Risk factors for a broken heart: understanding drug-induced causes for Takotsubo syndrome and pharmacological treatment options

ABSTRACT

Introduction

Takotsubo syndrome (TTS) is an acute inflammatory disorder involving first the vasculature and then the myocardium. It occurs relatively frequently, especially in aging women after acute physical and emotional stress. There is also increasing recognition that TTS attacks are sometimes precipitated by pharmacotherapy.

Areas covered

The pathogenesis of TTS is described, including components of a complex biochemical ‘cascade’ centering on aberrant post-receptor signaling following β₂-adrenoceptors stimulation and resultant nitric oxide (NO) release and development of nitrosative stress. Examples and significance of drug-induced TTS are also described. Currently available therapeutic information regarding TTS is presented, both for management of patients acutely and in the long-term. Furthermore, development of specific therapies to block components of the pathogenetic TTS ‘cascade’ is discussed.

Expert opinion

The biochemical ‘cascade’ in TTS revolves around an aberrant post-receptor response to β₂-adrenoceptor stimulation, increased responsiveness to NO and triggering of activation of poly(ADP-ribose) polymerase (PARP). In theory, interruption of this ‘cascade’ represents a logical approach to improving both symptomatic status and survival post TTS. Currently, there is some evidence supporting routine long-term treatment post TTS with either ACE inhibitors or angiotensin receptor antagonists, both to reduce risk of recurrence and to improve survival. Results of ongoing controlled clinical trials are awaited.

KEYWORDS:

• Takotsubo syndrome
• catecholamines
• nitric oxide
• inflammation
• ACE inhibitor
• angiotensin receptor blockade

Article highlights

• TTS is not a form of AMI, but rather an extensive inflammatory disorder, triggered, at least in part, by exposure of susceptible individuals (usually elderly women) to pulse release of catecholamines. This may be iatrogenic, via catecholamine or catecholamine-potentiating drug administration.

• Although TTS was once thought to be a transient problem, there is increasing evidence that most patients recover very slowly from a symptomatic point of view, and that some develop permanent myocardial fibrosis.

• Hypotension/shock represents the main basis for early mortality risk and is engendered mainly via vascular permeabilization and increased effect of nitric oxide (NO). Shock should best be treated by plasma volume expansion rather than via the use of positive inotropic agents.

• The biochemical ‘cascade’ underlying the early development of hypotension and the subsequently slow recovery revolves around aberrant post-receptor response to β₂-adrenoceptor stimulation, increased responsiveness to NO and triggering of activation of poly(ADP-ribose) polymerase (PARP) activation and resultant myocardial energetic impairment. In theory, interruption of this ‘cascade’ represents a logical approach to improving both symptomatic status and survival post TTS.

• There is some evidence supporting routine long-term treatment post TTS with either ACE inhibitors or angiotensin receptor antagonists, both to reduce risk of recurrence and to improve survival. Results of ongoing controlled clinical trials are awaited.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

G Ong was partially supported by a Postgraduate Scholarship from the University of Adelaide. The study was funded in part by a Vanguard Grant from the National Heart Foundation of Australia.