Takotsubo: The Myth of Rapid and Complete Recovery

Dana K Dawson, DM FRCP D. Phil FESC

Disclosures

Eur Heart J. 2018;39(42):3762-3763. 

As the youngest diagnostic entity in cardiology, Takotsubo has made a rapid transition from an initial curiosity proposed in Japan by Sato in 1990 to a reasonably frequent diagnosis in any cardiology department. This neuro-cardiac condition is an acute form of left ventricular dysfunction which mimics a myocardial infarction in its presentation with chest pain, ECG changes, and biomarker release. In contrast to a myocardial infarction patients have non-obstructed coronary arteries and a typical area of dyskinesia initially described as 'myocardial ballooning', which typically, is disproportionately larger than the cardiac troponin leak would suggest. The close resemblance of this peculiar left ventricular shape with a Japanese octopus-fishing pot gave it the name of 'Takotsubo', and it has also been widely presented in the media by the resonant layman term of 'broken heart syndrome'.

Takotsubo has been widely recognized as a strong, if not the strongest psycho-somatic interaction described in medicine, because the hallmark of this condition is that it is often precipitated by an intense episode of emotional or physical stress Although acute mortality and morbidity has been recognized, Takotsubo patients demonstrate a natural process of spontaneous recovery. Whilst this is of course very encouraging, it has led cardiologists to assume further, generally viewing Takotsubo as a self-limiting condition with rapid and complete recovery.

I started to review these patients in a dedicated clinic in 2011, mainly in an attempt to objectively demonstrate this complete recovery and understand the time frame for it. Before long, I learned that a significant number of patients with prior Takotsubo continued to suffer 3–4 months after their acute event: most were complaining of general fatigue, breathlessness, fleeting episodes of chest pain but mostly not being able to physically engage at the same level of activity as they had previously. Since the restoration of the left ventricular ejection fraction in these patients had been reinforced by the concept of general absence of scar on cardiac magnetic resonance,[1] what could be the mechanisms of such protracted recovery?

This initial clinical observation tallied with some rather new and unexpected findings that were just starting to emerge from small cohorts that had been followed-up in the medium term: Christopher Neil from Adelaide showed that these patients continued to have a degree of myocardial oedema at 3 months after acute presentation.[2] Our group added to that finding that cardiac energetics, whilst impaired during the acute episode also failed to return to normal levels 4 months after the acute event;[3] in addition, myocardial oedema was still seen at 4 months but only in the segments that had been ballooning during the acute episode.

In our next pursuit, we investigated in detail the very complex, three-dimensional motion of the left ventricle during the recovery of Takotsubo patients, cross-examining the apex-to-base, radial, and rotational contraction of the heart when compared with matched controls. We followed-up 52 Takotsubo patients who, at 4 months into follow-up continued to exhibit impaired cardiac deformation of the left ventricle and delays in the timing of contraction and relaxation patterns:[4] the orchestra was no longer in tune! Despite normalization of left ventricular ejection fraction and volumes, the heart appeared to lose its ability to achieve a full wringing motion that is required for an efficient ejection of the stroke volume.

Shortly thereafter two independent registries reported that the long-term mortality of Takotsubo cardiomyopathy appears comparable to that of patients with myocardial infarction.[5,6] As these prognostic registry data were in apparent contradiction with the universally observed resolution of left ventricular ejection fraction, the key question arising was, what additional processes intervened to confer these patients such an unexpectedly poor long-term prognosis?

Furthermore, do patients with a prior episode of Takotsubo ever achieve complete recovery?

The latter was the foundation to our next prospective investigation, the HEROIC study (NCT02989454: Persistent symptoms and e arly incomplete r ecovery after acute stress i nduced c ardiomyopathy: Is there o ngoing h eart distress?).

In this observational case–control study, we recruited 37 patients with prior (>12 month) Takotsubo cardiomyopathy, and 37 age, sex, and co-morbidity matched control subjects. In contrast to previous perceptions, HEROIC participants continued to report symptoms compatible with heart failure and had a cardiac limitation pattern on treadmill cardiopulmonary exercise testing with a reduced peak VO2 and increased VE/VCO2 slope.

Despite their normal left ventricular ejection fraction and serum biomarkers, patients with prior Takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain and global longitudinal strain), increased native T1 mapping values (implying microscopic fibrosis), and impaired cardiac energetic status (metabolic impairment). HEROIC showed for the first time that Takotsubo cardiomyopathy has long-lasting clinical consequences including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. These findings demonstrated that post-Takotsubo, patients can develop a persistent, long-term heart failure phenotype.[7]

Whilst the HEROIC study provided answers for that subgroup of patients who remain symptomatic, it also raises a series of important questions: assuming that patients have a normal physiology prior to developing an acute Takotsubo episode, what are the precise mechanisms that lead to the development of a phenotype of heart failure with preserved ejection fraction? And more importantly, if an intervention should be possible and successful to induce reversibility, at what stage after the acute presentation can it be implemented for maximal therapeutic success and what should that intervention be aimed at?

Undoubtedly, Takotsubo syndrome is offering an unprecedented opportunity to advance science in a pursuit for therapeutic strategies in a non-ischaemic remodelling heart failure phenotype. Given that this condition is not as rare as previously thought, a better understanding of the mechanisms and the development of therapeutic interventions is urgently required.

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