Atrial Arrhythmias in Takotsubo Syndrome

Is Inflammation the Missing Link?

Thomas Stiermaier; Ingo Eitel; Charlotte Eitel


Europace. 2019;21(2):184-185. 

Since its first description more than two decades ago, Takotsubo syndrome (TTS) is increasingly recognized worldwide as an important differential diagnosis in patients with suspected acute coronary syndrome. The disease is a form of acute heart failure caused by circumscribed left ventricular contraction abnormalities which completely recover within several weeks.[1] While the complex pathophysiology of TTS is still incompletely understood, recent studies shed light on the prognostic implications by showing a substantial risk of severe complications and considerable short- and long-term mortality rates.[2,3] These findings clearly rebut the initial assumption of a benign, transient state and were followed by efforts to determine predictive factors for adverse events in patients with TTS. Among other parameters, atrial arrhythmias were identified as major determinants of outcome and as useful marker for risk stratification in TTS.[4,5]

In this issue of EP-Europace, Jesel et al.[6] confirm and expand previous findings. The authors performed a retrospective study in 214 consecutive TTS patients without a history of atrial arrhythmias. The observed incidence of newly diagnosed atrial fibrillation and/or flutter during the index hospital stay was 24.8% with a low recurrence rate during follow-up (6 of 53 patients; 11.3%). Atrial arrhythmias were associated with elevated short- and long-term adverse event rates albeit an independent predictive value for mortality could not be established.[6] Instead, systemic inflammatory markers were identified as important factors. Peak leucocyte levels were related to in-hospital and cardiovascular mortality and peak C-reactive protein was a predictor for the occurrence of atrial arrhythmias in addition to peak troponin and left ventricular ejection fraction on admission.[6] From these results Jesel et al. conclude that acute and transient inflammation, myocardial damage, and left ventricular impairment are predictors of new onset atrial arrhythmias. They further hypothesize that these factors are responsible for the low recurrence rate of atrial arrhythmias during follow-up and compare atrial arrhythmias in TTS to post-thoracic surgery atrial fibrillation.

The results and the concluded interpretation are of interest, but caution is advised to make final conclusions on the aetiology and long-term course of atrial arrhythmias in TTS. In this way the interpretation of atrial arrhythmias as a transient inflammatory effect cannot be drawn from this study as the retrospective, single-centre design without systematic rhythm monitoring certainly goes along with an underestimation of pre-existing atrial arrhythmias, newly diagnosed events, and recurrent episodes during follow-up. Consequently, comparisons of atrial arrhythmias in TTS to post-thoracic surgery atrial fibrillation with potential implications on the need of long-term oral anticoagulation should be avoided. Instead, the relevance and prognostic implications of atrial arrhythmias as shown in larger, multi-centre studies should be kept in mind.[4,5] Considering previous analyses[4,5] and the results of this study by Jesel et al.,[6] it can be concluded that atrial arrhythmias are a frequent finding and linked to impaired prognosis in patients with TTS. However, two major questions are raised: what is the reason for the occurrence of atrial arrhythmias in TTS and why are they associated with worse outcome? The susceptibility of heart failure patients for atrial arrhythmias is well known[7] and the TTS population seems particularly predisposed given the advanced age and the high prevalence of concomitant factors, which are thought to impact the development and maintenance of atrial arrhythmias (e.g. heart failure, hypertension, or diabetes).[1] Furthermore, cardiac magnetic resonance imaging demonstrated left atrial dysfunction as an additional feature of acute TTS and a potential basis for arrhythmic events.[8] Sympathetically driven episodes of atrial arrhythmias seem also conceivable in view of the presumed pathophysiologic connection with catecholamine excess and sympathetic overdrive. Regarding prognostic implications, comprehensive evidence confirms higher mortality in heart failure patients with atrial arrhythmias.[7] However, a causal link between atrial arrhythmias and mortality has not been shown yet and it remains questionable whether or to which extent these deaths are directly caused by the arrhythmia. Although the risk of thromboembolic events is definitely increased, they only account for a small percentage of deaths.[4] In some cases, atrial arrhythmias might have worsened the course of TTS. This hypothesis is supported by the higher number of cardiovascular deaths and by the early divergence of survival curves between TTS patients with and without atrial arrhythmias.[4,6] On the other hand, prolonged monitoring in critically ill patients (e.g. with cardiogenic shock) might have increased the probability of detecting atrial arrhythmias. This potential bias in retrospective studies has to be considered although atrial fibrillation was an independent predictor of outcome in previous multivariate analyses.[4,5] Nevertheless, the basis for atrial arrhythmias in TTS and the reason for their strong prognostic implications are not entirely conclusive yet.

Jesel et al.[6] provide an interesting concept by suggesting inflammation as the missing link. Systemic inflammation is thought to contribute to initiation and perpetuation of atrial arrhythmias[9] and elevated circulating levels of inflammatory markers have been reported in TTS cohorts.[10] Besides, increased serum interleukin-6 and interleukin-10 levels at admission were identified as predictors of adverse events in TTS.[10] Consistently, this study associates systemic inflammatory markers with atrial arrhythmias and prognosis in patients with TTS.[6] Therefore, inflammation might be a crucial factor for both the occurrence of atrial arrhythmias and adverse events in TTS albeit current data do not allow a conclusion regarding the cause-and-effect relationships. The following concepts might be conceivable: (i) inflammation leads to atrial arrhythmias, which worsen the course of TTS and cause fatal events; (ii) inflammation is related to a severe course of TTS with a consequently increased detection rate of atrial arrhythmias due to intensified monitoring (bias in retrospective analyses); or (iii) inflammation is independently associated with both atrial arrhythmias and adverse outcome in TTS. A mixture of these explanations is probably the most likely mechanism. However, the exploration of the association between inflammation, atrial arrhythmias, and adverse events in TTS is an appealing subject for future research.

In conclusion, atrial arrhythmias are a frequent finding in patients with TTS and should be recognized as a marker for adverse outcome. Inflammation represents a potential pathophysiological explanation for the occurrence and the prognostic implications of atrial arrhythmias. Further research is required to reveal the exact causal links and to identify therapeutic targets to improve prognosis in TTS.