Inflammation in takotsubo cardiomyopathy? Inquiry from “Guidelines for Diagnosis and Treatment of Myocarditis (JCS 2009)”

Takotsubo cardiomyopathy, also referred to as stress cardiomyopathy [[1]Lyon A.R. Rees P.S. Prasad S. Poole-Wilson P.A. Harding S.E. Stress (takotsubo) cardiomyopathy – a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning.Nat Clin Pract Cardiovasc Med. 2008; 5: 22-29Google Scholar] is a clinical entity exhibiting transient (bi-)ventricular dysfunction of an unknown cause. Although the precise pathogenesis remains unclear, there are a lot of hypotheses and assumptions about mechanisms of takotsubo cardiomyopathy including myocarditis. The fact that takotsubo cardiomyopathy shows minimal myocardial enzymatic release offers clear evidence of the myocardial damage. The myocardial stunning is defined as postischemic transient ventricular dysfunction without microscopic injuries to the myocytes [[2]Kloner R.A. Przyklenk K. Patel B. Altered myocardial states. The stunned and hibernating myocardium.Am J Med. 1989; 86: 14-22Google Scholar]. Evidence of myocardial injury is not consistent with the concept of myocardial stunning. There are several case reports [3Bigalke B. Klingel K. May A.E. Kandolf R. Gawaz M.G. Human herpesvirus 6 subtype A-associated myocarditis with ‘apical ballooning’.Can J Cardiol. 2007; 23: 393-395Google Scholar, 4Bahlmann E. Schneider C. Krause K. Pankuweit S. Harle T. Kuck K.H. Tako-Tsubo cardiomyopathy (apical ballooning) with parvovirus B19 genome in endomyocardial biopsy.Int J Cardiol. 2007; 116: e18-e21Google Scholar, 5Caforio A.L. Tona F. Vinci A. Calabrese F. Ramondo A. Cacciavillani L. Corbetti F. Leoni L. Thiene G. Iliceto S. Angelini A. Acute biopsy-proven lymphocytic myocarditis mimicking takotsubo cardiomyopathy.Eur J Heart Fail. 2009; 11: 428-431Google Scholar] of biopsy-proven myocarditis mimicking takotsubo cardiomyopathy. So-called inflammatory activation is well documented in takotsubo cardiomyopathy. In the report from the Tokyo CCU Network, leukocyte count and C-reactive protein levels were mildly elevated (9676 ± 4006/μl, and 2.19 ± 4.04 mg/dl, respectively) [[6]Murakami T. Yoshikawa T. Maekawa Y. Ueda T. Isogai T. Konishi Y. Sakata K. Nagao K. Yamamoto T. Takayama M. Characterization of predictors of in-hospital cardiac complications of takotsubo cardiomyopathy: Multi-Center 127 Registry Tokyo CCU Network.J Cardiol. 2014; 63: 269-273Abstract Full Text Full Text PDF Scopus (63) Google Scholar]. In our 14 cases of takotsubo cardiomyopathy who underwent endomyocardial biopsy [[7]Kawai S. Pathology of takotsubo (ampulla) cardiomyopathy.in: Veselka J. Cardiomyopathies – from basic research to clinical management. InTech – Open Access Publisher, Rijeka, Croatia2012: 709-726Google Scholar], maximum creatine phosphokinase levels were 262 ± 212 IU/l, and maximum leukocyte counts were 9925 ± 3134/μl. Among case reports in the scientific meetings of the Japanese Circulation Society, many studies of patients with takotsubo cardiomyopathy reported the endomyocardial biopsy findings as normal or nonspecific, suspected myocarditis, or post myocarditis in the healing stage. Other investigators described infiltration of mononuclear lymphocytes, leukocytes, macrophages in the interstitium, myocardial fibrosis [[8]Friedrich M.G. Cocker M.S. Stress-induced cardiomyopathy: a syndrome of the susceptible patient?.Expert Rev Cardiovasc Ther. 2012; 10: 271-273Google Scholar], and contraction bands with or without overt myocyte necrosis [[9]Wittstein I.S. Thiemann D.R. Lima J.A. Baughman K.L. Schulman S.P. Gerstenblith G. Wu K.C. Rade J.J. Bivalacqua T.J. Champion H.C. Neurohumoral features of myocardial stunning due to sudden emotional stress.N Engl J Med. 2005; 352: 539-548Google Scholar] in the endomyocardial biopsy specimens. In the autopsied specimens of takotsubo cardiomyopathy, injury to myocytes was frequently observed (Fig. 1). Several lymphocytes accumulated around the injured myocytes (upper right). Injured myocytes are removed by infiltrated macrophages (upper left). In the case mimicking fulminant myocarditis (83-year-old, female, lower left) on the basis of endomyocardial biopsy findings (myocardial degeneration and necrosis, and severe infiltrates), marked myocyte injuries and myocytolysis and interstitial cell infiltration were observed in the apical portion of the right ventricle [[7]Kawai S. Pathology of takotsubo (ampulla) cardiomyopathy.in: Veselka J. Cardiomyopathies – from basic research to clinical management. InTech – Open Access Publisher, Rijeka, Croatia2012: 709-726Google Scholar]. Contrary to these histological findings of takotsubo cardiomyopathy, pathology of idiopathic interstitial myocarditis shows different features. In cases with interstitial myocarditis, so-called “inflammatory cells” infiltrate into the area of almost intact appearance myocytes (Fig. 1, lower right). In the patients with takotsubo cardiomyopathy, injury of the cardiac myocytes precedes infiltration of small round cells. The main pathology of the autopsied hearts from the patients with takotsubo cardiomyopathy is summarized as myocardial injury and its sequelae, which resembled the findings of catecholamine-induced myocardial injury. Myocarditis is an inflammatory disease of the heart muscle. Myocarditis is caused by a variety of bacterial and viral infections. Enteroviruses are often associated with acute myocarditis. In the majority of cases (more than 50% of cases), myocarditis is classified as idiopathic [[10]JCS Joint Working Group Guidelines for diagnosis and treatment of myocarditis (JCS 2009): digest version.Circ J. 2011; 75: 734-743Google Scholar], since a specific cause cannot be identified. Inflammatory cell is defined as any cell appearing as integral part of an inflammatory exudate, including the neutrophil, eosinophil, lymphocyte, plasmacyte, and histiocyte [[11]Blackiston's Gould Medical Dictionary.4th ed. McGraw-Hill Book Company, New York1979Google Scholar]. Table 1 shows clinical and pathological characteristics of acute myocarditis and takotsubo cardiomyopathy in accordance with items of “Guidelines for Diagnosis and Treatment of Myocarditis (JCS 2009)” [[10]JCS Joint Working Group Guidelines for diagnosis and treatment of myocarditis (JCS 2009): digest version.Circ J. 2011; 75: 734-743Google Scholar]. Numbers in the left column indicate the item number in the JCS Guidelines. Items of cardiac symptoms, myocardial constitutional proteins, C-reactive protein, exclusion of acute myocardial infarction, and histological findings on endomyocardial biopsy resemble those of takotsubo cardiomyopathy. However, items of preceding symptoms, electrocardiogram and its time course, echocardiographic findings, clinical condition, and paired serum tests for viral serology are apparently different between acute myocarditis and takotsubo cardiomyopathy. Prognosis of takotsubo cardiomyopathy is good [[12]Kurowski V. Kaiser A. von Hof K. Killermann D.P. Mayer B. Hartmann F. Schunkert H. Radke P.W. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis.Chest. 2007; 132: 809-816Google Scholar] in the majority of patients (95%). But, prognosis of acute myocarditis is different from case to case. Furthermore, the acute onset and the sex disparity in patients with takotsubo cardiomyopathy are very unlikely for myocarditis.Table 1Clinical and pathological characteristics of acute myocarditis and takotsubo cardiomyopathy.Item number of guideline JCS 2009ItemsAcute myocarditis (Diagnostic Guidelines: JCS 2009)Takotsubo cardiomyopathy1Preceding symptomsaFlu-like signs and symptoms, gastrointestinal signs and symptom, skin rash, joint pain, or muscle pain.Basically presentBasically absent1Cardiac symptomsChest pain, syncope, dyspnea, palpitations, shock, seizure, and cyanosisChest pain, dyspnea, or asymptomatic2Cardiac findingsTachycardia, bradycardia, arrhythmia, weakened heart sounds, gallop rhythm (III, IV), pericardial rubReversible left (or bi-)ventricular outflow tract obstruction3ECG and time courseAbnormal ECGs,bST-T segment changes, low voltage, frequent premature beats, reduced R wave height, abnormal Q waves, atrioventricular block (I–III degree), intraventricular conduction delay, supraventricular tachycardia, atrial fibrillation, sinus arrest, ventricular tachycardia, ventricular fibrillation, and asystole. time course variableST elevation, abnormal Q-waves and reduced R wave height during the acute stage. Thereafter, deep negative T wave, QT prolongation, relative bradycardia, etc. These changes improve gradually. Time course of ECGs are almost same4EchocardiographyLocalized or diffuse wall thickening, reduced wall motion, reduced cardiac chamber size, and pericardial effusionApical ballooning with akinesis and basal hyperkinesis in 60% of the cases [12]Kurowski V. Kaiser A. von Hof K. Killermann D.P. Mayer B. Hartmann F. Schunkert H. Radke P.W. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis.Chest. 2007; 132: 809-816Google Scholar5Myocardial constitutional proteinsModerate to severe elevation, proportional to the hypokinetic areaLow, compared to the hypokinetic area5C-reactive proteinElevatedMildly elevated6Clinical conditionThe clinical condition in item 2 and 5 above may progress within a few hours, changes over time in these condition should be followedTime course are almost same in the majority cases7Exclusion of acute myocardial infarctionExcludedExcluded8Histological findings on endmyocardial biopsy or autopsyInfiltration of many large or small mononuclear cellscCell infiltrates are often observed adjacent to cardiomyocytes.. Rupture, fusion and disappearance of cardiomyocytes. Interstitial edema (Diagnostic Criteria for Acute myocarditis in Endomyocardial Biopsy)Interstitial cell infiltration: mild to moderate, related to the myocardial damage or necrosis9Viral genome, separation of virus or identification of virus by antibody titerOften positiveSeveral cases reporteddItems not listed in Diagnostic Guidelines (JCS 2009).PrognosisVariable, including fulminant myocarditisThe majority of the cases rapidly recover, but some cases suffer pulmonary edema and other sequelae or deathdItems not listed in Diagnostic Guidelines (JCS 2009).Magnetic resonance imagingHigh T2 signal intensity (edema), increased myocardial early gadolinium enhancement ratio (hyperemia), late gadolinium enhancement (necrosis and fibrosis)Ballooning sites: Apical 82%, Midventricular 17%, Basal 1%, Biventricular 34% [13]Eitel I. von Knobelsdorff-Brenkenhoff F. Bernhardt P. Carbone I. Muellerleile K. Aldrovandi A. Francone M. Desch S. Gutberlet M. Strohm O. Schuler G. Schulz-Menger J. Thiele H. Friedrich M.G. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy.J Am Med Assoc. 2011; 306: 277-286Crossref PubMed Scopus (588) Google ScholarECG, electrocardiogram.a Flu-like signs and symptoms, gastrointestinal signs and symptom, skin rash, joint pain, or muscle pain.b ST-T segment changes, low voltage, frequent premature beats, reduced R wave height, abnormal Q waves, atrioventricular block (I–III degree), intraventricular conduction delay, supraventricular tachycardia, atrial fibrillation, sinus arrest, ventricular tachycardia, ventricular fibrillation, and asystole.c Cell infiltrates are often observed adjacent to cardiomyocytes.d Items not listed in Diagnostic Guidelines (JCS 2009). Open table in a new tab ECG, electrocardiogram. Recently, several researchers have documented the presence of myocardial edema, fibrosis, and necrosis in cases with takotsubo cardiomyopathy using cardiac magnetic resonance imaging (CMR) [13Eitel I. von Knobelsdorff-Brenkenhoff F. Bernhardt P. Carbone I. Muellerleile K. Aldrovandi A. Francone M. Desch S. Gutberlet M. Strohm O. Schuler G. Schulz-Menger J. Thiele H. Friedrich M.G. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy.J Am Med Assoc. 2011; 306: 277-286Crossref PubMed Scopus (588) Google Scholar, 14Neil C. Nguyen T.H. Kucia A. Crouch B. Sverdlov A. Chirkov Y. Mahadavan G. Selvanayagam J. Dawson D. Beltrame J. Zeitz C. Unger S. Redpath T. Frenneaux M. Horowitz J. Slowly resolving global myocardial inflammation/edema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted cardiac MRI.Heart. 2012; 98: 1278-1284Google Scholar, 15Eitel I. Lücke C. Grothoff M. Sareban M. Schuler G. Thiele H. Gutberlet M. Inflammation in takotsubo cardiomyopathy: insights from cardiovascular magnetic resonance imaging.Eur Radiol. 2010; 20: 422-431Google Scholar]. Using a comprehensive CMR approach, including T2-weighted imaging to calculate the edema ratio, T1-weighted imaging before and after contrast agent administration to calculate the global relative enhancement and late gadolinium enhancement imaging, myocardial inflammation can be detected with high diagnostic accuracy in acute myocarditis [[16]Friedrich M.G. Sechtem U. Schulz-Menger J. Holmvang G. Alakija P. Cooper L.T. White J.A. Abdel-Aty H. Gutberlet M. Prasad S. Aletras A. Laissy J.P. Paterson I. Filipchuk N.G. Kumar A. et al.Cardiovascular magnetic resonance in myocarditis: a JACC white paper.J Am Coll Cardiol. 2009; 53: 1475-1487Google Scholar]. Findings of edema and myocardial necrosis on CMR are diagnostic for myocarditis. However, these findings in takotsubo cardiomyopathy in which clinical suspicion for active myocarditis are lacking do not mean evidence of myocarditis. Edema are a common pathological phenomenon in catecholamine cardiomyopathy [[17]Rona G. Chappel C.I. Balazs T. Gaudry R. An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat.AMA Arch Pathol. 1959; 67: 443-455Google Scholar]. Fibrosis is a fundamental component of the adverse structural remodeling of myocardium. Replacement fibrosis appears at sites of previous myocardial necrosis to preserve the structural integrity of the myocardium [[18]Gandhi M.S. Kamalov G. Shahbaz A.U. Bhattacharya S.K. Ahokas R.A. Sun Y. Gerling I.C. Weber K.T. Cellular and molecular pathways to myocardial necrosis and replacement fibrosis.Heart Fail Rev. 2011; 16: 23-34Google Scholar]. Although CMR study provides further insights into the pathological mechanisms in takotsubo cardiomyopathy, it remains to be established whether CMR-defined inflammation is a direct cause of takotsubo cardiomyopathy or a secondary phenomenon of myocardial injury. Characterization of predictors of in-hospital cardiac complications of takotsubo cardiomyopathy: Multi-center registry from Tokyo CCU NetworkJournal of CardiologyVol. 63Issue 4PreviewTakotsubo cardiomyopathy (TC) is an acute cardiac syndrome characterized by transient left ventricular dysfunction and relatively good prognosis after discharge. However, cardiac complications during hospitalization remain to be fully determined. We attempted to determine features characterizing patients with adverse clinical outcome by comparing those with cardiac complication and without cardiac complication during hospitalization. Full-Text PDF Open Archive