The Role of Sympathetic Tone Regarding the Anatomical and Functional Recovery of the Left Ventricle in TakoTsubo Syndrome

TakoTsubo Syndrome (TTS) constitutes an increasingly recognised, heterogenous clinical entity which is associated with considerable short-term mortality. In addition, emerging evidence suggests that, in the long term, TTS can induce the expression of a phenotype similar to HFpEF . Apart from the typical (apical left ventricular) type, the current TTS definition has been expanded to also include the mid-ventricular, the basal and the focal type. Several previous studies on the typical form of the syndrome demonstrated that the principal underlying pathophysiology is sympathetic overactivation.

Purpose The aim of this study is to investigate the potential association between the sympathetic tone and the acute phase clinical features of TTS. Furthermore, the investigators aim at exploring possible correlations between the sympathetic tone activity and the diastolic dysfunction, a reported complication occurring one year after the acute phase.

This is a prospective observational study enrolling patients aged 18-85 years who fulfill the InterTaK diagnostic criteria and whose CMR within 14 days of the onset is not suggestive of an alternative diagnosis. All patients will be treated on individual basis according to the recent expert consensus statement for TTS. During the baseline evaluation the sympathetic tone will be assessed by means of Muscle Sympathetic Nerve Activity study (MSNA), heart rate and blood pressure variability parameters. Additionally, in a subgroup of participants sympathetic activity and cardiac sympathetic enervation will be evaluated with radioactive Iodine Metaiodobenzylguanidine scintigraphy (mIBG). Sequential echocardiography and CMR indices will be used for heart function and geometry assessment. The investigators will investigate the correlation between the sympathetic tone and the severity of cardiac dysfunction (systolic and diastolic) during the acute phase. Furthermore, the investigators will examine differences of the sympathetic tone effect in association with the localisation of the wall motion abnormality. Stress levels and quality of life will be assessed with respective validated questionnaires. The participants will be followed-up with quarterly clinic reviews for 12 months after the acute event. Baseline measurements will be repeated at the end of the follow-up period. Ethics approval has been obtained from the hospital ethical committee board.

The study results are expected to determine the role of the sympathetic tone on the extend, the severity and the localisation of cardiac dysfunction during the acute phase. They are also expected to demonstrate the role of the sympathetic tone on the long-lasting disorder that persists for months following the acute event.

TakoTsubo syndrome is the acute cardiac disorder which mimics an acute coronary syndrome and presents with signs of acute heart failure. It refers to a reversible regional dysfunction of the left ventricular contractility which cannot be attributed to coronary artery disease. Cardiac magnetic resonance is generally recommended as superior to echocardiography as the method to differentiate subjects with myocarditis or subendocardial infarction, but also to detect limited areas of reduced contractility and intracardiac thrombi. Usually, the condition follows an intense stressful event (physical condition or emotional distress). The affected area is usually regional, however cases of focal or global dysfunction of the left ventricle as well as others with right heart involvement have been also described. To date, many potential pathophysiologic processes have been suggested. These are the epicardial spasm, the self-limited acute myocardial infarction, the coronary microcirculatory dysfunction, the left ventricular outflow obstruction and the direct toxicity of the circulating catecholamines. Despite the comprehensive study of this entity during the last three decades, none of the aforementioned mechanisms has been adequately validated. On the other hand, there is increasing evidence regarding the leading role of the sympathetic tone as a main contributor. This has been shown in studies with 123mIBG which demonstrate that during the subacute phase of the syndrome the regional sympathetic enervation appears to be dysfunctional and improves after the recovery of the left ventricular systolic function. On the contrary, the sympathetic tone appears to be increased during the acute phase. There are no data available regarding the sympathetic innervation later than the period of three months from the episode. The MSNA, despite being a useful method to evaluate the sympathetic tone, has been used in TakoTsubo syndrome published series only twice. The available results are conflicting as there was a group of patients whose estimated sympathetic tone, being evaluated with MSNA appeared to be lower during the subacute phase compared with the follow - up period after the systolic recovery of the left ventricle.

Some years ago, despite its initial severity on presentation, the syndrome was regarded as having a benign course. New data, support that Takotsubo syndrome is accompanied by significant morbidity and mortality. Its incidence is estimated at around 2% of the acute coronary syndromes. It is exceptionally high in post-menopausal women. The available data support that short-term mortality ranges around 4-6% and is comparable to the one of the acute coronary syndromes. The disappointing short-term prognosis reflects the increased epidemiological data of in-hospital morbidity.

According to the International Takotsubo Registry, the men to women ratio is 9:1. The two genders share similar clinical and demographic characteristics, however in men, the stressful preceded event is more often physical but in women emotional. Typically, Takotsubo patients compared with others suffering from acute coronary syndromes suffer more frequently from depression and anxious disorder. Of great interest are the results which refer to the long-term morbidity. In detail, there are data for patients one year after the episode of Takotsubo syndrome who despite the left ventricular systolic recovery, express symptoms, functional status and laboratory results compatible with cardiac dysfunction. These findings are accompanied by increased myocardial fibrosis measured in CMR studies and abnormal metabolic function shown in cardiac magnetic spectroscopy. Moreover, it is suggested that the remaining diastolic dysfunction predisposes to worse outcomes. In general, Takotsubo syndrome is exceptionally heterogenous in terms of clinical expression and outcomes.

Aim of this study The main target of this study is to evaluate the sympathetic tone in patients with Takotsubo syndrome and particularly its potential prognostic value regarding its clinical severity on admission but also the left ventricular remodeling (structural and functional) one year after the event. It will be the first registry held in Greece and will try to re-evaluate the value of MSNA as a way to estimate the sympathetic tone in this population. Moreover, the sympathetic tone and sympathetic innervation integrity will be evaluated in patients with other than the typical - apical form of the syndrome according to the recent classification.

Methods This is a prospective, non-interventional observational study which will enroll patients 18-85-year-old, who fulfil the InterTAK diagnostic criteria. The diagnosis will be confirmed with CMR and ECHO which will show the LV systolic recovery. The sympathetic tone will be assessed with heart rate and blood pressure variability, MSNA and 123mIBG. Baseline measurements will be done during a 14-day interval from the acute onset. These will be repeated one year after the event. Signed consent form will be obtained and cases that the symptoms were attributed to myocarditis or subendocardial infarction (CMR result) will be excluded. Patients with severe chronic kidney disease (eGFR \< 30 ml/min), severe valvular disease, contraindication to perform any of the aforementioned measurements, chronic atrial fibrillation, permanent pacing, autonomic failure, pregnant or breastfeeding women, psychiatric disease which does not allow adequate co-operation or patients with life expectancy less than a year will not be enrolled. The enrolled cases will be followed up for one year. Data will be collected in a specific form (CRF). These include demographic and somatometric data, past medical history, hemodynamics and sympathetic tone measurements. In detail, the following parameters will be measured. Gender, height, body weight, waist - hip and neck circumference, stress levels (validated questionnaire), tobacco exposure, history of hypertension, diabetes, dyslipidemia, family history of cardiovascular disease. Additionally, the investigators will collect information about the concomitant coronary artery disease, heart failure, paroxysmal atrial fibrillation, chronic kidney disease, peripheral artery disease, sleep apnea, stroke. Moreover, vital signs on admission, ECG findings, ECHO results on admission, cath lab results and laboratory results (estimated renal function, lipids, serum glucose levels, uric acid levels, liver function tests, thyroid function tests, myocardial ischemia biomarkers, natriuretic peptids and inflammatory markers).

Sympathetic tone estimation:

Α. MSNA. After patient's stabilization the test will be performed and the derived data will be the number of bursts per min and the average bursts per 100 beats. The test will be repeated one year after the acute event.

B. 123 MIBG. Lugol solution will be administered prior to the scan for thyroid protection. After the MIBG administration planar view will be obtained at 15-20 min and this will be repeated 4 hours later together with tomographic scan with γ camera. The measured parameters will be the early and late heart to mediastinum ratio and the washout ratio.

C. ambulatory heart rate and blood pressure monitoring. Heart rate variability will be analyzed via Kubios software for linear parametric characterization of short-term and long-term heart rate variability. Blood pressure short-term variability will be expressed as SD, wSD, ARV, CV, tame rate of BP variation.

The left ventricle geometry and function will be assessed with:

A. CMR (pre enrollment and one year after the episode). LV, RV: ESV, EDV, RWMA, atrial volumes, tissue tracking: GLS, RS. T2W-Triple IR/STIR, early and late gadolinium enhancement.

B. ECHO (acute phase of Takotsubo syndrome, one year after the event). LVEF, E, A, E', A', LA vol, GLS

For data analysis, SPSS 24.0 software will be used. Continuous parametric data will be expressed as mean and SD. For categoric parametric data results will be presented in means of frequency and percentage. Comparisons between categoric parameters will be done with test x2. Comparisons between the mean values for continuous parameters with normal distribution will be done via unpaired student's test. Comparisons between categoric parameters will be done with Mann Whitney U test. Normal distribution will be checked with Kolmogorov-Smirnov test. Correlation analysis will be done via Pearson Phi coefficient or Spearman Rho. Statistically significant will be differences with p value \< 0.05. Evaluation of correlations between selected variables and cardiovascular events and mortality will be via Kaplan Maier curves.

Study limitations Sympathetic tone evaluation is not feasible during the hyper-acute phase of the syndrome. Systolic and diastolic function of left ventricle prior to the event will not always be available for comparison. Patients with severe comorbidities will probably not be enrolled in the study as it will be difficult to perform the necessary testing.

Estimated research outcome The present study estimates to include patients who express apart from the typical - apical form of the syndrome, as described in previous diagnostic criteria (revised Mayo) patients with basal, mid-ventricular and focal distribution of the systolic dysfunction of the left ventricle. It is interesting to investigate whether the currently available data regarding the sympathetic tone and the typical form of the syndrome apply for the atypical forms. As for the MSNA method, the investigators estimate to re-evaluate it as a means for sympathetic tone evaluation in takotsubo patients but also its potential prognostic value for the severity of syndrome on presentation and long-term morbidity. Regarding the MIBG scan, the investigators expect to reevaluate its value as an index of topical innervation integrity in patients who fulfil the new diagnostic criteria. Moreover, to test whether the hypokinetic area is related with impaired innervation during the subacute phase and permanent changes as expressed with fibrosis in CMR one year after the event.

Eligibility Criteria:
Inclusion Criteria:

* age limits
* Subjects able to provide ICF
* Cases fullfilling the InterTAK criteria with CMR to exclude acute myocarditis or myocardial infarction

Exclusion Criteria:

* age limits
* eGFR \< 30ml/min
* Cases diagnosed with acute myocarditis or acute myocardial infarction
* Severe valvular disease not related to TakoTsubo syndrome
* Pacemaker dependent patients
* Contraindications for CMR performance
* Permanent atrial fibrillation
* Neurological conditions related with autonomic failure
* Pregnancy, lactation
* Iodine allergy
* Chronic heart failure with LVEF \< 35%
* Any condition related with reduced life expectancy at recruitement
* Cancer on active treatment