We wish everyone a happy holiday season and a happy, healthy and successful 2018! We are grateful for the many interesting projects and collaborations that we have had the opportunity to work on in 2017 and are looking forward to continuing these successful collaborations (and establishing new ones!) in the year to come!
Two editorials and one review addressing a wide range of topics related to cardiac electrophysiology and signaling have been published recently. In an editorial for the International Journal of Cardiology, we discuss the paper by Alhede et al. which identified that antiarrhythmic drugs are better than ablation at preventing atrial ectopy, whereas ablation is better at preventing recurrence of atrial fibrillation. These data suggest that there may be ‘benign’ (non-AF-inducing) and malignant (AF-inducing) premature atrial complexes and that antiarrhythmic drugs may not be able to prevent the malignant ones. In another editorial for Circulation Arrhythmia and Electrophysiology, we discuss the antiarrhythmic potential of small-conductance calcium-activated potassium (SK) channels. Finally, in a review for Laboratory Investigation, we provide an update on the regulation of G-proteins by nucleoside diphosphate kinases and caveolins. The full references are listed below and a complete overview of all publications can be found on the publications page:
Heijman J, Dobrev D, Crijns HJGM (2017). Targeting supraventricular ectopic
complexes: Which approach should be used and how does it affect atrial
fibrillation? Int J Cardiol. 244:202-203.
Heijman J, Dobrev D (2017). Inhibition of Small-Conductance Ca2+-Activated K+
Channels: The Long-Awaited Breakthrough for Antiarrhythmic Drug Therapy of Atrial
Fibrillation? Circ Arrhythm Electrophysiol. 10(10). pii: e005776.
Abu-Taha IH, Heijman J, Feng Y, Vettel C, Dobrev D, Wieland T (2017). Regulation of
heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update.
Lab Invest. Oct 16 Epub ahead of print.
On August 22, the entire team came together for pizza and drinks to celebrate the summer and the excellent results achieved so far this year!
The month of July was a festive month for the lab with two graduation ceremonies! On July 12, 2017, Bart van Sloun completed his Master thesis internship “From Form to Function in Heart Muscle Cells” with the official graduation ceremony of the Master Systems Biology of Maastricht University. Bart will continue to work in the lab over the summer before starting as a PhD student at the Maastricht Center for Systems Biology on October 1.
On July 19, 2017, Pegah Erfanian-Trudrung successfully defended her PhD thesis “Experimental Analysis and Computer Modeling of the Sarcoplasmic Reticulum Ca2+-ATPase in Atrial Fibrillation” at the Faculty of Medicine, University Duisburg-Essen, Germany. Pegah is currently working as a pharmacist in Dortmund, Germany. Many congratulations to both for these important achievements!
Our recent article about the role of β-adrenergic receptor stimulation in repolarization alternans in post-infarction border zone cardiomyocytes published in Am. J. Physiol. Heart Circ. Physiol. has been selected as featured article! As part of this nomination, a podcast was recorded in which we discuss the impact of our work with Dr. Crystal Ripplinger (consulting editor) and Dr. Thomas Hund (external expert). This podcast is now available on the AJP Heart podcast website.
Repolarization alternans has been implicated in ventricular arrhythmogenesis and sudden cardiac death, particularly in the infarct border zone (BZ). There exist conflicting data about the effect of sympathetic hyperinnervation on alternans formation and arrhythmogenesis in the BZ. However, detailed experimental characterization of the role of hyperinnervation in BZ arrhythmias is challenging due to the numerous distinct effects of post-infarction remodeling and the diversity of species-specific (sub)cellular mechanisms controlling calcium handling, alternans, and other pro-arrhythmic factors, all of which are modulated by sympathetic stimulation. In this manuscript, we characterized the interplay of BZ electrophysiological remodeling and sympathetic stimulation on alternans formation by fusing an existing state-of-the-art computational model of βAR stimulation in the canine ventricular cardiomyocyte with a model of post-infarction electrophysiological remodeling in the BZ. Our results indicate that βAR stimulation can indeed suppress alternans and we identified a critical role for the regulation of SR calcium release, both through activation of RyR2 channels and indirectly through regulation of SR calcium load, in the suppression of alternans.
Reference: Tomek J, Rodriguez B, Bub G, Heijman J (2017) β-adrenergic receptor stimulation inhibits proarrhythmic alternans in post-infarction border zone cardiomyocytes: a computational analysis. Am J Physiol Heart Circ Physiol, Published online on May 26, 2017 – [PubMed]
A brief communication investigating the role of inhibitor-1, a modulator of protein phosphatase 1 (PP1), in the regulation of the cardiac ryanodine receptor type-2 (RyR2) channel appeared online today. The work from the group of Dr. Stefan Neef, University of Regensburg, Germany, to which we contributed, demonstrates that I-1 acutely modulates the activity of the calcium/calmodulin-dependent kinase II (CaMKII) by regulating PP1 activity. However, although ablation of I-1 should thus limit CaMKII-activation, CaMKII activity was exaggerated under β-adrenergic stress upon chronic loss of I-1 in knockout mice. Experimental and computational studies suggest that this is due to chronic upregulation of the exchange protein activated by cAMP (EPAC), leading to augmented CaMKII activation.
Neef S, Heijman J, Otte K, Dewenter M, Saadatmand A. R, Meyer-Roxlau S, Antos C. L, Backs J, Dobrev D, Wagner M, Maier L. S, El-Armouche A (2017) Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity. Naunyn Schmiedeberg’s Arch Pharmacol, Epub. [Pubmed]
In February, Henry Sutanto joined the team as a PhD student working on the computational modeling of cardiomyocyte calcium handling and its role in arrhythmias. Henry studied medicine and graduated from the Faculty of Medicine, Airlangga University in Surabaya, Indonesia in 2011. Thereafter, he worked as an intern doctor in Caruban General Hospital, East Java for a year and was appointed General Practitioner for 3 years in the District Health Agency of Surabaya. He continued his education with a master in cardiovascular science at the Institute of Cardiovascular Science (ICS), University College London (UCL), the United Kingdom in 2015. In 2016, He passed his master degree with distinction after defending my master thesis, entitled “Bioinformatic analysis of variants associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in a large whole exome sequencing dataset”. Moreover, this thesis received the best dissertation award from the board of examiners.
This week, two new papers that were recently accepted have become available online. In the first paper, a collaboration with the group of Prof. Dierk Thomas, Heidelberg University, we investigated the role K2P3.1 channel remodeling in patients with atrial fibrillation and/or left ventricular dysfunction. We found opposite regulation of these channels in both conditions, which affects the channel’s potential as an antiarrhythmic target and highlights the need for tailored therapeutic approaches. In the second paper, we review the role of serine/threonine phosphatases in atrial fibrillation.
Serine/Threonine Phosphatases in Atrial Fibrillation.
Heijman J, Ghezelbash S, Wehrens XH, Dobrev D.
J Mol Cell Cardiol. 2017 Jan 7. Epub ahead of print [Pubmed]
Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy.
Schmidt C, Wiedmann F, Zhou XB, Heijman J, Voigt N, Ratte A, Lang S, Kallenberger SM, Campana C, Weymann A, De Simone R, Szabo G, Ruhparwar A, Kallenbach K, Karck M, Ehrlich JR, Baczkó I, Borggrefe M, Ravens U, Dobrev D, Katus HA, Thomas D.
Eur Heart J. 2017 Jan 4. Epub ahead of print [Pubmed]
2017 is off to a good start for the lab with the publication of a podcast on cardiac computational modeling presented by Jordi Heijman, which was published on the website of the ‘Scientists of Tomorrow’ of the European Society of Cardiology (ESC). In this podcast, which was recorded during a visit to the University of Göttingen, Jordi describes some of the basic methods for computational modeling of cardiac electrophysiology and gives a demonstration of the Myokit software tool.
The podcast can be found here.