Author + information
- Thierry Hiestand, MD,
- Jürgen Hänggi, PhD,
- Carina Klein, PhD,
- Marlene S. Topka, MSc,
- Milosz Jaguszewski, MD,
- Jelena R. Ghadri, MD,
- Thomas F. Lüscher, MD,
- Lutz Jäncke, PhD and
- Christian Templin, MD, PhD∗ ()
- ↵∗University Hospital Zürich, Department of Cardiology, Rämistrasse 100, CH – 8091 Zürich, Switzerland
The exact pathophysiology of Takotsubo syndrome (TTS) still remains unknown. Among others, excessive levels of catecholamines resulting in toxicity-induced myocardial stunning (1), potentially originating from sympathetic overactivity from the central nervous system, are thought to be involved in the pathomechansims of TTS (2). There is also compelling evidence that a brain-heart association may be involved in TTS (3). Therefore, TTS might originate from structural brain alterations. The present study investigated structural and connectomic differences of brain regions controlling the autonomic nervous system (ANS), areas that are involved in emotion regulation and autonomic-limbic integration by magnetic resonance imaging (MRI).
Twenty Caucasian female TTS patients from the International Takotsubo Registry (4) and 39 healthy women participated. The 2 groups did not differ significantly in age, handedness, Mini-Mental State Examination or Hospital Anxiety and Depression Scale score, or global gray and white matter volume (all p > 0.05). The mean time between a TTS event and the acquisition of the MRI scans was 342 ± 274 days. None of the participants reported any history of head injuries, neurosurgery, current drug abuse, or other contraindications to MRI. Written informed consent was obtained from all participants prior to the study enrollment. The local ethics committee approved the study, and it was conducted according to the declaration of Helsinki.
With the T1-weighted MRI scans, we performed surface-based morphometry (SBM) and voxel-based morphometry (VBM). Region of interest (ROI)–based group comparisons have been performed to investigate cortical thickness, surface area, and volume (SBM) using FreeSurfer (Laboratory for Computational Neuroimaging, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts) and to investigate probabilistic gray matter volume using FSLVBM (Analysis Group, FMRIB, University of Oxford, Oxford, United Kingdom). A network-based analysis of the diffusion tensor imaging (DTI) data was performed using the network-based statistic tool. Besides a 90-node network, we also evaluated a network with a reduced number of nodes (24 ANS-specific brain regions). All statistical analyses were corrected for multiple comparisons. Methodological details are described elsewhere (5).
In the vertex-wise cortical ROI-based analysis (SBM) restricted to the insula, we found decreased cortical thickness in TTS compared with control subjects in both insulae (Figure 1A). The analysis showed 2 clusters (186.2/360.3 mm2) in the left/right antero-ventral insula with a mean cortical thickness of 2.525/3.006 mm in TTS patients and 2.689/3.235 mm in control subjects (p = 0.026 and p = 0.0002, respectively). The analysis of mean values within ROIs showed reduced cortical thickness in both cingulate cortices in TTS. There were no significant differences between groups for each of the 3 morphometric measures in the supramarginal gyrus that served as the control region.
The voxel-wise ROI-based analysis (VBM) delivered reduced gray-matter volume in TTS in 3 clusters: left amygdala (p = 0.016), right amygdala (p = 0.048), and 1 cluster at the right amygdala/hippocampus border (p = 0.049) (Figure 1A). There were no significant differences between groups either in the left and right supramarginal gyrus or in the thalami that served as control regions.
The structural brain connectivity analysis of the 90-node connectivity matrices showed reduced connectivity mainly within the limbic system in TTS (Figure 1B), whereas the ANS-specific connectivity analysis showed reduced connectivity in the TTS patients in a subnetwork (p < 0.0006) constituting the left amygdala, both hippocampi, left parahippocampal gyrus, left superior temporal pole, and right putamen (Figure 1B).
Our results demonstrate substantial anatomical differences between TTS patients and healthy control subjects in the limbic network comprising the insula, amygdala, cingulate cortex, and hippocampus, all of which are strongly involved in the control of emotional processing, cognition, and the autonomic nervous system. A tentative explanation for our findings could be that affective processing in these key areas is less efficiently controlled in TTS patients because of an anatomically suboptimal organization. However, because this is a cross-sectional study, it cannot be excluded that such anatomical alterations are the consequence rather than the cause of cardiac dysfunction. To disentangle cause and effect for these substantial anatomical alterations and to unveil the exact pathophysiological role of these brain structures in TTS, longitudinal studies of TTS patients will be necessary in the future.
Please note: This project was supported by the Foundation for Cardiovascular Research–Zurich Heart House; research grants from the Olten Heart Foundation and Swiss Heart Foundation (to Dr. Templin); a research grant from the Olten Heart Foundation and a research grant, “Filling the Gap,” from the University of Zurich (to Dr. Ghadri); and the University Research Priority Program “Dynamics of Healthy Aging” of the University of Zurich (to Dr. Jäncke). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors thank Hansruedi Baetschmann for the usage of his MATLAB scripts that support the network-based statistic tool. Drs. Hiestand and Hänggi contributed equally to this work and are joint first authors. Drs. Jäncke and Templin contributed equally to this work and share last authorship.
- 2018 American College of Cardiology Foundation