None listed
Conditions
Brief summary
Stress cardiomyopathy (Tako-Tsubo Cardiomyopathy; TTC) was once thought to be a relatively rare form of transient regional cardiac dysfunction, occurring largely in ageing women. Given the apparently benign course of this condition, little attention has been directed until recently to its cause, or to appropriate treatment. However, it is now apparent that TTC is neither rare nor benign and accounts for about 10% of “heart attacks” in women. Our studies have led to expedited diagnosis, and have delineated a number of aspects of the natural history of TTC. Specifically, attacks, presenting usually as episodes of chest pain and/or breathlessness, TTC actually represents a form of catecholamine-triggered myocardial(heart muscle) inflammation of varying severity, which may engender lethal arrhythmias (abnormal heart rhythms), However the main cause of death post hospital admission is the development of severe hypotension (low blood pressure), which causes death in 2 – 3% of cases. The recovery is slow, due to persistent inflammation and energetic impairment within myocardium (heart muscle), and is associated with prolonged impairment of quality of life. There is also a substantial risk of recurrence. Furthermore, we have data from post-mortem studies and from a rat model of TTC developed in our laboratory that the myocardial inflammation is associated with increased nitrosative stress. Currently, there has not been an established treatment for TTC. We wish to test the hypotheses that agents that limit nitrosative stress (such as NAC and ramipril) might:- (i) Reduce the severity of inflammation and associated myocardial energetic impairment in TTC, and (ii) Accelerate recovery from TTC
Interventions
Placebo controlled trial in a 2 by 2 factorial design, studying the effects of N-acetylcystein (NAC) and Ramipril on the severity and recovery of patients with TTC. NAC component involve 24 hours of intravenous infusion of 10g of NAC/placebo, and the Ramipril component involves 10mg daily of encapsulated ramipril tablet/encapsulated placebo tablet for a duration of 3 months.
Each arm of the study is as per the following:
Arm 1: 24 hours of intravenous infusion of 10g of NAC at baseline and daily
Placebo controlled trial in a 2 by 2 factorial design, studying the effects of N-acetylcystein (NAC) and Ramipril on the severity and recovery of patients with TTC. NAC component involve 24 hours of intravenous infusion of 10g of NAC/placebo, and the Ramipril component involves 10mg daily of encapsulated ramipril tablet/encapsulated placebo tablet for a duration of 3 months. Each arm of the study is as per the following: Arm 1: 24 hours of intravenous infusion of 10g of NAC at baseline and daily 10mg Ramipril for a duration of 3 months Arm 2: 24 hours of intravenous infusion of placebo at baseline and daily 10mg Ramipril for a duration of 3 months Arm 3: 24 hours of intravenous infusion of 10g of NAC at baseline and daily 10mg placebo for a duration of 3 months Arm 4: 24 hours of intravenous infusion of placebo at baseline and daily 10mg placebo for a duration of 3 months Adherence monitoring will be done by drug tablet return.
Sponsors
Cardiology Department, Queen Elizabeth Hospital
Study design
Allocation
Randomised controlled trial
Intervention model
Factorial
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
i) Acute episodes of TTC ii) Provisional diagnosis of TTC will be based on:- (a) Symptoms of chest pain and/or dyspnoea (b) Elevation of NT-proBNP levels (c) Demonstration of regional wall motion abnormality within LV consistent with TTC via ventriculography or echocardiography. Echocardiography will be performed on all patients, irrespective of whether or not they undergo initial cardiac catheterisation, within 48 hours of admission. Data will be archived for later blinded analysis. iii) Definitive diagnosis of TTC will require demonstration of myocardial oedema on cardiac MRI, and exclusion of myocardial infarction by cardiac MRI or exclusion of relevant coronary artery disease by angiography. The difference in diagnostic criteria reflects the fact that exclusion of myocardial infarction (usually by coronary angiography) may not be performed on admission in all presumptive NAC patients in the absence of ST-segment elevation electrocardiogram.
Exclusion criteria
For NAC component: (a) Delay beyond 24 hours post onset of symptoms before making presumptive diagnosis:- in all cases NAC infusion must begin within 24 hours of onset of symptoms. (b) Simultaneous administration of long-acting nitrates or intravenous glyceryl trinitrate (GTN). If the patient had been commenced on intravenous GTN on presentation, this should be immediately ceased. Patients can be invited to participate in the trial upon cessation of intravenous GTN. (c) Previous adverse reaction to NAC. (d) Patients with any contraindications to Cardiac MRI. ii) For Ramipril component (a) Previous adverse reaction to ACE inhibitors. (b) Current therapy with ACE inhibitor or angiotensin receptor blocker. (c) Severe renal functional impairment: calculated creatinine clearance <30mL/min. Patients with severe renal function impairment (calculated creatinine clearance <30mL/min) will be excluded from Gadolinium administration during MRI imaging due to its association with nephrogenic systemic sclerosis in this population. Patients who are unable to provide informed consent will be excluded from the study.
Outcome results
None listed