Plasma catecholamine levels in the acute and subacute stages of takotsubo syndrome: Results from the Stockholm myocardial infarction with normal coronaries 2 study

Abstract Aims It is well‐accepted that takotsubo syndrome (TS) is characterized by a massive surge of plasma catecholamines despite lack of solid evidence. The objective of this study was to examine the hypothesis of a massive catecholamine elevation in TS by studying plasma‐free catecholamine metabolites in patients participating in the Stockholm myocardial infarction (MI) with normal coronaries 2 (SMINC‐2) study where TS constituted more than one third of the patients. Methods and results The patients included in the SMINC‐2 study were classified, according to cardiac magnetic resonance (CMR) imaging findings (148 patients), which was performed at a median of 3 days after hospital admission. Plasma‐free catecholamine metabolites; metanephrine, normetanephrine, and methoxy‐tyramine were measured on day 2–4 after admission. Catecholamine metabolite levels were available in 125 patients. One hundred and ten (88%) of the 125 patients included in SMINC‐2 study, and 38 (86.4%) of the 44 patients with TS had completely normal plasma metanephrine and normetanephrine levels. All patients had normal plasma methoxy‐tyramine levels. Fourteen (11.2%) of the 125 patients included in SMINC‐2 study, and 5 (11.6%) of the 43 patients with TS had mild elevations (approximately 1.2 times the upper normal limits) of either plasma metanephrine or normetanephrine. One patient with pheochromocytoma‐triggered TS had marked elevation of plasma metanephrine and mild elevation of plasma normetanephrine. There were no significant differences between the number or degree of catecholamine metabolite elevations between the different groups of patients with CMR imaging diagnosis included in SMINC‐2 study. Conclusion There was no evidence of massive catecholamine elevations in the acute and subacute stages of TS apart from one patient with pheochromocytoma‐induced TS. Most of the TS patients had normal catecholamine metabolites indicating that blood‐borne catecholamines do not play a direct role in the pathogenesis of TS.

catecholamine metabolites; metanephrine, normetanephrine, and methoxy-tyramine were measured on day 2-4 after admission. Catecholamine metabolite levels were available in 125 patients. One hundred and ten (88%) of the 125 patients included in SMINC-2 study, and 38 (86.4%) of the 44 patients with TS had completely normal plasma metanephrine and normetanephrine levels. All patients had normal plasma methoxy-tyramine levels. Fourteen (11.2%) of the 125 patients included in SMINC-2 study, and 5 (11.6%) of the 43 patients with TS had mild elevations (approximately 1.2 times the upper normal limits) of either plasma metanephrine or normetanephrine. One patient with pheochromocytoma-triggered TS had marked elevation of plasma metanephrine and mild elevation of plasma normetanephrine.
There were no significant differences between the number or degree of catecholamine metabolite elevations between the different groups of patients with CMR imaging diagnosis included in SMINC-2 study.
Conclusion: There was no evidence of massive catecholamine elevations in the acute and subacute stages of TS apart from one patient with pheochromocytoma-induced TS. Most of the TS patients had normal catecholamine metabolites indicating that blood-borne catecholamines do not play a direct role in the pathogenesis of TS.

K E Y W O R D S
catecholamines, metanephrines, myocardial infarction, neurogenic stunned myocardium, takotsubo

| INTRODUCTION
Takotsubo syndrome (TS) is a well-recognized acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome (ACS). 1,2 The term "takotsubo-like" (tako = octopus, tsubo = a pot) was introduced by Sato and Dote in the early 1990s to describe the left ventricular shape during systole in patients presenting with clinical features of myocardial infarction (MI) but without obstructive coronary arteries. 3,4 The defining feature of TS is the reversible left ventricular wall motion abnormality (LVWMA), which has a characteristic circumferential pattern resulting in a conspicuous ballooning of the left ventricle during systole. The left ventricular dysfunction is incongruent with the coronary artery supply territory. 2 The LVWMA may have mid-apical, mid-ventricular, mid-basal, or focal left ventricular ballooning's pattern. 2 Global left ventricular contractile abnormality has also been reported. 5 The right ventricle is involved in about one third of patients with TS. 6 A trigger stress factor (an emotional or a physical) may precede the onset of TS in about 70% of cases. 2,7 TS affects predominantly post-menopausal women.
Several pathophysiological mechanisms for the development of TS have been discussed. The main proposed mechanisms are myocardial ischemia, left ventricular basal hyperkinesis causing severe intraventricular pressure gradient, autonomic nervous system dysfunction with sympathetic hyper-activation including local cardiac sympathetic disruption and norepinephrine seethe and spillover, blood-borne catecholamine myocardial toxicity, and epinephrine-induced switch in signal-trafficking. 2,[8][9][10][11][12][13] According to the literature, one of the characteristic features of TS is a massive elevation of circulating plasma catecholamines. 2,8,14 This is based on a study of 13 patients with emotional-induced TS, which showed "massive elevation of plasma catecholamines and their metabolites" during the first 7-9 days after admission. 15 However, a massive elevation of circulating plasma catecholamines has not been replicated in other studies. [16][17][18][19][20] One of the disadvantages in measurement of plasma catecholamines is their short half-lives where catecholamine elevations may be missed. The half-lives of the plasma-free catecholamine metabolites are longer than the parent catecholamines (epinephrine, norepinephrine, and dopamine) half-lives, which are <5 min. 21 The half-life of plasma free metanephrine was reported to be 60-105 min and that of plasma free normetanephrine was 95 min. 21 For this reason, measurement of plasma-free metanephrines (metanephrine and normetanephrine) or urine total metanephrines has replaced measurement of plasma catecholamines as the recommended screening test for pheochromocytoma/paraganglioma. The aim of this study was to examine the hypothesis of a massive catecholamine elevation in TS through studying plasma-free catecholamine metabolites in Stockholm MI with normal coronaries 2 (SMINC-2) study where TS constituted more than one third of the patients.

| METHODS
The plasma levels of catecholamine metabolites (metanephrine, normetanephrine, and methoxy-tyramine) were measured in patients F I G U R E 1 Flow chart illustrating the number of patients included in SMINC-2 study with CMR diagnoses including TS group and the number of patients with normal or elevated plasma catecholamine metabolites in TS and non-TS groups. *One of the patients had pheochromocytomainduced TS. CMR, cardiac magnetic resonance; TS, takotsubo syndrome

| Statistical analysis
Results are reported as mean ± SD except where indicated otherwise.

| RESULTS
Flow chart illustrating the number of patients included in SMINC-2 study with CMR diagnoses including TS group and the number of patients with normal or elevated plasma catecholamine metabolites in TS and non-TS groups is shown in Figure 1. The baseline characteristics of the study patients diagnosed by CMR findings are shown in   Table 2). This patient was later found to have pheochromocytoma-induced TS. There were no differences in patient characteristics between patients with and without increased plasmafree metanephrine and/or normetanephrine (Table 3)

| DISCUSSION
The main finding in this study was that most of the patients (88%) One patient with TS had marked elevation of metanephrine, which was due to pheochromocytoma. Furthermore, there were no differences in the plasma levels of plasma-free catecholamine metabolites between different groups of patients included in SMINC-2 study. tor. 19 On the other hand, the urinary metanephrines and normetanephrines were markedly elevated in pheochromocytoma/ paraganglioma-induced TS in the same study.

| The study with massive catecholamine elevation in TS
The only study, which has reported on massive catecholamine elevations, including catecholamine metabolites metanephrine and nor-  18 This results in myocardial stunning in a unique circumferential pattern typically regional following most probably cardiac sympathetic nerve distribution. 1,9,10 Further support for this hypothesis is the signs of local cardiac sympathetic denervation in the hypokinetic/akinetic regions, evidence of chemical (catecholamine) myocarditis in the regions of myocardial stunning and the histopathological findings of contraction band necrosis. 1,9,10

| Limitations
One limitation is that although the half-lives of the measured plasma The data that support the findings of this study are available from the corresponding author upon reasonable request.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.