Biobehavioral Processes in Tako-Tsubo Cardiomyopathy: a controlled study concerning physiological and psychological responses to stress

1. BACKGROUND
Significance
Tako-Tsubo cardiomyopathy (TTC) is characterized by major cardiac left
ventricular dysfunction with typical apical ballooning of the left ventrical
and symptoms and signs mimicking acute coronary syndromes. The most common
presentation includes chest pain and/or dyspnea with ST-segment elevation or
T-wave inversion with a mild increase in troponin I. The typical precipitants
of Tako-Tsubo syndrome involve mental and emotional arousal or distress. About
75% of the patients with TTC report a preceding event incorporating physical
and/or emotional distress. TTC is also known as *appical ballooning
syndrome* (ABS), *broken heart syndrome* (BHS), *stress cardiomyopathy*,
*ampulla cardiomyopathy*, *neurogenic stunning* and *transient left ventricular
apical ballooning*. The clinical course of patients who survive till hospital
admission is good, but little is known about the psychophysiological
characteristics of patients with Tako-Tsubo cardiomyopathy. Catecholamines may
be an important link between emotional stress and cardiac injury.
This study examines whether neurohormonal (catecholamines, ACTH and cortisol)
and hemodynamic (heart rate, blood pressure and cardiac contractility)
responses to a standardized mental challenge task are exaggerated in
individuals with a history of Tako-Tsubo cardiomyopathy as compared to healthy
controls and patient controls with stable heart failure, matched for time since
diagnosis, sex and age. Data obtained during the challenge study will be
cross-tabulated with 24-hour ambulatory ECG monitoring and psychological
questionnaires assessing behavioral traits. This study will establish
biobehavioral characteristics that identify patients with Tako-Tsubo
cardiomyopathy and determine pathophysiological characteristics of this
disorder.

Epidemiology and treatment of Tako-Tsubo cardiomyopathy
The prevalence of Tako-Tsubo cardiomyopathy ranges from 0,7 % to 4.87% in
patients admitted with symptoms and signs of acute coronary syndrome.
Tako-Tsubo is more common in women (90.7%) than men, and most women with TTC
are postmenopausal. The age of clinical presentation is often after 55 years. A
relatively large number of TTC patients has age-related comorbidities,
including cancer (23,6%.
The diagnosis of Tako-Tsubo syndrome is based on 1) akinesia or dyskinesia of
the apical and/or midventricular segments of the left ventricle with regional
wall motion abnormalities that extend beyond the distribution of a single
epicardial vessel; 2) Signs and symptoms suggesting acute coronary syndrome
(i.e., new-onset ECG abnormalities such as ST-segment elevation and/or T-wave
inversion, modest elevation in cardiac troponin levels, and/or typical angina
complaints); and 3) absence of obstructive coronary artery disease,
pheochromocytoma or myocarditis that could account for the condition. Typical
in TTC are an intense emotional trigger and marked increases in circulating
catecholamines, but those are not necessary conditions for TTC. Differential
diagnoses of TTC from other cardiac conditions with heart failure can be
complicated.

The catecholamine levels during admission are 2 to 3 times higher among
patients with TTC than among a control group of patients with Killip class III
myocardial infarction, and 7 to 34 times published normal values, suggesting
exaggerated sympathetic stimulation as a causal factor in TTC.

The optimal treatment of Tako-Tsubo has not been established. Hemodynamic
stabilizing and standard therapy invariably leads to spontaneous recovery.
Because the presentation of TTC mimics that of myocardial ischemia, initial
management should be directed toward the treatment of this acute coronary
syndrome combined with ECG monitoring, echocardiography and administration of
aspirin, heparin and β-blockers as needed.

1.1. The role of psychosocial factors in Tako-Tsubo cardiomyopathy

Psychological triggers, such as intense mental challenges and emotional arousal
are typical precipitants of Tako-Tsubo cardiomyopathy. Typical triggers include
news of an unexpected death, experiencing fear, having a fierce argument and
situations such as a surprise party can function as a trigger of TTC. A recent
study by Martin et al. suggests that patients with Tako-Tsubo cardiomyopathy
might be characteristically hyper-reactive to mental and emotional challenges
in terms of neurohormonal and hemodynamic responses as well as increased
reactive hyperemia compared to patients with a history of myocardial infarction
or healthy controls. Little is known about background cardiovascular measures
(e.g., history of coronary artery disease, hypertension, cardiac arrhythmias)
and psychological factors such as depression, hypochondria and personality
types (such as hostility and Type D personality) as risk factors for TTC. The
general aim of this project is therefore to examine the neurohormonal and
hemodynamic characteristics of patients with a history of Tako-Tsubo
cardiomyopathy at rest and in response to a low-grade standardized mental
challenge task (simple mental arithmetic, a speech task about the stressful
event that preceded the episode of TTC, followed by a low-intensity physical
stress task) and to cross-tabulate these measures with 24-hour ambulatory ECG
monitoring and psychological questionnaires. Two comparison groups will be
used: healthy age- and sex-matched controls and patient controls with stable
class I-II heart failure.

2. STUDY OBJECTIVES

Specific Aim 1. To determine whether Tako-Tsubo cardiomyopathy is associated
with hyper reactivity of the neurohormonal and cardiovascular systems.
Hypothesis 1: Patients with a clinical history of Tako-Tsubo cardiomyopathy
have elevated neurohormonal (norepinephrine, epinephrine, cortisol and ACTH)
and hemodynamic (systolic and diastolic blood pressures, heart rate and cardiac
contractility) responses to mental challenge tasks compared to healthy controls
or patients with stable heart failure. No differences will be found between
these groups in response to physical challenge.

Specific Aim 2. To determine whether psychological traits associated with
increased levels of distress are more common in Tako-Tsubo cardiomyopathy than
matched controls.
Hypothesis 2:
Patients with Tako-Tsubo cardiomyopathy experience more psychological distress
(perceived stress scores, depressive symptoms and anxiety) and psychological
vulnerability factors for distress (hostility, Type D personality, and
somatization) in comparison to healthy controls or patients with stable heart
failure. It is further hypothesized that patients with higher levels of
psychological distress have elevated neurohormonal and cardiovascular
reactivity during the laboratory/clinic evaluation (Aim 1).

Specific Aim 3: To establish whether increased reactivity observed during
laboratory testing in the clinic generalizes to daily life situations as
documented using 24-hour ECG and mood state monitoring. This would support the
ecological validity of the laboratory/clinic-based studies.

Hypothesis 3: Patients with Tako-Tsubo cardiomyopathy have elevated heart rate
and reduced heart rate variability combined with elevated levels of distress
during daily life activities compared to healthy controls and patients with
heart failure. It is further hypothesized that challenged induced
cardiovascular responsiveness (Aim 1) are associated with 24-hour ambulatory
measures.

This study has a cross-sectional observational design using three groups.

Other than the stand risk for collecting blood samples, there are no risks
associated with study participation.