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 K_2P3.1 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.

References:

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 K_2P3.1 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.

Heart failure (HF) remains a common cause of death and disability and is associated with altered signal transduction via b-adrenoceptors and G proteins, resulting in reduced adenylyl cyclase-mediated cAMP formation and contributing to contractile dysfunction. Nucleoside diphosphate kinases (NDPKs) can modulate G-protein activity and are enriched at the plasma membrane of end-stage HF patients. However, their relevance for HF pathophysiology is largely unknown, particularly for the NDPK‑C isoform.

Together with collaborators from various centers in Germany and abroad, Jordi Heijman published a study in the most recent edition of Circulation, showing for the first time a potential critical role for NDPK-C in the suppression of cAMP formation in HF patients. In particular, this study identified that NDPK-C is crucial for the interaction between NDPKs and G proteins, building complexes and scaffolding them at the plasma membrane. These interactions regulate cAMP levels and cardiomyocyte contractility. In HF patients, NDPK-C switched from predominantly Gas stimulation to activation of Gai. Our findings provide a potential mechanism for the detrimental decrease in cAMP and related dysfunction previously described in HF patients, and position NDPK‑C as a novel critical determinant of bAR/cAMP signaling that contributes to impaired cardiac function and remodeling in human HF.

Reference: Abu-Taha IH*, Heijman J*, Hippe HJ, Wolf NM, El-Armouche A, Nikolaev VO, Schäfer M, Würtz CM, Neef S, Voigt N, Baczkó I, Varró A, Müller M, Meder B, Katus HA, Spiger K, Vettel C, Lehmann LH, Backs J, Skolnik EY, Lutz S, Dobrev D^#, Wieland T^# (2016) Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure. Circulation, Published online on Dec 7, 2016. *equally contributing first authors, #co-senior and co-correspondence authors – [PubMed]

In response to the New Scientist nomination and the recent newspaper article in Dagblad de Limburger, Jordi Heijman has been asked to appear on the daily evening show of the local TV channel L1 called ‘Avondgasten‘. The show will be recorded on Tuesday, November 29, 2016 and will air that same evening at 17:55 h, with re-runs on 20:55 and 22:55 hours. In the show, Jordi will discuss his research on computational approaches to understand heart rhythm disorders.

Update November 30, 2016: The video of the interview can be found here

In response to the nomination by New Scientist, Jordi Heijman was interviewed by the local newspaper ‘Dagblad de Limburger’. The resulting article, entitled ‘The mathematics of the heart’ was published Saturday, November 5th.

During the 2016-2017 academic year, Bart van Sloun, a master student in the Systems Biology research master at Maastricht University, will write his thesis in the team. Bart will investigate subcellular structure-function relationships that influence cardiomyocyte calcium handling using super-resolution microscopy and computational modeling.