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J Stroke > Volume 24(1); 2022 > Article
Altermatt, Sinnecker, Aeschbacher, Springer, Coslovsky, Beer, Moschovitis, Auricchio, Fischer, Aubert, Kühne, Conen, Osswald, Bonati, Wuerfel, and for the Swiss-AF Study Investigators: Right Hemispheric Predominance of Brain Infarcts in Atrial Fibrillation: A Lesion Mapping Analysis
Dear Sir:
Atrial fibrillation (AF) increases the risk of an ischemic stroke three- to five-fold [1], and cardioembolic strokes are associated with worse outcomes than strokes of other origin [2]. Covert brain infarcts occur in more than a third of patients with AF and have been associated with cognitive impairment [3]. Regional distribution of brain infarcts may explain why most patients with AF and brain infarcts on neuroimaging have no clinical history of stroke or transient ischemic attack (TIA). Previous studies on a possible side-predominance of brain infarction in patients with AF have yielded conflicting evidence and were mostly done in patients with clinically manifest stroke [4]. In the present study, we systematically analyzed the anatomical distribution and localization of covert and overt brain infarcts according to different vascular territories in a large cohort study of patients with established AF.
This is a cross-sectional analysis of the Swiss-AF cohort, a prospective, multicenter cohort study of unselected patients with AF across 14 centers in Switzerland [5]. In total, the study has enrolled 2,415 participants with AF. At baseline visits, brain magnetic resonance imaging (MRI) was acquired in all patients (without contraindications for MRI) on either a 1.5 or a 3.0 Tesla scanner, depending on the participating site. The most frequent reason for missing MRI was the presence of an implanted cardiac device (n=461). The 1,716 patients with eligible baseline brain MRI data (mean age 73±8 years, 27% women, 20% with history of stroke or TIA) were included in the present study (Supplementary Table 1). Detailed methodological descriptions are provided in the Supplementary methods [3,5-11]. Briefly, we manually segmented brain infarcts on MRI. Lesions were classified into large non-cortical or cortical infarcts (LNCCIs) and small non-cortical infarcts (SNCIs) [7]. LNCCIs were considered infarcts of potentially embolic or atherothrombotic origin and included large non-cortical infarcts with a diameter of >20 mm, and cortical infarcts of any size. SNCIs were considered infarcts of potentially microangiopathic origin and defined as lesions with a diameter of ≤20 mm not involving the cortex. Lesion masks were co-registered separately to an age-specific brain template and overlaid to compute a voxel-based probability map.
We observed LNCCIs in 386 (22%) patients. Visually, in the voxel-based probability map, a clear right-hemispheric preponderance was observed (Figure 1A). Results of the statistical comparison of lesion counts, average lesion volumes, and percentages affected per vascular territory are reported in Supplementary Table 2. LNCCIs were most often located in the territory of the middle cerebral artery (MCA). While, in the MCA territory, LNCCI counts were evenly distributed between the hemispheres (Wilcoxon matched-pair rank test; P=0.796), the average volume of infarcts was significantly larger in the right compared to the left hemisphere (left [total]: 512.4 mL vs. right [total]: 1,240.1 mL; Wilcoxon matched-pair rank test; P=0.002). Similarly, the percentage of the MCA territory affected by LNCCIs (calculated by the proportion of lesional voxels per vascular territory per patient) was significantly larger in the right than in the left hemisphere (Wilcoxon matched-pair rank test; P=0.008). No side-preponderance of LNCCIs was detected for the vascular territories of the anterior and posterior cerebral arteries. No side-difference was observed for SNCIs (Figure 1B).
Our findings might indicate, that large emboli preferentially hit the right brain hemisphere. We hypothesize that both vascular anatomy (i.e., the right artery originating more proximally from the heart) and the physical properties of cardiac emboli (i.e. their size) contribute to the right-sided preponderance for embolic cerebral infarcts. The right common carotid artery originates more proximally from the heart and with less angulation from the aortic arch, which in turn increases the likelihood of these large emboli to enter the right carotid artery. This may especially be the case for larger cardiac emboli which are dragged to the outer curvature of the aorta. This hypothesis is supported by a study using anatomically accurate models of the human aorta and their branch arteries [12].
As no information on competing stroke etiologies was collected in SWISS-AF, we cannot know how many LNCCIs might have been of potential atheroembolic origin, which represents a major limitation of our study. However, it is unlikely that the observed asymmetry in LNCCIs is explained by atherosclerosis of the aortic arch or supra-aortic arteries.
A better understanding of the localization in relation to the size of brain infarcts might be helpful in clinical routine. Focal symptoms and signs originating from right hemispheric lesions may easily be missed by patients and physicians. The proportion of patients with a history of clinically manifest stroke or TIA was consistent with previous population-based studies in AF [1], but 37,1% of patients had an ischemic infarct on MRI (SNCI or LNCCI combined). We have previously shown that covert brain infarcts have a significant impact on cognitive decline in AF [3], and are associated with an increased risk of future strokes [13]. Whether routine brain MRI screening in patients with AF improves risk stratification remains to be elucidated by future prospective studies.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2021.03531.
Supplementary methods
jos-2021-03531-suppl1.pdf
Supplementary Table 1.
Baseline characteristics of patients
jos-2021-03531-suppl2.pdf
Supplementary Table 2.
Infarcts per vascular territory in all patients
jos-2021-03531-suppl3.pdf

Acknowledgments

Anna Altermatt is employee of the Medical Image Analysis Center Basel, Switzerland; Tim Sinnecker is employee of the Medical Image Analysis Center Basel, Switzerland; Stefanie Aeschbacher: none; Anne Springer: none; Michael Coslovsky: none; Juerg Beer reports grants from the Swiss National Foundation of Science, The Swiss Heart Foundation, grants from Bayer, lecture fees from Sanofi Aventis and Amgen, to the institution outside the submitted work; Giorgio Moschovitis reports consultant fees for participating to advisory boards from Novartis, Astra Zeneca, Bayer, and Böhringer Ingelheim, outside of the current work; Angelo Auricchio is a consultant to Boston Scientific, Backbeat, Biosense Webster, Cairdac, Corvia, Microport CRM, EPD-Philips, Radcliffe Publisher. He received speaker fees from Boston Scientific, Medtronic, and Microport. He participates in clinical trials sponsored by Boston Scientific, Medtronic, EPD-Philips. He has intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM; Urs Fischer received research grants for the Swiss National Science Foundation, Swiss Heart Foundation, Medtronic; Consultant for Stryker, Medtronic and CSL Behring; Carole E. Aubert was supported by an Early Postdoc.Mobility grant from the Swiss National Science Foundation (grant P2LAP3_184042); Michael Kühne reports personal fees from Bayer, personal fees from Böhringer Ingelheim, personal fees from Pfizer BMS, personal fees from Daiichi Sankyo, personal fees from Medtronic, personal fees from Biotronik, personal fees from Boston Scientific, personal fees from Johnson&Johnson, personal fees from Roche, grants from Bayer, grants from Pfizer, grants from Boston Scientific, grants from BMS, grants from Biotronik; David Conen speaker fees from BMS/ Pfizer, and consultancy fees from Roche Diagnostics, Switzerland, both outside of the current work; Stefan Osswald: none; Leo H. Bonati received grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the University of Basel. He received consultancy and advisory board fees from Bayer and Bristol-Myers Squibb; and Jens Wuerfel is employee of the Medical Image Analysis Center (MIAC AG) Basel, Switzerland. He is or was supported by grants of the EU (Horizon2020), the Swiss National Science Foundation, the Boehringer Ingelheim Foundation, the Novartis Foundation, the German Federal Ministries of Education and Research (BMBF) as well as Economic Affairs and Energy (BMWI). He has served on advisory boards of Actelion, Apellis, Bayer, Biogen, Cellgene, Genzyme-Sanofi, Idorsia, InmuneBio, Novartis, and Roche.
The Swiss-AF study is supported by grants of the Swiss National Science Foundation (Grant numbers 33CS30_148474, 33CS30_177520, 32473B_176178, 32003B_197524), the Swiss Heart Foundation, the Foundation for Cardiovascular Research Basel, the Foundation for gastroenterological, general clinical and imaging research and analysis, Basel, the Medical Image Analysis Center (MIAC AG) Basel, and the University of Basel.
Swiss-AF investigators
University Hospital Basel and Basel University: Stefanie Aeschbacher, Katalin Bhend, Steffen Blum, Leo Bonati, David Conen, Ceylan Eken, Urs Fischer, Corinne Girroy, Elisa Hennings, Elena Herber, Vasco Iten, Philipp Krisai, Michael Kühne, Maurin Lampart, Mirko Lischer, Nina Mäder, Christine Meyer-Zürn, Pascal Meyre, Andreas U. Monsch, Luke Mosher, Christian Müller, Stefan Osswald, Rebecca E. Paladini, Anne Springer, Christian Sticherling, Thomas Szucs, Gian Völlmin; Principal Investigator: Stefan Osswald; Local principal investigator: Michael Kühne. University Hospital Bern: Faculty (Drahomir Aujesky, Juerg Fuhrer, Laurent Roten, Simon Jung, Heinrich Mattle); Research fellows (Seraina Netzer, Luise Adam, Carole Elodie Aubert, Martin Feller, Axel Loewe, Elisavet Moutzouri, Claudio Schneider); Study nurses (Tanja Flückiger, Cindy Groen, Lukas Ehrsam, Sven Hellrigl, Alexandra Nuoffer, Damiana Rakovic, Nathalie Schwab, Rylana Wenger, Tu Hanh Zarrabi Saffari); Local principal investigator: Nicolas Rodondi, Tobias Reichlin.
Stadtspital Triemli Zurich: Christopher Beynon, Roger Dillier, Michèle Deubelbeiss, Franz Eberli, Christine Franzini, Isabel Juchli, Claudia Liedtke, Samira Murugiah, Jacqueline Nadler, Thayze Obst, Jasmin Roth, Fiona Schlomowitsch, Xiaoye Schneider, Katrin Studerus, Noreen Tynan, Dominik Weishaupt; Local principal investigator: Andreas Müller.
Kantonspital Baden: Simone Fontana, Corinne Friedli, Silke Kuest, Karin Scheuch, Denise Hischier, Nicole Bonetti, Alexandra Grau, Jonas Villinger, Eva Laube, Philipp Baumgartner, Mark Filipovic, Marcel Frick, Giulia Montrasio, Stefanie Leuenberger, Franziska Rutz; Local principal investigator: Jürg-Hans Beer.
Cardiocentro Lugano: Angelo Auricchio, Adriana Anesini, Cristina Camporini, Giulio Conte, Maria Luce Caputo, Francois Regoli; Local principal investigator: Tiziano Moccetti.
Kantonsspital St. Gallen: Roman Brenner, David Altmann, Michaela Gemperle; Local principal investigator: Peter Ammann.
Hôpital Cantonal Fribourg: Mathieu Firmann, Sandrine Foucras, Martine Rime; Local principal investigator: Daniel Hayoz.
Luzerner Kantonsspital: Benjamin Berte, Virgina Justi, Frauke Kellner-Weldon, Brigitta Mehmann, Sonja Meier, Myriam Roth, Andrea Ruckli-Kaeppeli, Ian Russi, Kai Schmidt, Mabelle Young, Melanie Zbinden; Local principal investigator: Richard Kobza.
Ente Ospedaliero Cantonale Lugano: Elia Rigamonti, Carlo Cereda, Alessandro Cianfoni, Maria Luisa De Perna, Jane Frangi-Kultalahti, Patrizia Assunta Mayer Melchiorre, Anica Pin,Tatiana Terrot, Luisa Vicari; Local principal investigator: Giorgio Moschovitis.
University Hospital Geneva: Georg Ehret, Hervé Gallet, Elise Guillermet, Francois Lazeyras, Karl-Olof Lovblad, Patrick Perret, Philippe Tavel, Cheryl Teres; Local principal investigator: Dipen Shah,
University Hospital Lausanne: Nathalie Lauriers, Marie Méan, Sandrine Salzmann, Jürg Schläpfer; Local principal investigator: Alessandra Pia Porretta.
Bürgerspital Solothurn: Andrea Grêt, Jan Novak, Sandra Vitelli; Local principal investigator: Frank-Peter Stephan.
Ente Ospedaliero Cantonale Bellinzona: Jane Frangi-Kultalahti, Augusto Gallino, Luisa Vicari; Local principal investigator: Marcello Di Valentino.
University of Zurich/University Hospital Zurich: Helena Aebersold, Fabienne Foster, Matthias Schwenkglenks.
Medical Image Analysis Center AG Basel: Jens Würfel (Head), Anna Altermatt, Michael Amann, Marco Düring, Petra Huber, Esther Ruberte, Tim Sinnecker, Vanessa Zuber.
Clinical Trial Unit Basel: Michael Coslovsky (Head), Pascal Benkert, Gilles Dutilh, Milica Markovic, Pia Neuschwander, Patrick Simon.
Schiller AG Baar: Ramun Schmid.

Figure 1.
The distribution of infarcts. Figure depicting the voxel-based sum of all large cortical and non-cortical infarcts and small non-cortical infarcts overlaid on an age-specific standard brain template. The color scale indicates the number of patients with an infarct in a given voxel.
jos-2021-03531f1.jpg

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