Impaired hemodynamic response to tilt, handgrip and Valsalva manoeuvre in patients with takotsubo syndrome

Abstract

Purpose

Long-term β-adrenolytics treatment in takotsubo syndrome (TTS) patients is based on the premise, that TTS is strongly associated with sympathetic nervous system overactivity. The aim of the study was to establish hemodynamic response to tilt, handgrip and Valsalva manoeuvre in patients with takotsubo syndrome compared to healthy subjects (CONTROL) and patients after ST Elevation Myocardial Infarction (STEMI).

Material and method

Echocardiographic examination was performed at rest, ECG and continuously non-invasively measured arterial blood pressure were used for evaluation of hemodynamic responses to Valsalva manoeuvre, static handgrip (HG) followed by post-exercise ischemia, and tilt. Ten healthy women, 20 with TTS and 20 after STEMI, mean age 64 ± 8.5 years, participated in the study.

Results

Pressor response to Valsalva manoeuvre and tilt in TTS group was diminished in comparison to CONTROL and close to that of STEMI. During HG, increase of SBP was the lowest in TTS group. Data indirectly suggest that it was due to deficient stroke volume in TTS and STEMI patients during these manoeuvres; though echocardiographic findings at rest did not reveal any significant differences between groups.

Conclusions

Our data show that despite apparent resolution of the immediate effects of TTS, impaired response to cardiovascular challenge, similar to that in STEMI patients, persisted. As the manoeuvres applied mimic daily life situations, causes of impairment should be searched for and potential health risk evaluated.

Introduction

Takotsubo syndrome (TTS) is a clinical syndrome, characterized by transient regional wall motion abnormalities of left or right ventricle in the absence of obstructive coronary artery disease. The reasons for susceptibility of the individual patient remain unknown, however exaggerated adrenergic response to emotional or physical stimuli may be the underlying mechanism. The hypothesis that such exaggerated adrenergic response is underlying mechanism of TTS seems to be confirmed by the finding that typically two- to threefold higher plasma catecholamine level compared to patients presenting with acute myocardial infarction were found immediately after the episode of TTS. Several days later this level declined however remained substantially higher than that in patients with myocardial infarction (Wittstein et al., 2005). In the recovery phase the level of plasma catecholamine was not different from that in control subjects (Christensen et al., 2016).

Episodes of TTS most often appear in postmenopausal women and are preceded by stressful event (Peters et al., 2015). Lavi et al. demonstrated that cardiac vagal tone and baroreflex sensitivity decrease significantly in postmenopausal women and in addition, cardiovascular β-adrenoreceptor responsiveness decreases, whereas α-1 adrenoreceptor responsiveness increases (Lavi et al., 2007). Therefore, sympathetic activity replaces parasymphathetic one as the main regulator of cardiovascular system in this group. Furthermore, systemic baroreflex buffering ability is significantly reduced in postmenopausal women. These changes would affect cardiovascular responses during acute stress and would increase both heart rate and vasoconstriction. Lyon et al. have proposed that β1 (positive inotropic effects with norepinephrine) and β2 (negative inotropic effects with high concentrations of circulating epinephrine) adrenergic receptors are unevenly distributed through the myocardium. A relative abundance of β2 receptors in the apical myocardium could explain the tendency for apical suppression with basal sparing (i.e., the takotsubo morphology) during the high adrenergic states with increased levels of circulating epinephrine (Lyon et al., 2008). Changes in the sensitivity or density of local myocardial adrenergic receptors from base to apex during menopause could help explain the pathophysiology in this group.

As it is hypothesised that TTS is strongly associated with autonomic nervous system dysfunction, various studies attempting to assess sympathetic and parasympathetic activity have been undertaken. Analysis of the autonomic tests performed in TTS patients showed that they are predisposed towards prolonged sympathetic activation, catecholamine stunning and suppressed parasympathetic modulation of the heart, in response to stressors, long after the initial TTS episode (Norcliffe-Kaufmann et al., 2016).

Contribution of the sympathetic activity in the cardiovascular reaction on Valsalva manoeuvre, handgrip test, and tilt is substantial (Zygmunt and Stanczyk, 2010). Some studies have shown that in patients with TTS these reactions are intensified, which suggests association with increased responsiveness of the sympathetic nervous system (Norcliffe-Kaufmann et al., 2016).

Despite the lack of convincing evidence for the effectiveness of long-term β-adrenolytics treatment in TTS patients, they are widely used, so it is worth knowing whether this affects their hemodynamic responses to manoeuvres that evoke strong sympathetic activation. Therefore we designed the study in which TTS patients medicated with β-adrenolytics were asked to perform Valsalva manoeuvre, handgrip combined with post-exercise ischemia and tilt. Their hemodynamic responses were compared with control subjects and post myocardial infarction patients, both groups also medicated with β-adrenolytics. It gave the possibility to compare TTS group with two other groups of subjects, one with apparently intact cardiovascular system and other with impaired one, in order to find out whether hemodynamic responses of TTS subjects are normal in line with apparent recovery of cardiac function at rest. It must be stressed that as the use of β-adrenolytics affects the sympathetic nervous system activity the cardiovascular response to autonomic tests will be altered. It is therefore reasonable to define these stimuli as functional tests and not autonomic tests.