Understanding the Complex Interplay Between Coronary Artery Disease and Takotsubo Syndrome: Not All Swans Are White

Guido Parodi; Giuseppe Damiano Sanna; Pier Sergio Saba


Eur Heart J. 2020;41(34):3268-3270. 

…no matter how many instances of white swans we may have observed, this does not justify the conclusion that all swans are white.
Karl Popper

Takotsubo syndrome (TTS) is a clinical entity that manifests with a pattern of presentation mimicking an acute myocardial infarction.[1] TTS accounts for ~2% of all patients presenting with apparent symptoms of acute coronary syndrome.[2] This syndrome, frequently associated with an emotional or physical stress, is characterized by transient myocardial stunning that fully recovers spontaneously within days or weeks, and by definition cannot be related to (epicardial) obstructive coronary artery disease (CAD). However, in the medical literature, several cases and small registries of TTS associated with CAD have been reported[1,3] and, in clinical practice, numerous typical TTC cases show obstructive or non-obstructive coronary atherosclerosis that cannot justify the myocardial dysfunction.

In this issue of the European Heart Journal, Napp and colleagues, on behalf of the InterTak Registry investigators, analysed the data of 1016 patients with TTS from a large international multicentre observational registry, with the aim to determine the coexistence, features, and prognostic role of CAD.[4] The authors found a surprisingly high prevalence of coexistent CAD in TTS patients. In fact, 64.2% of the enrolled patients showed CAD by angiography; in particular, 41.2% had non-obstructive CAD, and 23% had obstructive CAD (with visually assessed stenoses of ≥50% of the coronary lumen diameter). Finally, three patients had an acute coronary occlusion concomitant with TTS. In this study, only a minority (about a third) of Takotsubo patients showed truly normal coronary arteries, leading to a reconsideration of the contribution of epicardial CAD in the pathophysiology of this condition. Of note, the presence of obstructive CAD in TTS patients was associated with adverse outcomes, and the mortality of TTS patients with obstructive CAD was comparable with that of age- and gender-matched patients with acute coronary syndrome (ACS). There was an acute outcome effect of CAD in patients with TTS beyond the potentially expected impact of CAD on long-term outcomes.[4]

While at first glance these results simply reinforce the theory of an 'ischaemic substrate' in TTS, actually they disclose different clinical scenarios. In fact, the relationship between TTS and CAD is complex and the interplay between them may act following two different pathways. (i) TTS with occasionally detected concomitant CAD; in this case, pre-existing coronary atherosclerosis might be simply a bystander or an aggravating factor. (ii) TTS developing in the context of ACS due to coronary occlusion in a different territory; here the two conditions may be concomitant or, more probably, one may be the consequence of or triggered by the other. In the first and more frequent scenario, a stable coronary lesion (not necessarily a bystander but a potentially concurrent factor) determines a coronary reserve impairment. In this case, the reduction of cardiac output accompanying the transient left ventricular dysfunction of TTS due to direct and indirect effects of catecholamines on myocytes and coronary vasculature might compromise the coronary perfusion, finally leading to additional myocardial ischaemia and myocardial stunning. In the second, and more rare, scenario, TTS occurs in the context of an ACS (or vice versa) and the common underlying mechanism may be represented by the physical or emotional stress or the adrenergic trigger which causes coronary artery spasm, increased myocardial oxygen demand, enhanced platelet reactivity, and even plaque rupture (Take home figure). However, the complex interplay between TTS and CAD can occur more deeply inside the coronary artery tree. Coronary microvascular dysfunction (with a pathological state of the endothelium) is in fact now considered the trigger that leads to acute myocardial ischaemia in the affected patients, and TTS is no longer considered as cardiomyopathy.[9] Accordingly, TTS should be included within the spectrum of ischaemic heart disease. This paradigm shift has led to further investigations of the potential relationship between TTS and atherosclerotic CAD; meanwhile, the growing clinical experience and observations have progressively questioned the axiom of two mutually exclusive pathological conditions.

Take home figure.

The complex interplay between coronary artery disease and Takotsubo syndrome.

The study by Napp and colleagues gives rise to some epidemiological considerations since the prevalence of concomitant obstructive CAD found in their cohort is higher as compared with previous smaller studies. Data involving 450 patients from the Takotsubo Italian Network (TIN) Registry showed a prevalence of relevant CAD of 9.6%.[3] Similarly, two single-centre studies from Germany and Japan reported a prevalence of obstructive CAD in TTS of 19% and 10%, respectively.[5,6] How do we explain this great heterogeneity in terms of results? Of note, in the early reports, the diagnosis of TTS was based on the TIN Criteria[7] or Mayo Clinic Diagnostic Criteria;[8] however, the study by Napp and colleagues is based on the InterTak Diagnostic Criteria, which are very inclusive and different from previous Takotsubo diagnostic criteria, allowing the presence of a wall motion abnormality congruent with a single coronary artery territory in patients matching all the other criteria.[4] Furthermore, CAD was defined differently from previous studies and assessed by revision of coronary angiograms by two independent board-certified senior interventional cardiologists. Since it is well known how coronary angiography can underestimate the presence and severity of CAD, it can be easily speculated that intracoronary imaging [i.e. intravascular ultrasound (IVUS) or optical coherence tomography (OCT)], if routinely performed, could have documented an even higher prevalence of CAD in TTS patients. Of note, patients with TTS and concomitant CAD (particularly those with an obstructive form) had a prevalence of diabetes mellitus (DM) higher than that of patients in the ACS-matched cohort (35.3% vs. 26.1, P = 0.031). This is surprising since autonomic sympathetic nervous system overactivity is a traditional cornerstone of TTS and therefore the prevalence of DM is expected to be low in TTS. Previous observations confirmed a lower prevalence of diabetes in TTS than in ACS.[2,8] It has also been hypothesized that patients with peripheral neuropathy in the setting of DM might be protected from developing TTS.[10] Further studies should assess in more depth the role of DM as a trigger (e.g. adrenergic surge following drug-induced hypoglycemia) or risk factor (due to diabetes-related autonomic imbalance) for TTS.

In the study by Napp et al., CAD emerged as an important risk factor for adverse outcome in TTS patients, allowing us to speculate regarding the potential link between CAD and poor prognosis. Is it the result of the natural history of atherosclerosis itself, or does it reflect the fact that coexisting CAD is prone to be 'neglected' and undertreated in TTS patients (generally perceived as low-risk subjects)? The authors reported that 20% of the patients with obstructive CAD did not receive an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and 30% did not receive a statin at discharge.[4] This should be regarded as a cultural heritage (more properly, a fixation error) due to our classical perception of TTS patients as 'immune' from coronary atherosclerotic disease and with a usual favourable outcome. In this regard, it should be considered that the great majority of TTS patients are female. Unfortunately, despite their overall cardiovascular risk burden, women with CAD are usually undertreated per se[11] and this gender divide could negatively impact the overall prognosis of TTS patients. The CAD prognostic role which emerged in the study by Napp et al. provides further information for our understanding of the complex TTS natural history.[12] However, the prognostic impact of other comorbidities, underlined in previous reports,[13,14] was not addressed in this study.

Finally, the study by Napp et al., questioning at least in part our state of knowledge of TTS, raises the opportunity for a revision of diagnostic criteria of this syndrome.[1,7,8] In fact, the study results suggest that neither the presence of regional wall motion abnormalities extending beyond a single vascular epicardial distribution nor the absence of culprit atherosclerotic CAD might be considered 100% accurate for the diagnosis of TTS instead of ACS. Given their frequent coexistence and considering, as discussed above, the complex interplay between CAD and TTS, broader use of intracoronary imaging and functional tests could be appropriate, since other cardiac imaging modalities, including magnetic resonance, may be unable to exactly reveal the relationship between the two coexisting pathologies.

To conclude, the study by Napp confirms that 'the times are changing' since TTC and CAD should no longer be considered mutually exclusive diseases. As stated by Karl Popper, when theories are falsified by such observations, scientists can respond by revising the theory, or by rejecting it in favour of a new one. This methodological approach should be summarized by the quote 'no number of sightings of white swans can prove the theory that all swans are white; the sighting of just one black may disprove it'.[15] We just saw a black swan!