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Clinical Features and Outcome of Pheochromocytoma-Induced Takotsubo Syndrome: Analysis of 80 Published Cases
Accepted Manuscript Clinical Features and Outcome of Pheochromocytoma-induced Takotsubo Syndrome: Analysis of 80 Published Cases Shams Y-Hassan, MD PII:
S0002-9149(16)30365-4
DOI:
10.1016/j.amjcard.2016.03.019
Reference:
AJC 21760
To appear in:
The American Journal of Cardiology
Received Date: 19 December 2015 Revised Date:
25 February 2016
Accepted Date: 1 March 2016
Please cite this article as: Y-Hassan S, Clinical Features and Outcome of Pheochromocytoma-induced Takotsubo Syndrome: Analysis of 80 Published Cases, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.03.019. 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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Clinical Features and Outcome of Pheochromocytoma-induced Takotsubo Syndrome: Analysis of 80 Published Cases Short title: Pheochromocytoma-induced takotsubo
Karolinska Institute at Karolinska University Hospital
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Department of Cardiology
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Shams Y-Hassan, MD
Corresponding Author Shams Y-Hassan, MD
Address: Karolinska University Hospital, Huddinge, Department of Cardiology, S- 141 86
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Stockholm, Sweden Tel number: +46 8 58582805
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Fax number: +46 8 58586710
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E-mail: [email protected]
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ACCEPTED MANUSCRIPT Abstract Myriads of physical stress factors including pheochromocytoma have been reported triggering takotsubo syndrome (TS). The aim of this study is to report on the clinical
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features and outcome of pheochromocytoma-induced TS (Pheo-TS) in a large cohort of patients. Eighty published cases of Pheo-TS were retrieved from the literature and compared to 1750 cases of All-TS published recently by Templin et al. Pheo-TS
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patients were on average 19.87 years younger than patients with All-TS (p<0.0001). The women were still predominating in Pheo-TS but significantly in a lower
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percentage (70% in Pheo-TS vs 89.8% in All-TS, P< 0.00001). Almost one third (30%) of Pheo-TS cases had basal TS pattern compared to 2.2% of cases in All-TS (p<0.00001) and one fifth (20%) had global TS compared to no cases in ALL-TS. Two thirds of Pheo-TS cases (67.9%) developed complications, which was significantly
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higher than complication rates in All-TS (21.8%) but there was no difference in the inhospital mortality between the two groups. The most important risk factors for the
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development of complications in Pheo-TS were age <50 years and global and basal TS localization pattern. The recurrence rate of 17.7% in Pheo-TS was significantly
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higher than 3.26% in All-TS (p<0.00001). In conclusion; Pheo-TS is characterized by a dramatic clinical presentation with high complication rates and relatively high recurrence rate. Pheo-TS patients are significantly younger than ALL-TS. The TS localization pattern in Pheo-TS differed significantly from All-TS with basal pattern in almost one third of cases and global pattern in one fifth of the cases. Key words: Takotsubo; pheochromocytoma; catecholamines; apical ballooning; broken heart syndrome; myocarditis 2
ACCEPTED MANUSCRIPT Introduction Takotsubo syndrome (TS), an acute cardiac disease entity, is characterized by a striking left ventricular wall motion abnormality (LVWMA) with a circumferential
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pattern extending beyond the coronary artery supply region and resulting in a conspicuous ballooning of the left ventricle during systole. 1,2 Countless physical stress factors have been reported to trigger the disease.3 Among the physical stressors
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are the disease processes causing hypercatecholaminemia as pheochromocytoma and paraganglioma.4 Pheochromocytoma is a catecholamine-secreting tumor that arises
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from chromaffin tissue of the sympathetic nervous system. Clinical manifestation of pheochromocytoma is highly variable leading to its designation as the disease of “multiple faces” 5 or the “great mimic”. In this report, the clinical features and outcomes of 80 cases of pheochromocytoma-induced TS or transient left ventricular
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dysfunction (Pheo-TS) reported in the literatures (supplementary list of references) are described and compared to a large study recently reported by Templin et al
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Methods
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including all TS patients (All-TS).3
All cases of Pheo-TS from 1990, the year where the Japanese term
takotsubo was introduced, to November 2015 are critically reviewed. The cases were retrieved by searching in the pubmed using the search terms “takotsubo,” “apical ballooning,” “stress cardiomyopathy,” and “broken heart syndrome” and linking them with the terms “pheochromocytoma”, “paraganglioma” and “catecholamines”. For the reasons mentioned in the discussion, cases with pheochromocytoma-induced transient left ventricular dysfunction where the clinical features and course were 3
ACCEPTED MANUSCRIPT consistent with TS are also included. Eighty one cases were retrieved; because of the extreme similarities between two reported cases, one case which was reported later was excluded. Eighty case reports constitute the patient material of this manuscript. Nine of the cases deemed to be Pheo-TS were reported before the TS-era; with the TS-
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era is meant the cases reported after 1999 where the first reports on TS were
published in English language. Seventy one cases were reported during TS-era. One
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case from 1987 with features typical of mid-apical TS was also included. The articles included were published in English language, one case in Swedish and one in
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German, where sufficient information could be obtained. In 7 cases sufficient information could be acquired from only the abstract. The following information was abstracted from the publications: the year of publications, age and gender of the patients, the clinical presentation, the type of ECG changes and the cardiac
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biomarkers in all patients. The TS localization was deemed by the description in the text or the available figures in the manuscripts. The hemodynamic complication rates after the presentation, the in-hospital mortality, the clinical course of the disease, the
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recovery and the recurrence rate where available were reviewed (Table-1). The
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results in this study were compared to the 1750 patients in a recently published study by Templin et al where all types of TS (All-TS) were included (Table-2) when comparable information were available in both studies. Continuous variables are presented as means ± standard deviations and categorical data as absolute values and percentages. Fisher´s exact test or Chi-square test was used as appropriate to compare categorical data, and 2-tailed unpaired student´s t test was used for continuous variables; A p<0.05 was considered significant.
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ACCEPTED MANUSCRIPT Results The clinical features, ECG changes, complications, clinical course and the recurrence are presented in Table-1. At presentation, the age of the 78 out of 80
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patients were 16 to 86 years (mean age 46.53 ± 15.6 years). Patients with Pheo-TS were 19.87 years younger than the All-TS patients (p<0.0001). Although the majority of the patients 56 (70%) were women, the percentage of men in Pheo-TS cohort of
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patients (30%) was significantly higher than in All-TS patients (Table-2). In all of the patients, pheochromocytoma was documented as a possible physical trigger factor
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for TS. However, in 19 patients out of 77 patients (24.7%) additional potential trigger factor could have induced TS (emotional stressor in 8 cases, physical stressor in 11 cases)
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Chest pain, which occurred in 33 patients (42.25%), was the most common presenting symptom in Pheo-TS. It was followed by abdominal pain in 9 cases (11.25%), dyspnea in 7 (8.75%), headache in 7 (8.75%), palpitation in 5 (6.25%),
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cough in 3 (3.75%), dizziness in 3 (3.75%), cardiogenic shock in 3 (3.75%). In the remainder 10 cases (12.5%), other cardiac and noncardiac presenting symptoms
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occurred. In 61cases (76.25%), signs and symptoms suggestive of pheochromocytoma as dizziness, palpitation, profuse sweating, pallor, headache and hypertension were present either during presentation or admission days. The heart rate records were available in 45 patients (56.25%) and it was 60 -190 beats/min (mean 116 ± 30). Labile blood pressure was recorded in 38 of the cases (47.5%). At presentation, a combination of tachycardia, tachypnea and hypoxemia was found in 28 cases (35%). The most common ECG changes during presentation were ST-elevation myocardial 5
ACCEPTED MANUSCRIPT infarction (STEMI) like changes in 30 (37.5%) cases, ST-depression in 20 (25%), Twave inversion in 11 (13.75%), non-specific changes in 7 (8.75%), sinus tachycardia in 9 (11.25%) and tall peaked T-wave in one (1.25%) case, arrhythmias in 2 (2.5%) cases. Information about myocardial infarction biomarkers was available in 66 (82.5%)
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cases. The cardiac biomarkers were mildly elevated in 63 out of 66 cases (95.45%). Coronary angiography was almost normal in 67 cases including 2
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patients examined with cardiac computed tomography. One patient was previously stented, and 2 patients had minor atherosclerotic changes. Information on coronary
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angiography was not available in 13 patients. The LVWMA pattern in Pheo-TS was localized to the apical region in 35 (43.75%) cases (4 apical and 31 mid-apical), basal in 24 (30%) cases (3 basal and 21 mid-basal), mid-ventricular in 4 (5%) cases, global in 16 cases (20%) and focal in one case (1.25%). Interestingly, the STEMI-like ECG
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changes and T-wave inversions were found almost exclusively in the apical or midventricular patterns of TS and the ST-depression or peaked T-wave in the basal
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patterns of TS. Information on left ventricular ejection fraction was available in 48 patients (60%); the range of ejection fraction was 5-56% and the mean ejection
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fraction was markedly reduced 27.7 ± 11.6. Information on plasma or urinary catecholamines was available in 72 cases and it was increased in 71 out of 72 cases (98.6%). One case (case 25) had urinary catecholamine at the upper normal limit, likely due to the urine collection during the use of hypertensive drugs according to the authors of the manuscript. The complication rate was high in Pheo-TS. It occurred in 53 out of 78 cases (68%) with the available information. Multiple complications in the same 6
ACCEPTED MANUSCRIPT patient were observed in 24 cases (30.8%); the most common combination of complications was heart failure, pulmonary edema, cardiogenic shock, circulatory and respiratory failure. Heart failure occurred in 40 (51%) cases, pulmonary edema in 35 (45%) cases, cardiogenic shock in 27 (34.6%) cases, respiratory failure in 8 (10.25%)
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cases, thrombo-embolic complications in 6 (7.7%) cases (5 out of 6 of thrombo-
embolic complications occurred in the apical-TS pattern), arrhythmias in 5 (6.4%)
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patients, metabolic acidosis in 5 (6.4%) cases, ,cardiac arrest in 4 (5%) cases,
electromechanical dissociation in 3 (3.8%) cases, multiple organ failure in 2 (2.5%)
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cases, and left ventricular outlet obstruction in one case (1.3%) Two patients died (2.5%) as described below. There was no difference in the rate of complications between men and women. On the other hand, the complication rates were significantly higher in patients <50 years than patients than >50 years age (38 out 49
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cases (77.6%) in age <50 years compared to15 out 31 cases (48.4%) in age >50 years, p=0.014). The complications occurred more frequently (albeit not significant p=0.26) in the basal pattern (75%) of TS than the apical type (51.4%). The highest level of
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complications occurred in the global type of TS (94%) which was significantly higher
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than the apical pattern (p=0.003) and non-significantly higher than the basal type (p=0.2).
Twenty five of 77 cases (32.5%) have received inotropic medications. The
most common used inotropics were dobutamine in 14 cases, norepinephrine in 7, dopamine in 7, epinephrine in 4, amrinone or milrinone in two cases. The inotropic medication was non-identified and described as vasopressor agents in 5 cases. The inotropic medications were frequently used in combinations. Mechanical ventilation
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ACCEPTED MANUSCRIPT was used in 15 out 69 patients (21.7%).Extracorporeal life support (ECLS) treatment was used in 14 out of 77 cases (18.2%). In 9 patients intra-aortic balloon pump was utilized; extra-corporeal life support as extra-corporeal membrane oxygenation was used in 6 patients and both of them in 2 cases. In 11 cases, all the three treatment
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modalities (inotropic medications, mechanical ventilation and ECLS) were needed. Two patients died. The first patient was a 71 years woman who died
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during recurrence of TS 6 months after the first episode; she developed pulmonary edema and shock, had resistant fever up to 42 oC and died within hours. The second
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patient was an 86-year-old man who had left ventricular ballooning and persistent ST-segment elevation (not due to myocardial infarction); he died due to pneumonia following an unfavorable course at 64 days after admission. The remainder of the cases recovered. The time of recovery was reported in 37 patients (46.25%). In 11
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cases (29.7%), the recovery occurred within 1-3 days, in 12 cases (32.4%) within 4-7 days, in 12 cases (32.4%) within 2 weeks, in one cases within 3 weeks and in another,
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it took 90 days to recover.
Recurrence of TS in the Pheo-TS cohort of patients occurred in 14 out of
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79 cases (17.7%) with available information. In 11 cases the recurrence occurred one time, in 2 cases two times and in one case five times. In 8 out of 14 cases, the localization of TS could be deemed during recurrence; the recurrent TS had the same TS localization as the index presentation in 5 cases and different localization in 3 cases. One patient died during the recurrence
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ACCEPTED MANUSCRIPT Discussion The main findings in this study, which hitherto includes the largest numbers of patients with Pheo-TS are: 1) The patient population were 19.87 years younger in Pheo-TS than All-TS (p<0.0001). 2) The women were still predominating
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in Pheo-TS population but the frequency of men population was significantly higher in Pheo-TS (30%) than All-TS (4.4%). 3) Chest and abdominal pain, dyspnea, and
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headache were among the most common presenting symptoms. Signs and symptoms suggestive of pheochromocytoma as palpitation, profuse sweating, pallor, labile
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blood pressure and headache were present in 76.25%. 4) One fifth (20%) of the patients had global TS localization. Almost one third (30%) of patients had basal TSlocalization, which is significantly higher than 2.2%in All-TS 3 population. The 30% basal pattern in this study is comparable to 32% of inverted TS reported by Agarwal
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et al 4 in a previous review of 38 cases of Pheo-TS. The “classical” apical (apical and mid-apical) TS pattern was significantly lower (43.76% compared to 83%) in Pheo-TS than All-TS. It should be acknowledged that the description of LVWMA is not
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always accurate especially in the cases described before the TS-era. Five out of 9
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patients published before 2000 were described to have severe left ventricular dysfunction or severe myocardial depression with a clinical course consistent with TS.6-10 The other 4 patients had typical mid-apical or basal TS pattern.11-14 The cases with severe left ventricular dysfunction were deemed to have global TS in this study. Global TS induced by other physical factors has also been reported.15,16 Patients with Pheo-TS may deteriorate rapidly and the TS localization may transform from regional to global. Such change have been well-demonstrated in the case reported by Flam et al17 where the patient had mid-basal TS during the first admission day and 9
ACCEPTED MANUSCRIPT this progressed very rapidly to severe biventricular failure during the following day. Several cases with pheo-TS with such startling course complicated by respiratory failure, metabolic acidosis and cardiogenic shock have been reported in the literature 18,19.
In a study of 140 patients with pheochromocytoma and paraganglioma,
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Giavarini et al 20 found that 15 (11%) patients suffered “acute catecholamine
cardiomyopathy”. Six out of 15 patients displayed classical mid-apical or inverted
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(mid-basal) TS. The remainder had severe extensive or global hypokinesia and a
clinical picture of pulmonary oedema. These findings may indicate that patients with
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pheochromocytoma triggered global biventricular failure may in fact have global TS. Worth mentioning and as a further support to our previous reports,21,22 is that the occurrence of the apical TS in less than half of the cases, apical sparing (basal and mid-ventricular) pattern in 35% of cases and the global pattern in 20% of cases
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challenges strongly against the epinephrine-induced switch in the intracellular signal trafficking hypothesis causing TS proposed byLyon et al 23 in 2008. 5) Pheo-TS was characterized by high complication rates. Two thirds of Pheo-TS developed some
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kinds of complications and almost one third of patients had multiple complications. .
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The complication rates in Pheo-TS were significantly higher than that in All-TS population reported by Templin et al 3, Sharkey et al 24 and Gianni et al25. The combined endpoint of serious in-hospital complications, reported by Templin et al 3 was 21.8%, which was significantly lower than the complication rates (67.9%) in the current study (p<0.00001). The most important risk factors for the development of complications in Pheo-TS are; first, TS-localization pattern; the global TS localization had significantly higher hemodynamic complications than the apical TS-localization
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ACCEPTED MANUSCRIPT pattern (p=0.0039). On the other hand, the thrombo-embolic complications occurred mainly in the apical TS pattern. Second, patients with pheo-TS younger than 50 years suffered significantly higher complication rates compared to patients older than 50 years (p=0.014). Two out of 80 patients (2.5%) died26,27; there was no difference in the
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in-hospital mortality between Pheo-TS and All-TS. 7) The recurrence rate of TS was relatively high in the Pheo-TS population. It occurred in 17.7% of the patients; the
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disease recurred two times in 2 cases and 5 times in one case. In one case, the patient developed multiple complications with multi-organ failure and resistant fever and
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died within hours during the recurrence, which occurred 6 months after the first attack 26. The recurrence rate of 17.7% is significantly higher than that in All-TS reported Templin et al 3 of 3.26% (p<0.00001) and that reported by Sharkey et al 24 of 5% (p=0.0039). The high recurrence rate of TS in Pheo-TS population is most
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probably attributed to the delay in the diagnosis of pheochromocytoma where episodes of hypercatechoaminemia has acted as a trigger factor.28
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The analysis of Pheo-TS was based on a retrospective study of case or a series of case reports, which limit the results of the study. The absolute levels of the
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various laboratory studies including various catecholamine levels, cardiac biomarkers could not be utilized for the estimation of comparable mean values because of the lack of standardization and uniformity across the case reports. As mentioned in the discussion the TS localization pattern is not always accurate and this point has been touched in other reports.24 The possibility of additional trigger factor (found in 19 cases), which could have triggered TS cannot be ruled out.29
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ACCEPTED MANUSCRIPT 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;21:203-214. 2. Y-Hassan S. Acute cardiac sympathetic disruption in the pathogenesis of the takotsubo syndrome: a systematic review of the literature to date. Cardiovasc Revasc Med 2014;15:35-42.
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3. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, Cammann VL, Sarcon A, Geyer V, Neumann CA, Seifert B, Hellermann J, Schwyzer M, Eisenhardt K, Jenewein J, Franke J, Katus HA, Burgdorf C, Schunkert H, Moeller C, Thiele H, Bauersachs J, Tschope C, Schultheiss HP, Laney CA,
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Rajan L, Michels G, Pfister R, Ukena C, Bohm M, Erbel R, Cuneo A, Kuck KH, Jacobshagen C, Hasenfuss G, Karakas M, Koenig W, Rottbauer W, Said SM, Braun-Dullaeus RC, Cuculi F, Banning A, Fischer TA,
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Vasankari T, Airaksinen KE, Fijalkowski M, Rynkiewicz A, Pawlak M, Opolski G, Dworakowski R, MacCarthy P, Kaiser C, Osswald S, Galiuto L, Crea F, Dichtl W, Franz WM, Empen K, Felix SB, Delmas C, Lairez O, Erne P, Bax JJ, Ford I, Ruschitzka F, Prasad A, Luscher TF. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015;373:929-938.
J Cardiol 2011;153:241-248.
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4. Agarwal V, Kant G, Hans N, Messerli FH. Takotsubo-like cardiomyopathy in pheochromocytoma. Int
5. Tolis G, Kuchel O. The multiple faces of the pheochromocytoma. Can Med Assoc J 1977;116:337-
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6. Salathe M, Weiss P, Ritz R. Rapid reversal of heart failure in a patient with phaeochromocytoma
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and catecholamine-induced cardiomyopathy who was treated with captopril. Br Heart J 1992;68:527-
7. Quezado ZN, Keiser HR, Parker MM. Reversible myocardial depression after massive catecholamine release from a pheochromocytoma. Crit Care Med 1992;20:549-551. 8. Suga K, Tsukamoto K, Nishigauchi K, Kume N, Matsunaga N, Hayano T, Iwami T. Iodine-123-MIBG imaging in pheochromocytoma with cardiomyopathy and pulmonary edema. J Nucl Med 1996;37:1361-1364.
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ACCEPTED MANUSCRIPT 9. Gatzoulis KA, Tolis G, Theopistou A, Gialafos JH, Toutouzas PK. Cardiomyopathy due to a pheochromocytoma. A reversible entity. Acta Cardiol 1998;53:227-229. 10. Brilakis ES, Young WF, Jr., Wilson JW, Thompson GB, Munger TM. Reversible catecholamineinduced cardiomyopathy in a heart transplant candidate without persistent or paroxysmal
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12. Murai K, Hirota K, Niskikimi T, Kawarabayashi T, Yoshiyama M, Yasuda M, Teragaki M, Akioka K, Oku H, Takeuchi K, Takeda T. Pheochromocytoma with electrocardiographic change mimicking
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angina pectoris, and cyclic change in direct arterial pressure--a case report. Angiology 1991;42:157-
13. Elian D, Harpaz D, Sucher E, Kaplinsky E, Motro M, Vered Z. Reversible catecholamine-induced cardiomyopathy presenting as acute pulmonary edema in a patient with pheochromocytoma.
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Cardiology 1993;83:118-120.
14. Nanda AS, Feldman A, Liang CS. Acute reversal of pheochromocytoma-induced catecholamine cardiomyopathy. Clin Cardiol 1995;18:421-423.
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16. Y-Hassan S, Tornvall P, Tornerud M, Henareh L. Capecitabine caused cardiogenic shock through induction of global Takotsubo syndrome. Cardiovasc Revasc Med 2013;14:57-61. 17. Flam B, Broome M, Frenckner B, Branstrom R, Bell M. Pheochromocytoma-Induced Inverted Takotsubo-Like Cardiomyopathy Leading to Cardiogenic Shock Successfully Treated With Extracorporeal Membrane Oxygenation. J Intensive Care Med 2015 ;30:365-372. 18. Di Palma G, Daniele GP, Antonini-Canterin F, Piazza R, Nicolosi GL. Cardiogenic shock with basal transient left ventricular ballooning (Takotsubo-like cardiomyopathy) as first presentation of pheochromocytoma. J Cardiovasc Med (Hagerstown)2010;11:507-510. 13
ACCEPTED MANUSCRIPT 19. Kaese S, Schulke C, Fischer D, Lebiedz P. Pheochromocytoma-induced takotsubo-like cardiomyopathy and global heart failure with need for extracorporal life support. Intensive Care Med 2013;39:1473-1474. 20. Giavarini A, Chedid A, Bobrie G, Plouin PF, Hagege A, Amar L. Acute catecholamine
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ACCEPTED MANUSCRIPT 29. Tanriver Y, Betz MJ, Nibbe L, Pfluger T, Beuschlein F, Strowski MZ. Sepsis and cardiomyopathy as rare clinical manifestations of pheochromocytoma--two case report studies. Exp Clin Endocrinol
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S0002-9149(16)30365-4
DOI:
10.1016/j.amjcard.2016.03.019
Reference:
AJC 21760
To appear in:
The American Journal of Cardiology
Received Date: 19 December 2015 Revised Date:
25 February 2016
Accepted Date: 1 March 2016
Please cite this article as: Y-Hassan S, Clinical Features and Outcome of Pheochromocytoma-induced Takotsubo Syndrome: Analysis of 80 Published Cases, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.03.019. 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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Clinical Features and Outcome of Pheochromocytoma-induced Takotsubo Syndrome: Analysis of 80 Published Cases Short title: Pheochromocytoma-induced takotsubo
Karolinska Institute at Karolinska University Hospital
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Department of Cardiology
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Shams Y-Hassan, MD
Corresponding Author Shams Y-Hassan, MD
Address: Karolinska University Hospital, Huddinge, Department of Cardiology, S- 141 86
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Stockholm, Sweden Tel number: +46 8 58582805
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Fax number: +46 8 58586710
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E-mail: [email protected]
1
ACCEPTED MANUSCRIPT Abstract Myriads of physical stress factors including pheochromocytoma have been reported triggering takotsubo syndrome (TS). The aim of this study is to report on the clinical
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features and outcome of pheochromocytoma-induced TS (Pheo-TS) in a large cohort of patients. Eighty published cases of Pheo-TS were retrieved from the literature and compared to 1750 cases of All-TS published recently by Templin et al. Pheo-TS
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patients were on average 19.87 years younger than patients with All-TS (p<0.0001). The women were still predominating in Pheo-TS but significantly in a lower
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percentage (70% in Pheo-TS vs 89.8% in All-TS, P< 0.00001). Almost one third (30%) of Pheo-TS cases had basal TS pattern compared to 2.2% of cases in All-TS (p<0.00001) and one fifth (20%) had global TS compared to no cases in ALL-TS. Two thirds of Pheo-TS cases (67.9%) developed complications, which was significantly
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higher than complication rates in All-TS (21.8%) but there was no difference in the inhospital mortality between the two groups. The most important risk factors for the
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development of complications in Pheo-TS were age <50 years and global and basal TS localization pattern. The recurrence rate of 17.7% in Pheo-TS was significantly
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higher than 3.26% in All-TS (p<0.00001). In conclusion; Pheo-TS is characterized by a dramatic clinical presentation with high complication rates and relatively high recurrence rate. Pheo-TS patients are significantly younger than ALL-TS. The TS localization pattern in Pheo-TS differed significantly from All-TS with basal pattern in almost one third of cases and global pattern in one fifth of the cases. Key words: Takotsubo; pheochromocytoma; catecholamines; apical ballooning; broken heart syndrome; myocarditis 2
ACCEPTED MANUSCRIPT Introduction Takotsubo syndrome (TS), an acute cardiac disease entity, is characterized by a striking left ventricular wall motion abnormality (LVWMA) with a circumferential
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pattern extending beyond the coronary artery supply region and resulting in a conspicuous ballooning of the left ventricle during systole. 1,2 Countless physical stress factors have been reported to trigger the disease.3 Among the physical stressors
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are the disease processes causing hypercatecholaminemia as pheochromocytoma and paraganglioma.4 Pheochromocytoma is a catecholamine-secreting tumor that arises
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from chromaffin tissue of the sympathetic nervous system. Clinical manifestation of pheochromocytoma is highly variable leading to its designation as the disease of “multiple faces” 5 or the “great mimic”. In this report, the clinical features and outcomes of 80 cases of pheochromocytoma-induced TS or transient left ventricular
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dysfunction (Pheo-TS) reported in the literatures (supplementary list of references) are described and compared to a large study recently reported by Templin et al
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Methods
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including all TS patients (All-TS).3
All cases of Pheo-TS from 1990, the year where the Japanese term
takotsubo was introduced, to November 2015 are critically reviewed. The cases were retrieved by searching in the pubmed using the search terms “takotsubo,” “apical ballooning,” “stress cardiomyopathy,” and “broken heart syndrome” and linking them with the terms “pheochromocytoma”, “paraganglioma” and “catecholamines”. For the reasons mentioned in the discussion, cases with pheochromocytoma-induced transient left ventricular dysfunction where the clinical features and course were 3
ACCEPTED MANUSCRIPT consistent with TS are also included. Eighty one cases were retrieved; because of the extreme similarities between two reported cases, one case which was reported later was excluded. Eighty case reports constitute the patient material of this manuscript. Nine of the cases deemed to be Pheo-TS were reported before the TS-era; with the TS-
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era is meant the cases reported after 1999 where the first reports on TS were
published in English language. Seventy one cases were reported during TS-era. One
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case from 1987 with features typical of mid-apical TS was also included. The articles included were published in English language, one case in Swedish and one in
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German, where sufficient information could be obtained. In 7 cases sufficient information could be acquired from only the abstract. The following information was abstracted from the publications: the year of publications, age and gender of the patients, the clinical presentation, the type of ECG changes and the cardiac
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biomarkers in all patients. The TS localization was deemed by the description in the text or the available figures in the manuscripts. The hemodynamic complication rates after the presentation, the in-hospital mortality, the clinical course of the disease, the
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recovery and the recurrence rate where available were reviewed (Table-1). The
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results in this study were compared to the 1750 patients in a recently published study by Templin et al where all types of TS (All-TS) were included (Table-2) when comparable information were available in both studies. Continuous variables are presented as means ± standard deviations and categorical data as absolute values and percentages. Fisher´s exact test or Chi-square test was used as appropriate to compare categorical data, and 2-tailed unpaired student´s t test was used for continuous variables; A p<0.05 was considered significant.
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ACCEPTED MANUSCRIPT Results The clinical features, ECG changes, complications, clinical course and the recurrence are presented in Table-1. At presentation, the age of the 78 out of 80
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patients were 16 to 86 years (mean age 46.53 ± 15.6 years). Patients with Pheo-TS were 19.87 years younger than the All-TS patients (p<0.0001). Although the majority of the patients 56 (70%) were women, the percentage of men in Pheo-TS cohort of
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patients (30%) was significantly higher than in All-TS patients (Table-2). In all of the patients, pheochromocytoma was documented as a possible physical trigger factor
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for TS. However, in 19 patients out of 77 patients (24.7%) additional potential trigger factor could have induced TS (emotional stressor in 8 cases, physical stressor in 11 cases)
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Chest pain, which occurred in 33 patients (42.25%), was the most common presenting symptom in Pheo-TS. It was followed by abdominal pain in 9 cases (11.25%), dyspnea in 7 (8.75%), headache in 7 (8.75%), palpitation in 5 (6.25%),
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cough in 3 (3.75%), dizziness in 3 (3.75%), cardiogenic shock in 3 (3.75%). In the remainder 10 cases (12.5%), other cardiac and noncardiac presenting symptoms
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occurred. In 61cases (76.25%), signs and symptoms suggestive of pheochromocytoma as dizziness, palpitation, profuse sweating, pallor, headache and hypertension were present either during presentation or admission days. The heart rate records were available in 45 patients (56.25%) and it was 60 -190 beats/min (mean 116 ± 30). Labile blood pressure was recorded in 38 of the cases (47.5%). At presentation, a combination of tachycardia, tachypnea and hypoxemia was found in 28 cases (35%). The most common ECG changes during presentation were ST-elevation myocardial 5
ACCEPTED MANUSCRIPT infarction (STEMI) like changes in 30 (37.5%) cases, ST-depression in 20 (25%), Twave inversion in 11 (13.75%), non-specific changes in 7 (8.75%), sinus tachycardia in 9 (11.25%) and tall peaked T-wave in one (1.25%) case, arrhythmias in 2 (2.5%) cases. Information about myocardial infarction biomarkers was available in 66 (82.5%)
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cases. The cardiac biomarkers were mildly elevated in 63 out of 66 cases (95.45%). Coronary angiography was almost normal in 67 cases including 2
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patients examined with cardiac computed tomography. One patient was previously stented, and 2 patients had minor atherosclerotic changes. Information on coronary
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angiography was not available in 13 patients. The LVWMA pattern in Pheo-TS was localized to the apical region in 35 (43.75%) cases (4 apical and 31 mid-apical), basal in 24 (30%) cases (3 basal and 21 mid-basal), mid-ventricular in 4 (5%) cases, global in 16 cases (20%) and focal in one case (1.25%). Interestingly, the STEMI-like ECG
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changes and T-wave inversions were found almost exclusively in the apical or midventricular patterns of TS and the ST-depression or peaked T-wave in the basal
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patterns of TS. Information on left ventricular ejection fraction was available in 48 patients (60%); the range of ejection fraction was 5-56% and the mean ejection
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fraction was markedly reduced 27.7 ± 11.6. Information on plasma or urinary catecholamines was available in 72 cases and it was increased in 71 out of 72 cases (98.6%). One case (case 25) had urinary catecholamine at the upper normal limit, likely due to the urine collection during the use of hypertensive drugs according to the authors of the manuscript. The complication rate was high in Pheo-TS. It occurred in 53 out of 78 cases (68%) with the available information. Multiple complications in the same 6
ACCEPTED MANUSCRIPT patient were observed in 24 cases (30.8%); the most common combination of complications was heart failure, pulmonary edema, cardiogenic shock, circulatory and respiratory failure. Heart failure occurred in 40 (51%) cases, pulmonary edema in 35 (45%) cases, cardiogenic shock in 27 (34.6%) cases, respiratory failure in 8 (10.25%)
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cases, thrombo-embolic complications in 6 (7.7%) cases (5 out of 6 of thrombo-
embolic complications occurred in the apical-TS pattern), arrhythmias in 5 (6.4%)
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patients, metabolic acidosis in 5 (6.4%) cases, ,cardiac arrest in 4 (5%) cases,
electromechanical dissociation in 3 (3.8%) cases, multiple organ failure in 2 (2.5%)
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cases, and left ventricular outlet obstruction in one case (1.3%) Two patients died (2.5%) as described below. There was no difference in the rate of complications between men and women. On the other hand, the complication rates were significantly higher in patients <50 years than patients than >50 years age (38 out 49
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cases (77.6%) in age <50 years compared to15 out 31 cases (48.4%) in age >50 years, p=0.014). The complications occurred more frequently (albeit not significant p=0.26) in the basal pattern (75%) of TS than the apical type (51.4%). The highest level of
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complications occurred in the global type of TS (94%) which was significantly higher
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than the apical pattern (p=0.003) and non-significantly higher than the basal type (p=0.2).
Twenty five of 77 cases (32.5%) have received inotropic medications. The
most common used inotropics were dobutamine in 14 cases, norepinephrine in 7, dopamine in 7, epinephrine in 4, amrinone or milrinone in two cases. The inotropic medication was non-identified and described as vasopressor agents in 5 cases. The inotropic medications were frequently used in combinations. Mechanical ventilation
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ACCEPTED MANUSCRIPT was used in 15 out 69 patients (21.7%).Extracorporeal life support (ECLS) treatment was used in 14 out of 77 cases (18.2%). In 9 patients intra-aortic balloon pump was utilized; extra-corporeal life support as extra-corporeal membrane oxygenation was used in 6 patients and both of them in 2 cases. In 11 cases, all the three treatment
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modalities (inotropic medications, mechanical ventilation and ECLS) were needed. Two patients died. The first patient was a 71 years woman who died
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during recurrence of TS 6 months after the first episode; she developed pulmonary edema and shock, had resistant fever up to 42 oC and died within hours. The second
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patient was an 86-year-old man who had left ventricular ballooning and persistent ST-segment elevation (not due to myocardial infarction); he died due to pneumonia following an unfavorable course at 64 days after admission. The remainder of the cases recovered. The time of recovery was reported in 37 patients (46.25%). In 11
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cases (29.7%), the recovery occurred within 1-3 days, in 12 cases (32.4%) within 4-7 days, in 12 cases (32.4%) within 2 weeks, in one cases within 3 weeks and in another,
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it took 90 days to recover.
Recurrence of TS in the Pheo-TS cohort of patients occurred in 14 out of
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79 cases (17.7%) with available information. In 11 cases the recurrence occurred one time, in 2 cases two times and in one case five times. In 8 out of 14 cases, the localization of TS could be deemed during recurrence; the recurrent TS had the same TS localization as the index presentation in 5 cases and different localization in 3 cases. One patient died during the recurrence
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ACCEPTED MANUSCRIPT Discussion The main findings in this study, which hitherto includes the largest numbers of patients with Pheo-TS are: 1) The patient population were 19.87 years younger in Pheo-TS than All-TS (p<0.0001). 2) The women were still predominating
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in Pheo-TS population but the frequency of men population was significantly higher in Pheo-TS (30%) than All-TS (4.4%). 3) Chest and abdominal pain, dyspnea, and
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headache were among the most common presenting symptoms. Signs and symptoms suggestive of pheochromocytoma as palpitation, profuse sweating, pallor, labile
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blood pressure and headache were present in 76.25%. 4) One fifth (20%) of the patients had global TS localization. Almost one third (30%) of patients had basal TSlocalization, which is significantly higher than 2.2%in All-TS 3 population. The 30% basal pattern in this study is comparable to 32% of inverted TS reported by Agarwal
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et al 4 in a previous review of 38 cases of Pheo-TS. The “classical” apical (apical and mid-apical) TS pattern was significantly lower (43.76% compared to 83%) in Pheo-TS than All-TS. It should be acknowledged that the description of LVWMA is not
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always accurate especially in the cases described before the TS-era. Five out of 9
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patients published before 2000 were described to have severe left ventricular dysfunction or severe myocardial depression with a clinical course consistent with TS.6-10 The other 4 patients had typical mid-apical or basal TS pattern.11-14 The cases with severe left ventricular dysfunction were deemed to have global TS in this study. Global TS induced by other physical factors has also been reported.15,16 Patients with Pheo-TS may deteriorate rapidly and the TS localization may transform from regional to global. Such change have been well-demonstrated in the case reported by Flam et al17 where the patient had mid-basal TS during the first admission day and 9
ACCEPTED MANUSCRIPT this progressed very rapidly to severe biventricular failure during the following day. Several cases with pheo-TS with such startling course complicated by respiratory failure, metabolic acidosis and cardiogenic shock have been reported in the literature 18,19.
In a study of 140 patients with pheochromocytoma and paraganglioma,
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Giavarini et al 20 found that 15 (11%) patients suffered “acute catecholamine
cardiomyopathy”. Six out of 15 patients displayed classical mid-apical or inverted
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(mid-basal) TS. The remainder had severe extensive or global hypokinesia and a
clinical picture of pulmonary oedema. These findings may indicate that patients with
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pheochromocytoma triggered global biventricular failure may in fact have global TS. Worth mentioning and as a further support to our previous reports,21,22 is that the occurrence of the apical TS in less than half of the cases, apical sparing (basal and mid-ventricular) pattern in 35% of cases and the global pattern in 20% of cases
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challenges strongly against the epinephrine-induced switch in the intracellular signal trafficking hypothesis causing TS proposed byLyon et al 23 in 2008. 5) Pheo-TS was characterized by high complication rates. Two thirds of Pheo-TS developed some
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kinds of complications and almost one third of patients had multiple complications. .
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The complication rates in Pheo-TS were significantly higher than that in All-TS population reported by Templin et al 3, Sharkey et al 24 and Gianni et al25. The combined endpoint of serious in-hospital complications, reported by Templin et al 3 was 21.8%, which was significantly lower than the complication rates (67.9%) in the current study (p<0.00001). The most important risk factors for the development of complications in Pheo-TS are; first, TS-localization pattern; the global TS localization had significantly higher hemodynamic complications than the apical TS-localization
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ACCEPTED MANUSCRIPT pattern (p=0.0039). On the other hand, the thrombo-embolic complications occurred mainly in the apical TS pattern. Second, patients with pheo-TS younger than 50 years suffered significantly higher complication rates compared to patients older than 50 years (p=0.014). Two out of 80 patients (2.5%) died26,27; there was no difference in the
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in-hospital mortality between Pheo-TS and All-TS. 7) The recurrence rate of TS was relatively high in the Pheo-TS population. It occurred in 17.7% of the patients; the
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disease recurred two times in 2 cases and 5 times in one case. In one case, the patient developed multiple complications with multi-organ failure and resistant fever and
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died within hours during the recurrence, which occurred 6 months after the first attack 26. The recurrence rate of 17.7% is significantly higher than that in All-TS reported Templin et al 3 of 3.26% (p<0.00001) and that reported by Sharkey et al 24 of 5% (p=0.0039). The high recurrence rate of TS in Pheo-TS population is most
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probably attributed to the delay in the diagnosis of pheochromocytoma where episodes of hypercatechoaminemia has acted as a trigger factor.28
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The analysis of Pheo-TS was based on a retrospective study of case or a series of case reports, which limit the results of the study. The absolute levels of the
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various laboratory studies including various catecholamine levels, cardiac biomarkers could not be utilized for the estimation of comparable mean values because of the lack of standardization and uniformity across the case reports. As mentioned in the discussion the TS localization pattern is not always accurate and this point has been touched in other reports.24 The possibility of additional trigger factor (found in 19 cases), which could have triggered TS cannot be ruled out.29
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ACCEPTED MANUSCRIPT 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;21:203-214. 2. Y-Hassan S. Acute cardiac sympathetic disruption in the pathogenesis of the takotsubo syndrome: a systematic review of the literature to date. Cardiovasc Revasc Med 2014;15:35-42.
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3. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, Cammann VL, Sarcon A, Geyer V, Neumann CA, Seifert B, Hellermann J, Schwyzer M, Eisenhardt K, Jenewein J, Franke J, Katus HA, Burgdorf C, Schunkert H, Moeller C, Thiele H, Bauersachs J, Tschope C, Schultheiss HP, Laney CA,
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Rajan L, Michels G, Pfister R, Ukena C, Bohm M, Erbel R, Cuneo A, Kuck KH, Jacobshagen C, Hasenfuss G, Karakas M, Koenig W, Rottbauer W, Said SM, Braun-Dullaeus RC, Cuculi F, Banning A, Fischer TA,
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Vasankari T, Airaksinen KE, Fijalkowski M, Rynkiewicz A, Pawlak M, Opolski G, Dworakowski R, MacCarthy P, Kaiser C, Osswald S, Galiuto L, Crea F, Dichtl W, Franz WM, Empen K, Felix SB, Delmas C, Lairez O, Erne P, Bax JJ, Ford I, Ruschitzka F, Prasad A, Luscher TF. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015;373:929-938.
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5. Tolis G, Kuchel O. The multiple faces of the pheochromocytoma. Can Med Assoc J 1977;116:337-
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ACCEPTED MANUSCRIPT 9. Gatzoulis KA, Tolis G, Theopistou A, Gialafos JH, Toutouzas PK. Cardiomyopathy due to a pheochromocytoma. A reversible entity. Acta Cardiol 1998;53:227-229. 10. Brilakis ES, Young WF, Jr., Wilson JW, Thompson GB, Munger TM. Reversible catecholamineinduced cardiomyopathy in a heart transplant candidate without persistent or paroxysmal
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angina pectoris, and cyclic change in direct arterial pressure--a case report. Angiology 1991;42:157-
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15. Win CM, Pathak A, Guglin M. Not takotsubo: a different form of stress-induced cardiomyopathy-a case series. Congest Heart Fail 2011;17:38-41.
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16. Y-Hassan S, Tornvall P, Tornerud M, Henareh L. Capecitabine caused cardiogenic shock through induction of global Takotsubo syndrome. Cardiovasc Revasc Med 2013;14:57-61. 17. Flam B, Broome M, Frenckner B, Branstrom R, Bell M. Pheochromocytoma-Induced Inverted Takotsubo-Like Cardiomyopathy Leading to Cardiogenic Shock Successfully Treated With Extracorporeal Membrane Oxygenation. J Intensive Care Med 2015 ;30:365-372. 18. Di Palma G, Daniele GP, Antonini-Canterin F, Piazza R, Nicolosi GL. Cardiogenic shock with basal transient left ventricular ballooning (Takotsubo-like cardiomyopathy) as first presentation of pheochromocytoma. J Cardiovasc Med (Hagerstown)2010;11:507-510. 13
ACCEPTED MANUSCRIPT 19. Kaese S, Schulke C, Fischer D, Lebiedz P. Pheochromocytoma-induced takotsubo-like cardiomyopathy and global heart failure with need for extracorporal life support. Intensive Care Med 2013;39:1473-1474. 20. Giavarini A, Chedid A, Bobrie G, Plouin PF, Hagege A, Amar L. Acute catecholamine
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cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma. Heart 2013;99:1438-1444.
21. Y-Hassan, Henareh L. Plasma catecholamine levels in patients with takotsubo syndrome:
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Implications for the pathogenesis of the disease. Int J Cardiol 2015;181:35-38.
22. Y-Hassan. The causal link between the blood borne catecholamines and takotsubo syndrome: Too
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many flaws. Int J Cardiol 2015;189:194-195.
23. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008;5:22-29.
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24. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, Haas TS, Hodges JS, Maron BJ. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010;55:333-341.
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25. 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;27:1523-1529.
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ACCEPTED MANUSCRIPT 29. Tanriver Y, Betz MJ, Nibbe L, Pfluger T, Beuschlein F, Strowski MZ. Sepsis and cardiomyopathy as rare clinical manifestations of pheochromocytoma--two case report studies. Exp Clin Endocrinol
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