Adenosin to Rapidly Reverse Left Ventricle Impairment in Takotsubo Syndrome

Brief Title

Adenosin to Rapidly Reverse Left Ventricle Impairment in Takotsubo Syndrome

Official Title

Rapid Recovery of Left Ventricular Function in Patients With Takotsubo Syndrome Undergoing Systemic Infusion of Adenosine: a Randomized Controlled Trial (TITAN Study)

Brief Summary

      The investigators will randomize patients admitted to hospital with Takotsubo diagnosis to
      systematic high-dose adenosine infusion for 3 minutes (in addition to standard of care) vs.
      standard of care. The primary aim of the study is to demonstrate that adenosine infusion is
      associated with a larger and more rapid recovery of left ventricle function.

Detailed Description

      Takotsubo syndrome is a heart condition that is characterized by the rapid onset of left
      ventricular dysfunction, usually reversible, and meeting the following diagnostic criteria:

        -  Transient alterations of regional contractility of the myocardial wall of the right or
           left ventricle, which are frequently, but not always, preceded by a stressful event
           (emotional or physical).

        -  The regional changes in contractility of the myocardial wall, often extend beyond the
           distribution of a single coronary vessel, and often result in a circumferential
           ventricular dysfunction of the involved segments.

        -  Absence of a culprit coronary lesion (eg. Of atherosclerotic plaque rupture, thrombus
           formation, coronary dissection) or other pathological conditions that may explain the
           regional changes in contractility of the myocardial wall (eg. Hypertrophic
           cardiomyopathy, viral myocarditis)

        -  Reversible electrocardiographic abnormalities of the EKG (ST-T segment elevation or
           depression, new onset of left bundle branch block, inversion of t wave and / or QTc
           elongation) during the acute phase (3 months).

        -  Significant increase in serum natriuretic peptide (BNP or NT-proBNP) during the acute

        -  Troponin significant increase, but relatively small, (disparity between the degree of
           left ventricular dysfunction and the value of troponin).

        -  The recovery of left ventricular function during follow-up (3-6 months).

      Epidemiology Since the Takotsubo syndrome has been described for the first time in 1991, its
      incidence, with the passing of years has been increasing, thanks to the possibility with
      networks for the treatment of acute myocardial infarction, to have a early access to coronary
      angiography study. Currently this syndrome accounts for 2% of all acute coronary syndromes
      who are undergoing coronary angiography.

      Pathophysiology The pathophysiology of Takotsubo syndrome is complex, and not fully
      clarified. There are several causes have been suggested over the years to explain the
      occurrence of this syndrome (vascular and / or myocardial). One of the mechanisms suggested
      is that there is a systemic response, by the body, to a severe stress which causes a sudden
      increase of catecholamines endogenous and exogenous; this increase has an effect on the
      cardiovascular system leading to acute heart failure.

      Stress is one of the most common causes behind the onset of this syndrome, and emotional
      stress (eg. Mourning,quarrel, etc.) and physical (eg. Surgical emergencies, obstetric or
      psychiatric), but it is not always a present condition.

      Recent case reports and clinical studies have shown that patients with this syndrome may
      experience a reversible damage of the coronary microcirculation, which could be the basis of
      the important ventricular dysfunction that is observed in these patients. This characteristic
      may play a significant role in the management of these patients. In fact any targeted
      therapies to the rapid recovery of the coronary microcirculation function with subsequent
      improvement in left ventricular function could reduce or prevent the complications related to
      this case.

      Complications During the acute phase of Takotsubo Syndrome the incidence of complications is
      frequent (18-34% involvement of the right ventricle; obstruction of left ventricular outflow
      12-54%; mitral regurgitation 14-25%, 9-20% cardiogenic shock, ventricular thrombus 2-8%,
      5-15% atrial fibrillation, ventricular arrhythmias 4-9%, 2-5% bradycardia-asystole) and these
      complications are often the consequence of left ventricular dysfunction. In fact, the
      presence of major depression of the ejection fraction (EF) is the main cause of complications
      in patients with Takotsubo and that the slow pace of recovery of normal EF is closely
      connected to this risk of complications.

      Diagnosis Takotsubo syndrome diagnosis requires, as basic examinations, coronary angiography
      (allows us to exclude the coronary artery diseases and to highlight the presence of the
      typical pattern "apical balloon" to the ventriculography) and the echocardiogram ( allow us
      to highlight the regional alterations of left ventricular kinetics).

      Risk Stratification Patients in whom the diagnosis of Takotsubo syndrome is made, they have
      to be stratified according to their risk profile in patients at high and low risk

      Therapy Recently the European Society of Cardiology has prepared a document in which it is
      suggested therapy to be performed in patients with Takotsubo syndrome according to risk
      stratification and clinical and echocardiographic data, based on a consensus among the
      authors in the absence of current randomized clinical studies in support of this strategy.

      Mortality The data available report an in-hospital (1-4.5%) and 5 years (3-17%) mortality

      Follow-up A recovery of ventricular function is shown at 3-6 months from acute event

      Rationale of the study In patients with symptomatic Takotsubo, therapeutic strategies
      currently used are designed to address, not the pathophysiological mechanism underlying this
      event, but the complications faced by patients (ie acute heart failure, arrhythmias and
      hyperkinetic left ventricular thrombosis). No data are currently available about targeted
      therapies to the treatment of Takotsubo syndrome.

      Adenosine is an extracellular signaling molecule that plays a fundamental role in human
      physiology. Its main effects are: vascular vasodilation, regulation of the activity of the
      sympathetic nervous system, antithrombotic and regulating blood pressure and heart rate. One
      of the main uses of adenosine in the cardiovascular field is the production of vasodilation
      of the coronary microcirculation to produce hyperemia, as for example in the assessment of
      intermediate coronary stenoses using fractional flow reserve (FFR). It also finds use even in
      the course of acute myocardial infarction in reducing the phenomenon of slow-flow in the
      course of primary angioplasty, even if the results of the studies currently available are not
      unambiguous interpretation.

      Galiuto et al. have demonstrated that, regardless of the underlying etiology, in patients
      with Takotsubo syndrome, it shows the presence of an acute and reversible vasoconstriction of
      the coronary microcirculation, which may represent a common pathophysiologic mechanism in
      these patients. In the study the investigators underline also as the use of a systemic
      infusion of adenosine at a dose of 140 micrograms / kg / min for 90 seconds determines an
      initial improvement, statistically significant, of the left ventricular function in these
      patients. The study was observational, and have not been taken into consideration clinical

      Numerous studies performed in patients with STEMI (ST-segment elevation myocardial
      infarction) have shown that the adenosine infusion systems, although at high doses, causes
      only mild adverse effects (es. dyspnea, chest pain, transient ventricular atrium block,
      hypotension ) and all quick resolution with the suspension of the infusion.

      Objective of the study The objective of this study is to demonstrate that in patients with
      Takotsubo syndrome diagnosis, the use of adenosine infusion at high doses, immediately after
      the diagnosis of disease, and the absence of documentation of coronary artery disease, it is
      able to enhance the EF of these patients to 48 hours after diagnosis, compared with standard

      Study Design It is an multicenter, randomized, single-blind study, phase IIa.

      Once coronary angiography demonstrated the absence of coronary artery disease and confirmed
      the diagnosis of Takotsubo syndrome patients will undergo a baseline echocardiography and
      then randomized, using a randomization system electronic, 1: 1 to receive:

        -  Systemic infusion of adenosine to 140μg / kg / min for 3 minutes + standard therapy

        -  Placebo (saline to 3 minutes) + standard therapy

      Randomization will be stratified by the following variables:

        -  gender (male vs. female)

        -  age (<65 years vs. ≥65 years) The standard therapy, will be allocated based on the risk
           stratification of patients enrolled. Patients will then be assessed by echocardiography
           at 24 hours, 48 hours and 1 month according to the parameters given in the
           echocardiographic analysis section.

      All patients will be followed up with clinical follow-up up to one year.

      PRESPECIFIED SUBSTUDY As has been shown in previous studies, patients with Takotsubo syndrome
      have reversible coronary microvascular damage.

      The purpose of our study is to assess whether the infusion of high-dose adenosine e.v favors
      the improvement of left ventricular ejection function quickly.

      With this sub-study we want to evaluate, also, if there is also in our series a damage of the
      coronary microcirculation.

      Patients participating in the sub-study, randomized in the Adenosine arm, the evaluation of
      coronary microcirculation will be performed by calculating the IMR (microcirculatory
      resistance index) during the infusion of adenosine required by randomization.

      The IMR is a validated method for measuring the function of the coronary microcirculation. By
      using a previously positioned guide pressure on the left anterior descendent (LAD) coronary
      artery, IMR is evaluated by the thermodilution technique analyzing the transit time of a
      predetermined quantity (3 ml) of saline at room temperature injected into the coronary

      3 consecutive injection of 3 mL of saline solution are performed at baseline, and evaluated
      the average transit time for resting (Tmn). Later, during maximal hyperemia induced by
      systemic infusion of Adenosine a140μg / kg / min, 3 new injections of saline at room
      temperature are performed, and the mean transit temple during hyperemia (Tmnhyp) is measured.
      Tmnhyp multiplying by the average value of distal coronary pressure (Pd) registered during
      maximal hyperemia, get the IMR value (IMR: Tmnhyp x Pd) which is considered in the normal
      range if less than 25. A value above 25 indicates the presence of a damage of the coronary

Study Phase

Phase 2

Study Type


Primary Outcome

left ventricle ejection fraction (%)

Secondary Outcome

 left ventricle ejection fraction (%)


Takotsubo Cardiomyopathy



Study Arms / Comparison Groups

Description:  Patients in this arm will receive systemic infusion of adenosine at 140μg/kg/min for 3 minutes plus standard therapy according to current guidelines


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

August 2016

Completion Date

October 2018

Primary Completion Date

October 2018

Eligibility Criteria

        Inclusion Criteria:

          -  18 years old

          -  Evidence of typical anatomical pattern to the left ventriculography (total akinesia of
             the mid-apical segments with hypercontractility basal segments) associated with the
             presence of criteria for the diagnosis of Takotsubo syndrome (Table 1)

          -  signing of informed consent

        Exclusion Criteria:

          -  allergy to adenosine

          -  known and documented diagnosis of asthma

          -  pre-existing ischemic heart disease

          -  presence of arrhythmic complication (AV block grade II type 2 and third degree)




18 Years - N/A

Accepts Healthy Volunteers



Matteo Tebaldi, MD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

University Hospital of Ferrara

Study Sponsor

Matteo Tebaldi, MD, Principal Investigator, Azienda Ospedaliera Universitria di Ferrara

Verification Date

October 2018