Proposed causative mechanisms

The pathophysiological mechanism of TTS appears to be complex and multifactorial and as yet, not completely understood. Several pathophysiological mechanisms for Takotsubo syndrome (TTS) have been proposed, and awareness is growing that although these mechanisms may not be the cause in all cases, TTS may result from more than one pathophysiological phenomenon.Solving the enigma of TTS is like putting together a complex jigsaw puzzle as depicted below by Templin and colleagues,2 with researchers working to find out where the pieces fit as new information becomes available.

Figure 1: The unsolved puzzle of Takotsubo syndrome

Templin et al. 2016. The unsolved puzzle of Takotsubo syndrome.

It is generally accepted that catecholamines have a central role in the pathophysiology of  TTS.

  • There are many published reports of TTS following administration  of adrenalin (epinephrine), noradrenalin (norepinephrine), isoprenaline (isoproteranol), dopamine, and phenylephrine have all been used successfully to induce TTS-like changes in humans and animal models.4
  • Several clinical conditions associated with acute severe sympathetic neural activation or adrenal catecholamine release such as acute subarachnoid haemorrhage, phaeochromocytoma, and acute thyrotoxicosis can trigger TTS.5,6
  • The multiple morphological changes seen in the myocardium in TTS match those seen after catecholamine-induced cardiotoxicity.3,6








Previously proposed mechanisms are discussed briefly below.

Vasomotor dysfunction (coronary artery spasm and microvascular dysfunction)

There is growing evidence of a strong association between vasomotor dysfunction and TTS,7.8 especially during the acute phase, but it is not clear whether it is a cause of TTS, or an effect of the myocardial dysfunction and associated myocardial oedema that occurs in TTS.8 Further research is needed to investigate whether vasomotor function persists after TTS and if so, whether therapeutic interventions can improve vascular function, augment recovery, and prevent recurrence of TTS.8

Myocardial infarction and spontaneous coronary artery dissection (SCAD)

Aborted myocardial infarction caused by a transient thrombosis in a long wrap‑around left anterior descending artery (LAD) has been proposed as a possible cause of TTS9 but has not been shown to be the single causative mechanism.  A long wrap-around LAD is not present in most cases of TTS,10  and would does not explain forms of TTS with apical sparing.6 However, TTS can co-exist with myocardial infarction and it is possible that this could have been the trigger in some cases. Severe chest pain, breathlessness and fear associated with acute thrombotic  coronary occlusion or spontaneous coronary artery dissection (SCAD)11 are major stress factors and could conceivably trigger TTS.6

Left ventricular outflow tract obstruction (LVOTO)

Left ventricular outflow tract obstruction (LVOTO) has been observed in patients with TTS.  LVOTO has been proposed as a possible cause of TTS in patients anatomically predisposed to severe midcavity obstruction during periods of excessive sympathetic stimulation leading to apical ballooning.12  LVOTO is more likely a complication of TTS than a cause, but it may be one of the causes of cardiogenic shock in TTS.

Click image to enlarge



End-diastolic and end-systolic apical four-chamber (A and B) and three-chamber (C and D) echocardiographic views demonstrating the typical apical and mid-ventricular LV wall-motion abnormalities that raised the suspicion of Takotsubo cardiomyopathy. SAM of the mitral valve with LVOT obstruction is signaled by the red arrow (D). Continuous-wave Doppler profile outlining the degree of LVOT obstruction at rest (E) and during the Valsalva maneuver (F).
Image source: Lousinha et al. Rev Port Cardiol 2012, 31, 49-51.

Epinephrine‑induced switch in signal trafficking

It has been proposed that high levels of circulating epinephrine may trigger a switch in the intracellular signal trafficking from Gs (stimulatory) to Gi (inhibitory) protein signaling through the B2 adrenoreceptor (B2AR) that is negatively inotropic with greatest effect at the apical myocardium, explaining apical ballooning seen in TTS. It is proposed that this mechanism is cardioprotective. and may have evolved  to limit catecholamine-induced myocardial toxicity during acute stress.13 However, it is not certain how this applies to forms of TTS other than apical ballooning.6

Nitrosative stress

Immunohistologic studies of myocardium from people with TTS have shown evidence of nitrosative stress,14 with increased 3-nitrotyrosine (a marker of nitrosative stress) and potentially poly(ADP-ribose), a downstream product of poly (ADP-ribose) polymerase (PARP)-1 activation, which can impair cardiac energetics,15 a factor that may explain why people with TTS experience fatigue and symptoms long after the initial event. Also of interest, nitric oxide synthase can couple to the β2AR.16

Recently added pieces to the puzzle


Following initial contractile dysfunction, the longer term sequelae of TTS involves cardiac inflammation.16 Endomyocardial biopsy shows mononuclear infiltrates and contraction band necrosis, a unique form of myocyte injury characterised by hypercontracted sarcomeres, dense eosinophilic transverse bands, and an interstitial mononuclear inflammatory response. Contraction-band necrosis has been described in clinical states of endogenous and exogenous catecholamine excess.5 Slowly resolving global myocardial oedema is present on magnetic resonance imaging17 and as this subsides, a process of global microscopic fibrosis develops in its place, which can be detected as early as 4 months.18

For some who have experienced TTS, extreme fatigue and lethargy  continues for months. Many also report ongoing symptoms of chest pain, dyspnoea, palpitations and lightheadedness. It is it is important to understand the processes linking the acute changes in contractility with the downstream inflammatory changes that worsen long-term prognosis for people with TTS.

The brain-heart axis

The pathophysiology of TTS integrates neuroendocrine physiology, potentially involving the cognitive centres of the brain, including the hypothalamic–pituitary–adrenal (HPA) axis. Templin and colleagues have recently demonstrated that structural anatomical brain differences exist between patients with TTS and healthy controls. These differences involve the limbic network ,including the insula, amygdala, cingulate cortex, and hippocampus, all of which are thought to contribute to emotional processing and the autonomic nervous system. These findings strengthen the current concept of the involvement of the brain–heart interaction in TTS. It is not clear whether these differences existed before TTS, and so they could be a cause or an effect of TTS. 19


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