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

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).