The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM): Rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo Syndrome

Contemp Clin Trials. 2020 Mar;90:105894. doi: 10.1016/j.cct.2019.105894. Epub 2019 Nov 16.


Background: Takotsubo Syndrome(TTS), contrary to historical reports, is now increasingly recognised to be associated with substantial mortality and morbidity, both in the short- and long-term. Although TTS is often precipitated by a catecholamine "pulse", in-hospital hypotension is a common occurrence, increasing the risk of mortality. Furthermore, despite the transient catecholamine stimulus, there is increasing evidence that there are significant long term sequelae, including persistently impaired left ventricular(LV) systolic dysfunction, myocardial oedema with fibrosis, as well as persistent impairment of quality of life. A definitive therapeutic option to limit the extent of initial myocardial injury, and to accelerate recovery in TTS is therefore justified. However to date, there has been a lack of prospective studies in this area.

Design and rationale: NACRAM is a multi-centre, randomised, placebo-controlled trial, sequentially testing early use of intravenous N-acetylcysteine(NAC), followed by/or oral ramipril for 12 weeks. The rationale for utilising these agents is related to their effects on limiting nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein(TXNIP); both processes fundamental to the pathogenesis of TTS.

End points: NACRAM is assessing resolution of myocardial oedema on cardiac magnetic resonance imaging(CMR), improvements in LV systolic function as measured by global longitudinal strain(GLS) on echocardiography, quality of life, and inflammatory markers.

Discussion: To the best of our knowledge, NACRAM will be the first prospective study to help definitively evaluate a therapeutic option in acute attacks of TTS.

Keywords: H(2)S; N-acetylcysteine; Nitrosative stress; Ramipril; TXNIP; Takotsubo.

Publication types

  • Clinical Trial Protocol
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Acetylcysteine / administration & dosage
  • Acetylcysteine / therapeutic use*
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Carrier Proteins / drug effects
  • Double-Blind Method
  • Free Radical Scavengers / administration & dosage
  • Free Radical Scavengers / therapeutic use*
  • Humans
  • Inflammasomes / drug effects
  • Prospective Studies
  • Quality of Life
  • Ramipril / administration & dosage
  • Ramipril / therapeutic use*
  • Takotsubo Cardiomyopathy / drug therapy*
  • Takotsubo Cardiomyopathy / physiopathology


  • Angiotensin-Converting Enzyme Inhibitors
  • Carrier Proteins
  • Free Radical Scavengers
  • Inflammasomes
  • TXNIP protein, human
  • Ramipril
  • Acetylcysteine