did net snow myocardial hypereshancerent even ‘he dolayed paso ). Adapted ‘tor No tal wth parmasen. predictive value to distinguish takotsubo cardiomyopathy from acute coronary syndrome in individual patients.”> In addition, ischemic myocardial stunning does not produce the histological changes usually observed in takotsubo cardiomy- ‘pathy. Finally, spontaneous o inducible coronary arterial spasms has not been found in most eases of akotsubo candiomyop- aby, Accordingly, myocardial stunning resulting from epicantial coronary artery spasm does not seem to cause takotsubo cardiomyopathy. Coronary Microvascular Impairment Because abnormal left venteicular wall motion occurs in a relatively large area of the apical myocardium in patients with by guest on October 30,201alerorirculacory Tepanted in paired coronary perfusion and severe myocardial metabolic abnormalities in patients with takotsubo cardiomyopathy on ‘he basis of results ofthallium-201 myocardial single-photon emission computed tomography and "F-fuorodeoxyglucose snyocardial positron emission tomography. Blesber et al! demonstrated the presence of microvascular dysfunction in a significant proportion of patients with this syndkome and noted 4 cortelation between microvascular dysfunction and the severity of myonecrasis and ECG abnormalities. Taken together, these studies suggest that coronary microcirculatory abnormalities may accompany takotsubo cardiomyopathy; however, the association does not imply 1 cause-and-effect relationship. For instance, the possibil- ity remains that the microcirculatory abnormalities result from increased mechanical wall stress as a consequence of apical ballooning. Catecholamine Cardiotoxicity ‘Witstein etal"? compared admission plasma catecholamine concentrations between @ group of 13 patients with stress ceardiopathy who had transient apical ballooning and x group fof 7 patients hospitalized for acute myocardial infarction (Killip class 11), The plasma levels of hoth epinephrine and norepinephrine were remarkably increased in the stress car- iopathy patients. The authors suggested thatthe remarkably clevated catecholamine levels might be the main pathogenetic factor. However, elevated catecholamine levels are not uni formly found in patients with this syndrome.” High plasma catecholamine levels in patients with pheochromocytoma are well known to induce reversible cardiomyopathy.” ‘The myocardial histological changes in takotsubo eardio- myopathy strikingly resemble those seen in catecholamine cardiotoxicity in both animals"! and humans»? These changes, sis, include contraction band a ich differ from those in ischemic cardiac necro- crosis, neutrophil infiltration, and fibrosis. These findings probably reflect consequences of high intracellular concentrations of Ca’, and it has been proposed that Ca’’ overload in myocardial cells produces the ventricular dysfunction in catecholamine cardiotoxicity 2° Although diffuse heart failure can produce high cieculating catecholamine concentrations, the atained levels are not nearly as high asin akotsubo cardiomyopathy and by definition would not explain the takotsubo pater, Because citculaiing epinephrine exerts far more potent hormonal effects on the heart than norepinephrine does, ‘akotsubo cardiomyopathy could in particular reflect epinep- rine-induced toxicity. Concurrent cardiac neuronal and adze- omedullary hormonal stimulation might occur, and this combination accompanies emotional distress. Lyon et al” bbave hypothesized that the high circulating epinephrine levels righ trigger a switch in cardiomyocyte intracellular signal Ing after occupation of B,-adrenoceptors from Gs protein to Gi protein coupling Akashi ct al Takotsubo Cardiomyopathy 2757 Neurogenie Stunned Myocardium ‘he cardiac functional and ECG abnormalities in takotsubo cardiomyopathy might reflect activation of central neuro- genic mechanisms analogous to those evoked by subarach- ‘oid hemorthage” Intracranial pathology can produce the same myocardial histopathological findings seen in takotsubo cardiomyopathy." Because the basal myocardium has a somewhat higher norepinephrine content? and greater den- sity of sympathetic nerves than the apical myocardium does, at first glance, cardiac sympathetic stimulation would not appear (o explain the apical ballooning that characterizes takotsuo cardiomyopathy; however, the let ventricular apex. contains a higher concentaion of adrenoceptors. Thus, myocar- dial responsiveness to adrenergic stimulation is pronounced im the apex.”” In addition, cardiac sympathectomy prevents brain-mediated cardiac injury.©* Therefore, takolsubo cardio myopathy may reflect stunned myocardium from a neuro- {genic source. Animal studies have reported decreased inotzo- pic responses to norepinephrine in the seiting of catecholamine-induced cardiomyopathy” that is associated with a decreased number of myocardial -adrenoceptors ‘Thas, takotsubo cardiomyopathy might reflect a combination of myocardial necrosis and decreased -adrenoceptor respon- siveness with high local catecholamine concentrations that cause both abnormalities. The heast stands out among organs of the body in terms of dependence on neuronal uptake for inactivating catecholamines in the extracellular Muid.>® High circulating catecholamine levels such as in pheochromocy- oma can interfere with the neuronal uptake process” and augment occupation of adrenoceptors on myocardial cells “These findings help to explain why emotional distress would Induce mainly cardiac toxicity as a result of high plasma catecholamine levels despite being delivered to all organs via the attesial blood In summary, the available pathophysiological information indicates that the apical ballooning that characterizes takot- subo cardiomyopathy reflects toxic bigh local concentrations ff catecholamines, not coronary artery or microvascular disease, The pattern of left ventricular dysfunction may result from both myocardial cellular rupture and withdrawal of B-adtenoceptors. The "frst cause” would be neurogenic, with the precipitant sudden, unexpected, severe emotional distress ‘Stunning-ike involvement atthe left ventricular base also has been observed in patients with pheochromocytoma and even jn takotsubo cardiomyopathy patients.? Individual differ- ences in the anatomy of cardiac sympathetic innervation or the distributions of adrenoceptors might result in the involve ‘ment of a variety of let ventricular myocardial segments. In ‘ypical apical ballooning, high local concentrations of norepi- nephrine might evoke basal hyperkinesis, increasing mechan- Jal wall stress at the apex and thereby increasing end-ia- stolic pressure and BNP levels.* Prognosis “The prognsis of patients with takotsubo cardiomyopathy is generally favorable; however, we have hal some fatal com- plications with takotsubo cardiomyopathy such as lft ven- wicular free wall rupture2> Heart failure, with or without pulmonary edema isthe most common clinical complication Downloaded from hrtp ere ahajournals. orp! by guest on October 30,2012OnIya handful fof recurrent takotsubo cardiomyopathy cases have been reported, Mechanisms underlying susceptibility to recurrence are not understood, One article has reported that the recur- nce rate of takotsubo cardiomyopathy is 10%. Management ‘There ate no specific treatments forthe lft ventricular failure characterizing takotsubo cardiomyopathy because cardiac function is nonmalized within a few weeks, When shock ‘ecurs, intraaortic balloon pumping is established as adi- sional support for the eiculation.® We use upright posture, ‘oxygen, and diuretics for pulmonary edema, although given the putative pathophysiological mechanism, it would be reasonable to teat pulmonary edema with sedation and mompin. Arthythinia resulting from QT prolongation is commonly cbserved in patients with takotsubo cardiomyopathy”; how ever, we do not administer antiarhythmics prophylactically. In our experience, administration of magnesium sulfate is effective for venticular tachycardia in the acute phase of takotsubo cardiomyopathy if the QT interval is prolonged. We believe that administration of cardiotonic agents is not appropriate because of the likely underlying mechanisms. We also do not administer B-adrenoceptor blockers, which can olong the QT interval and leave unopposed the potentially audverse effects of igh local concentrations of catechol at a-adcenocepiors. The use of B-adtenoceptor block- crs in the acute phase of takotsubo cardiomyopathy is stl a ratter of debate. Given the findings in the animal model tweatment with a combined a- and B-blocker seems rational, ‘whereas treatment with a catecholamine as a cardiotonic scems contraindicated It should be Kept in mind that Adrenalin (Parke-Davis & Co, Detroit, Mich) was originally marketed as a agent, not ® pressor or cardiotonic. We often encounter thrombosis in takotsubo cardiomyopathy cases,” which sigh reflect vasoconstrictor, platelet activation, oF prothrom- otic effects of extremely high epinephrine levels. Because apical ballooning increases the risk of cardiac rupture, itis still controversial whether treatment with aspirin or heparin is indicated. The fat that epinephrine promotes platelet activa- tion by stimulating platelet a, adrenoceptors provides addi- tional rationale for treatment with a combined a and Beblocker. Because extrogen treatment is heneficial in preventing the animal model of takotsubo cardiomyopathy (see below), such treatment might be considered in elderly women who have suffered an episode of takotsubo cardiomyopathy; however clinical tials of estrogen administration in takotsubo candio- "myopathy patients have not been performed. static Animal Model of Takotsubo Cardiomyopathy ‘A number of important pathophysiological questions remain Why ate elderly women particularly susceptible to devel- oping takotsubo cardiomyopathy? How does profound psychological stress trigger the condition? Finally is regional heterogeneity of adrenoceptor numbers sufficient to explain apical ballooning? The development of appropriate snimal models has begun to addiess these issues Experimental approaches to mimic the clinical manifestations may provide new insights into the pathogenesis of takot- subo cardiomyopathy. Clisieal provocation tests to induce this condition have not been reported and ethically are not accept able. Therefore, in the development of an appropriate animal ‘model, we allempted to replicale severe, emotional distress induced sympathetic neuronal and adrenomedullary activation, as seen in Iakotsubo cardiomyopathy. In rats, simple immobilization is well known to evoke profound sympathoadrenal activation * During immobiliza- lion, the increment in plasma epinephrine is derived wholly from the adrensl medulla, winereas most of the increment in plasma norepinephrine is derived from sympathetic nerves Patients with takotsubo cardiomyopathy have increased plasma epinephrine and norepinephrine levels compated with those seen during immobilization in rats? suggesting that {immobilization in rats mimics the clinical condition, Increased citculating epinephrine levels within a physio- logical range are well known to result in skeletal vasodilation and increases in heart rate and cardiac output, whereas norepinephrine increases total peripheral resistance to blood flow and mean arterial blood pressure. At relatively low cirvtlating levels, there are no appreciable ECG or left ventric lular functional abnormalities. In contrast, in response to immobilization, pathologically high epinephrine and norepi nephrine levels are associated with characteristic ECG: changes, including ST-segment elevation and, importantly, reversible left ventricular apical ballooning (Figure 3), strike ingly reproducing the abnormalities seen in takotsubo cardio myopathy. Aa instance of sudden death caused by ventric lular fibrillation in response to iramobilization has been noted (Figure 3). Immobilization induces upregulation of immedi ate early genes, functional mazkers of cellular excitation’® such as ¢-fos and c-jun in endothelial cells, myocardial cells, and coronary vascular smooth muscle cells (Figure 3). Ex pression of immediate early genes diffusely in coronary arteries suggests possible coronary spastic changes and con- sequent microvascular dysfunction, ‘ST-segment elevation in rats subjected to immobilization is prevented by combined blockade of a- and f-adrenoceptors (aot by a- oF B-blockade alone), calcium channel blockers, or nitroglycerin.» Left ventricular dysfunction and induction of immediate early genes in the heart also are prevented by combined blockade of «- and B-adrenoceptors. These find ings suggest that high myocardial concentrations of catechol- amines and consequent activation of adrenoceptors in the heart produce the acute cardiae changes." Estrogen receptors (ERai and ER@) are expressed widely in the cardiovascular and central nervous systems, Estrogens exert vatious functions, including prevention of some cardio vascular diseases, modulation f sexual behavior and memory processes, and some autonomic nervous functions.*"" We Uherefore have hypothesized that tie reduced estrogen levels after menopause explain the predisposition of elderly women {o takotsubo cardiomyopathy. Esogen supplementation at. tenuated the immobilization-induced cardiac dysfunction and Downloaded from hrtp ere ahajournals. orp! by guest on October 30,2012Figure 2. Left ventculographic A trough ©) and ECG @ and {Changes in response to immadlization of rats. Left venvicule- cram, right anteror oblique (80) projection. A, Diastole. B,sys= {ole C, The trace of A and B. Rediced ft vontreular conirac~ fon around the let Venticula apex was observed in response ta stress, £CG, lead I Line incboates 0.2 second, ST-sagment elevation 0} was observed in response to s'ress. A case of ven- ‘icularfbrlation also was observed (Q). Daréfeld photomiero- ‘raph showing signals for e-jun mFINA in the heart (F} and cere- ary arteries (@ ana H) sampled at 30 minutes from tre onset of Irnmobitzation. Strang sigrals were observed in ayacardury surrounding the wit and right ventricular cates (These sig- hale algo were observed In encothallal cols and smooth muscle Cells of coronary arteries (@ and Hf). Bar=600 um () ara 100 lum (G and H). A through C, Adapted and moctied ‘rom Seyama etal" with permission rom tne Japanese Circulation Sotlty increased heart rate and blood pressuse.*? These effects also were observed in estrogen-treated castrated male rats (&.Tehikura, unpublished observation). The reduced estrogen levels induced vulnerability to stress, whereas estrogen sup- plementation attenuated the exaggerated responses, including sympathoadzenal activation and vagal iabibition,® which is ‘observed in takotsubo cardiomyopaty 2° Emotional sress also causes rapid and transient expression of immediate early genes in the brain, and monitoring of expression of these genes has enabled visualization of the central neurocircuitry of distress.” Treatment with estrogen attenuated the immobilization-induced increase in c-Fos im smunoreacivity or cor mRNA expression in the laerl septum, rmodial amygdaloid nucleus, paraventricular hypothalamic mi cleus, dorsomedial hypothalamic nucleus, laterodorsal tegmental ‘nucleus, and locus caeraleus, regions that are pars of the central autonomic network and possess immunoreactive estrogen recep- tors. Estrogen attenuated immobilizaion-induced c-fos miRNA, Downloaded from hvtp/cire shajournals. ofp! by guest on October 30, 20 Akashi et al Takotsubo Cardiomyopathy 2759 expression in the adrenal gland and heart, suggesting protective effects atthe level of the target organs.“ Estrogen treatment also Increased the levels of possibly cardioprotective substances such fs atrial natriuretic peptide and heat shock protein 70 in the heart Moreover, administration of estrogen attenuated isoproterenolinduced tachycardia and cAMP production and reduced the incidence of ischemialreperfusion-indiced archyth- ania in 1at heats“ Conversely, bilateral ovuiectomy inczeased Ca" sensitivity of cazdiae myofilaments, and estrogen replace ‘ment abolished this change.“ The density and pretein content of Bradrenergic receptors were upregulated in bilateral ovariec- tomy, and estrogen/progesterone supplementation reversed these changes.” Taken together, these data suggest that reduced estrogen levels, by actions on both the nervous system and the heart, after menopause might constitute the basis of susceptibil- lay of elderly women to takotsubo cardiomyopathy. To test this hypothesis, clinical data comparing incidences of takotsubo cardiomyopathy with or without estrogen supplementation are required. Tae estrogen hypothesis alone does nol seem sulficient to explain the occurrence—alheit uncommon—of takotsubo cardiomyopathy in mea, Recently, we have found that the expression of oxidative stress-related substances such as heme oxigenase-1 and cy clooxygenase-2 is increased in the cardiovascular system of rats after exposure to immobilization and that treatment with ‘a and B-adrenoceptor blockers attenuates these responses (unpublished observation). Therefore, stress-induced high circulating catecholamine levels may alter redox states in the cardiovascular system, Induction of heme oxigenase-1 and cyclooxygenase-2 may suggest oxidative stress and adaptive responses in the cardiovascular system, A Pathogenetic Concept About Takotsubo Cardiomyopathy (On the bass of the above-ited clinical tereture and findings from the rat immobilization model, we propose 2 possible sechanists for the pathogenesis of takotsubo catdiomyopa- ly (Figure 4). In response to sudden, unexpected, severe emotional distress, neurons of the central autonomic network expressing estrogen receptors axe activated, followed by smarked increases in sympathetic neuronal and adrenomedul- lary hormonal outflows. Epinephrine released trom the adre- nal medulla and norepinephrine from cardiac and extricar diac sympathetic nerves reach adrenoceptors in the blood vessels and heart. Contraction of the resistance vessels rapidly inereases systemic blood pressure and cardiac after load, Meanwhile, within the heart, high etculating levels of norepinephrine and epinephrine, along with increased release and decreased reuptake by sympathetic nerves, induce cate- cholamine toxicity in the cardiomyocytes via occupation of adrenoceptors. Hypercontraction and possibly functional basal obstruction of the left ventricular outflow result in increased mechanical wall stress in the left ventricular apex, in conjunction with high BNP levels and increased end-ti stolic pressure.” Contraction bands and myocardial cell rupture occur in a regionally heterogeneous sreater apical expression of adrenoceptors, Disturbance in the coronary microcizculation, as suggested by diffuse expression cof immediate early genes in coronary arteries, and increases ine related toFecitation of presynaptic sympathetic neuron Excitation of postsyaplic sympathetic neuron — NE adrenal medulla — pi Increase of blo pressure and afterload Decreased NO prodition B-Receptor w-Recepor Hypocontaction ‘Of LV apex Contraction ofaeies Disturbance of oroniry stress Increased activities in neuronal ells and cardiac ells Reduction of estrogen fllewing menopanse Down regulation of SPT and ANP Hypervontration and obstruction of TV outflow | Mechanical wal otros Sy Increase of oxygen demand Catecholamine toxicity » circulation > Osidaivestess Figure 4, Possible undedying mechanism of classic takotaubo caraiomyopathy. See text fr deta, in oxygen demand inthe cardiomyocytes alter the redox state and tigger oxidative stress, which precipitates a variety of postive feedback loops that lead to stunning of the apical myocardium. In postmenopausal women, the loss of estrogen effects exaggerates the responses of central neurons and cardiac cells and possibly attenuates the production of car Gioproteotive substances Atypical Contractile Pattern of Takotsubo Cardiomyopathy Recent case reports have described takotsubo caudiomyopa- lay associated with suppression of basal contraction and apical sparing, a kind of “iaverted takotsubo."® Kuowski et ab found that 40% of patients with wansient venteicular dysfunction had this atypical pattern. We also have reported 1 case of recurrent akotsubo cardiomyopathy witha different contractile pattern* Ischemia resulting from multivessel coronary vasospasm seems unlikely in these cases because it would not be expected to be associated with apical sparing, ‘Various pattems of left ventricular wall motion abnormalities therefore seem possible in takotsubo cardiomyopathy, with ‘wansient left ventricular apical ballooning being more com- mon and other regional wall motion abnormalities less common, Further research in both clinical and preclinical settings is required to determine whether individual differ. ences in pattems of wall motion abnormalities are related to local differences in patterns of excessive sympathetic activity for in responses to sympathetic stimulation Conclusions ‘he recently recognized syndrome of takotsubo cardiomyop- thy constitstes a novel form of lear failure that is precipt- tated by sudden, unexpected emotional distress and is rela- tively common in elderly women. Precipitating mechanisms are probably complex, and the observations detailed in this review represent only the beginning of the process of under- standing this condition, Abnormal catecholamine dynamics related to emotional distress seems to play a major role in the pathogenesis of this cardiomyopathy, rendering takotsubo cardiomyopathy a type of neurocardiological disorder that manifests as acute but reversible heart false, Combined a= and adrenoceptor blockade might therefore mitigate the syndrome. Theoretically, on the basis of findings in the rat immobilization model, supplementation of estrogen in post. ‘menopausal women might protect against its development This cardiomyopathy should be considered a possible cause of sudden cardiac death resulting from arshythmia or cardiae rupture in individuals without obvious heart disease, Th prognosis is good in patients who survive the initial severe insult without complications. To understand the pathogenesis and to devise rational treatment and prevention strategies, ‘more allention should be paid not oaly to the myocardium and coronary arteries but also to the integration of central neural, autonomic, endocrine, and circulatory systems in emotional distress.” Source of Funding Dr Goldstein i supported by the Division of hnuamural Resear, National Institute of Neurological Disorders and’ Soke, National Downloaded from hrtp ere ahajournals. orp! by guest on October 30,2012Disclosures References 1 Tooke K, Wes K, Uehia T, Oh-MaraN, Kimura K. Owe ‘Yoauon Mi, Miya 8. Hae K. Ogun, Hons Hae M, KB ‘Merit Transet Tet veneslr apical baoonng Wibot oroary ‘sry sons a oovel bout syndrome mimicking ace myocwrdi Infarction” Angina Peconi Myocardial Infection investigations a Span J Am Coll Crd BH3811-1 ‘Kovo Y, Unemsice T, Nakamura 8. Take-bovke let vetetat assoc with ST-egmem slevtion + novel cardia syndrome mimicking acute myoeatdal Infarction. 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