Elsevier

International Journal of Cardiology

Volume 224, 1 December 2016, Pages 226-230
International Journal of Cardiology

Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome,☆☆,

https://doi.org/10.1016/j.ijcard.2016.09.008Get rights and content

Abstract

Background

Takotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease.

Methods

In this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests.

Results

The study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4 ± 2.4% vs. 4.8 ± 1.9%, p = 0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3 ± 15.1 vs 24.7 ± 12.8 mm2, p = 0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5 ± 28.4 vs. 29.4 ± 16.5 bursts/100 heart beats, p = 0.09) with no significant differences in muscle sympathetic activity in response to stress.

Conclusions

Our findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome.

ClinicalTrials.gov identifier

NCT01249599

Introduction

Takotsubo syndrome (TTS), also known as stress cardiomyopathy or apical ballooning syndrome is a transient but potentially lethal disease mimicking acute myocardial infarction [1]. In the majority of patients, it is induced by intense emotional or physical stress [2]. First described in Japan in 1990 by Sato et al. [3], TTS is characterized by acute onset of severe chest pain and/or acute left ventricular failure with dyspnoea, ECG changes, typical left ventricular angiographic findings and in most cases resolution of the morphological and clinical manifestations [4], [5].

The pathogenesis of the disorder is not well understood and possibly involves excess of catecholamines [6] and endothelin-17, myocardial stunning and coronary microvascular dysfunction [8]. Endothelial dysfunction, a pathological state of the endothelium characterized by an imbalance between vasoconstricting and vasodilating factors [9], may represent an important link between stress and myocardial dysfunction in TTS. It is a key factor in the development of cardiovascular disease, particular in atherosclerosis [10] but also in microvascular dysfunction and is a potent predictor of clinical outcome [11].

We have previously shown that mental stress can induce endothelial dysfunction [12]. Pre-existing vascular dysfunction may predispose TTS patients to myocardial dysfunction in the presence of mental or physical stress and abnormal reactivity of the sympathetic nervous system may be involved in this process. Systematic assessments of vascular function and structure and sympathetic nervous system activity in TTS beyond case reports are still scarce. It was thus the aim of this study to assess the extent of vascular dysfunction and sympathetic nervous system activity in patients with stable TTS compared to matched controls.

Section snippets

Study population

Patients with a history of TTS according to standard clinical criteria [13] as well as controls matched for age, cardiovascular risk factors and pharmacological therapy were included in this prospective observational study. Exclusion criteria were use of long-acting nitrates or phosphodiesterase 5 inhibitors, alcohol or drug abuse, malignancy, disease with systemic inflammation (e.g. rheumatoid arthritis, Crohn's disease) and pulmonary hypertension. Patients were recruited in the University

Results

A total of 22 patients with TTS (median age 67.9 ± 10.4 years; 21 female) and 21 controls (median age 68.2 ± 8.2 years; 20 female) were included in the study. Their clinical characteristics, laboratory parameters and concurrent drug therapy are presented in Table 1. Both study groups were well matched with no significant differences in age, sex, cardiovascular risk factors and concomitant drug therapy. TTS patients were in the stable phase of the disease and were measured at a mean of 3.45 ± 1.5 years

Discussion

Our systematic study of vascular function and structure showed that patients with TTS compared to matched controls have a significant increase in endothelial dysfunction and a trend of higher basal sympathetic nervous activity even in the stable phase of the disease. These findings may explain why patients with TTS have similar in-hospital mortality than patients with myocardial infarction [25], [26] and why their long-term outcome is worse than previously assumed [26], [27].

Endothelial

Study limitations

Our study has some limitations. First, even though our population was well-matched in regards to age, sex, cardiovascular risk factors and concomitant drug therapy, we cannot exclude relevant unmeasured confounding factors. Second, although our study cohort of TTS patients represents one of the largest with available endothelial function measurements so far, a higher sample size would increase generalizability of the findings. Third, as all patients were in the remission phase of the disease we

Conclusions

Our findings highlight the relevance of endothelial dysfunction in TTS patients even in the stable disease phase. Endothelial dysfunction may be an important pathophysiological link between stress and myocardial dysfunction in TTS. More studies are needed to assess if therapeutic strategies aiming at improving endothelial function have an impact on long-term prognosis of the disease.

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

Acknowledgements

This study was supported by grants of the Swiss National foundation (32003B-130624 to GN/IS), the Swiss Heart Foundation (to IS/AJF) and the Foundation for Cardiovascular Research – Zurich Heart House.

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    All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

    ☆☆

    Grant support: Swiss National Foundation, Swiss Heart Foundation, Foundation for Cardiovascular Research – Zurich Heart House.

    Conflict of interest: The authors report no relationships that could be construed as a conflict of interest

    1

    Authors contributed equally.

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