Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Post-Operative Atrial Fibrillation

Post-operative atrial fibrillation (POAF) is a common complication after surgery, affecting ~30% of patients undergoing open-heart surgery. POAF-management remains challenging, partly due to incomplete understanding of underlying mechanisms. Although there is clinical evidence pointing to the presence of a pre-surgical vulnerable substrate contributing to POAF development, its nature and role in POAF development were largely unknown until now.

In an extensive multi-year effort with numerous international collaborators, Henry Sutanto and Jordi Heijman have provided new insight into the mechanisms of POAF. The study, which was published online in Circulation Research on July 30th, employed state-of-the-art biochemical and electrophysiological analyses in 265 human atrial samples and advanced in silico models to identify the presence of a subclinical pre-surgical atrial cardiomyopathy comprising NLRP3-inflammatory signaling and CaMKII-mediated calcium-handling changes that predispose POAF-patients to AF development. 

In addition, acute IL-1β stimulation activates a self-amplifying feed-forward loop promoting NLRP3-inflammasome activation and CaMKII-dependent RyR2 hyperphosphorylation, exacerbating proarrhythmic cardiomyocyte Ca2+-handling abnormalities. Thus, this preexisting substrate determines which atria will cross the AF threshold, initiating POAF, when acted upon by post-operative triggers. These observations provide a unifying model of AF involving a vulnerable substrate and inflammatory triggering that accounts for the transient occurrence of POAF post-operatively along with the high long-term AF recurrence rate in POAF patients.

Heijman J*, Muna AP*, Veleva T, Molina CE, Sutanto H, Tekook M, Wang Q, Abu-Taha I, Gorka M, Künzel S, El-Armouche A, Reichenspurner H, Kamler M, Nikolaev VO, Ravens U, Li N, Nattel S, Wehrens XHT, Dobrev D (2020) Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Post-Operative Atrial Fibrillation. Circ Res. Epub July 30, 2020. *equally contributed first authors

Graduation Cristian Barrios

After defending his Master Thesis research via Zoom with a presentation on “Assessing Outcomes and Risk Factors Of Atrial Fibrillation Through A Lifetime Population-Level Markov Model“, Cristian Barrios Espinosa officially graduated from the Master Systems Biology program on July 6th during an online ceremony. Cristian received an 8.8 out of 10 for his master thesis research and graduated cum laude. Congratulations! From September 2020 onwards, Cristian will be working as a PhD student at the Karlsruhe Institute of Technology, Germany, as part of the Marie-Curie ITN project PersonalizeAF.

Jordi Heijman promoted to Associate Professor

From November 1st 2019 onwards, Dr. Jordi Heijman has been promoted to Associate Professor at the Department of Cardiology, Maastricht University. After several years of postdoctoral research in Germany, Jordi returned to Maastricht in 2015. Together with a team of highly motivated students, his ambition is to improve our mechanistic understanding and treatment of cardiovascular diseases through a combined computational-experimental approach.

MSc student Cristian Barrios Espinosa joins the team

During the 2019-2020 academic year, Cristian Barrios Espinosa, a master student in the Systems Biology research master at Maastricht University, will write his thesis in the team. Cristian has a degree in theoretical mathematics (2006-2011 from the Universidad Sergio Arboleda) and another degree in medicine (2008-2014 from the Pontificia Universidad Javeriana), both in Bogota, Colombia. As part of his MSc thesis, he will develop a patient-level model for atrial fibrillation patients to reduce the gap between mechanistic and statistical models.

New manuscript: A novel computational tool for better understanding of antiarrhythmic drugs

Cardiac arrhythmias remain a global burden. Antiarrhythmic drugs (AADs) can be beneficial for the acute and long-term management of cardiac arrhythmias, but may also have proarrhythmic side effects. Therefore, understanding the cellular mechanisms-of-action of such drugs is important, yet challenging. In this new paper, we present the Maastricht ANTiarrhythmic drugs evAluator (MANTA), an educational tool to better understand the basic electrophysiological features of AADs. We incorporated 17 widely used computational models of cardiac cellular electrophysiology and a library of 24 AADs from various Vaughan-Williams classes into the tool, which is built using the support of Myokit. We also included state-of-the-art state-dependent regulation of INa to simulate more realistically the effects of class I AADs. MANTA facilitates the simulation of various conditions (e.g. hypo/hyperkalemia, hypo/hypernatremia, hypo/hypercalcemia, tachycardia, bradycardia, etc.) and comparison of APD, dV/dtmax, RMP and ERP from two different models side-by-side. Using MANTA we demonstrated the species-, concentration- and frequency-dependent effect of AADs. Finally, we showed how disease-related electrical remodeling can alter AAD effects. Information on how to obtain MANTA can be found here.

Henry Sutanto attends Computational Physiology Summer School

Henry Sutanto, a PhD student in the lab, received an opportunity to attend the Simula Summer School in Computational Physiology (SSCP) 2019, which was held by Simula Research Laboratory – University of Oslo and UC San Diego (California). This summer school was fully supported by a Simula Travel Grant (15,000 NOK) and took place in Oslo (2 weeks) and San Diego (1.5 weeks). During the summer, Henry worked together with Ana Maria Sanchez de la Nava (Hospital GU Gregorio Marañón, IiSGM, CIBERCV,Madrid – PI Maria Guillem, PhD) and Savannah Bifulco (University of Washington, Seattle – PI Patrick Boyle PhD) on a project entitled “Machine learning tools to uncover ischemic markers in a population of image-based virtual hearts”. This summer project was supervised by three outstanding Simula supervisors: Valeriya Naumova, PhD; Hermenegild Arevalo, PhD and Per Magne Florvaag, and was presented in UC San Diego in August 2019. Overall, their summer project is the first to employ machine learning on cardiac fibrosis detection in patient-specific virtual hearts.

Summer Internship Su Min Pack

During the summer, Su Min Pack, a bachelor student of the Biomedical Sciences program at Maastricht University, will join the team to obtain experience doing cardiovascular research. Su Min will help to integrate a recently published model of the human induced pluripotent stem cell (hIPSC)-derived cardiomyocyte into our Maastricht Antiarrhythmic Drug Evaluator (MANTA) tool, thereby facilitating comparisons between the electrophysiological response of hIPSC-derived cardiomyocytes and adult human cardiomyocytes to different drugs.

Graduation Lian Laudy

On July 11, 2019, Lian Laudy successfully completed her Masters with the official graduation ceremony of the Master Systems Biology of Maastricht University. She received an excellent grade (8.9/10) for her Master thesis research “Computational modelling of calcium-dependent signalling pathways and their long-term effects on cardiac calcium handling and arrhythmogenesis” and graduated cum laude – congratulations! Since then, Lian has started working as a PhD student in the team of Dr. Joost Lumens at the Department of Biomedical Engineering on a joint project and will continue to be involved in the lab.

Panel Discussion at Gordon Research Seminar

Last week, Jordi Heijman participated in the panel discussion ‘How to build your own lab’ together with Profs. Patrick Boyle, Ursula Ravens and Crystal Ripplinger during the 2019 edition of the Gordon Research Seminar on Cardiac Arrhythmia Mechanisms, which took place in Lucca (Barga) , Italy. During the lively discussion, a wide range of topics, including obtaining faculty positions, setting up a lab, and maintaining a reasonable work-life blend were addressed. The discussion was moderated by Drs. Axel Loewe and Mathilde Rivaud, chairs of this edition of the Gordon Research Seminar.