Characterization of the Myocardial Inflammatory Response in Acute Stress-Induced (Takotsubo) Cardiomyopathy

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SUMMARY
Takotsubo cardiomyopathy is an acute stress-induced heart failure syndrome for which the exact pathogenic mechanisms are unclear, and consequently, no specific treatment exists. In an experimental model of stressinduced takotsubo-like cardiomyopathy, the authors describe the temporal course of a chronic inflammatory response post-induction, with an initial early influx of neutrophils into myocardial tissue followed by macro- A cute stress-induced (takotsubo) cardiomyopathy has a dramatic clinical presentation, mimicking a myocardial infarction (MI) (1) and is often precipitated by major emotional/physical stress. Despite unobstructed coronary arteries, the left ventriculogram shows characteristic myocardial ballooning, not corresponding to a single coronary artery territory, and the heart function is severely reduced. Regardless of a spontaneous process of recovery as a recognized feature of takotsubo cardiomyopathy, the mortality risk and long-term mortality are also comparable with MI (2,3). There is no current treatment, and the etiology is unclear, therefore its pathophysiology needs to be resolved before targeted therapies can be trialed. We have previously demonstrated severe global edema in both left and right ventricular myocardium of takotsubo patients during the acute phase with incomplete resolution at 4 months (4)(5)(6)(7). The substrate of this persistent edema is most likely an ongoing inflammatory response, which remains to be characterized in detail.
However, this is challenging in patients, where coexistent cardiac pathologies, lack of access to tissue, very small biopsies that do not reflect global changes, and tissue availability only at a single time point, are the norm.
Here, we used a previously established and wellreported rodent experimental model of catecholamine (stress)-induced takotsubo-like cardiac dysfunction (8)(9)(10)(11)(12), where the disease process is consistent and reproducible, and there are no confounding complications or major limitations to tissue availability. Although it remains unclear whether a "catecholamine surge" is fundamentally causal in triggering human takotsubo cardiomyopathy, this experimental model results in a similar wall motion abnormality that is observed in the human disease in the absence of an ischemic or infectious insult (8)(9)(10)(11)(12).
Our aim was to establish the type and time course of the myocardial inflammatory changes in this stressinduced experimental model and to then determine whether similar changes existed in viable, nonfibrotic myocardium from necessarily more complex human post-mortem cases. We specifically focused on detecting and characterizing macrophages, a heterogeneous cell population that infiltrates damaged tissue and functionally range between proinflammatory (M1 macrophages) and anti-inflammatory/tissue reparative/profibrotic (M2 macrophages) subtypes (13,14  Most insults occurred in regional areas of the section as illustrated in Supplemental Figure 3. 3 and were typically found in regional clusters.  Figures 3B and 3C), peaking at day 4. The percentages

DISCUSSION
Several mechanisms have been implicated in pathogenesis of takotsubo cardiomyopathy, including coronary artery spasm, microvascular dysfunction, and excessive release of catecholamines in response to stress (17,18). None of these mechanisms, however, has been conclusively proven to be responsible for the disease solely or in combination, accounting for the lack of targeted therapies. Inflammation has been implicated from noninvasive imaging, because of the intense myocardial edema observed on cardiac magnetic resonance imaging (3,5), and inflammatory changes in the heart have been reported from biopsies of patients, albeit these were taken from the right ventricular myocardium (19). Proteomic analysis of apical cardiac tissue in an experimental model also proposes inflammation might be involved (12), and an increase in macrophage infiltration has been observed 24 h after disease induction (20).  levels. This is followed by increased M2 macrophages (days 5 to 7) that initiates myocardial remodeling and potentially scarring (24,25  Takotsubo Cardiomyopathy and Myocardial Inflammation