Prof’in Dr’in Cristina E. Molina

Heisenberg Professur für Kardiale Zelluläre Elektrophysiologie

Universitätsklinikum Hamburg-Eppendorf

• Vorhofflimmern
• Herzinsuffizienz
• 3R
• Drug testing
• Biomarker
• Gentherapie

• Enhanced Ca2+ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation. Circulation Research 2023. DOI: 10.1161/CIRCRESAHA.122.321858
• Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism. European Heart Journal 2023. DOI: 10.1093/eurheartj/ehad086
• Effects of Atrial Fibrillation on the Human Ventricle. Circ Res 2022. DOI: 10.1161/CIRCRESAHA.121.319718
• Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia. Redox Biology 2021. DOI: 10.1016/j.redox.2021.102179
• Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling. Cells. Special Issue "Electrical Remodeling in Cardiac Disease" 2021. DOI: 10.3390/cells10113042
• EWGCCE Position Paper: Relevance, Opportunities and Limitations of Experimental Models for Cardiac Electrophysiology Research. EP Europace, euab142, 2021. DOI: 10.1093/europace/euab142
• cAMP imaging at ryanodine receptors reveals ß2-adrenoceptor driven arrhythmias. Circulation Research 2021. DOI: 10.1161/CIRCRESAHA.120.318234
• Molecular Basis of Atrial Fibrillation Initiation and Maintenance. Hearts 2021. DOI: 10.3390/hearts2010014
• Regulation of basal and norepinephrine-induced cAMP and I Ca in hiPSC-cardiomyocytes: Effects of culture conditions and comparison to adult human atrial cardiomyocytes. Cellular Signalling 2021. DOI: 10.1016/j.cellsig.2021.109970
• Mapping genetic changes in the cAMP-signaling cascade in human atria. Journal of Molecular and Cellular Cardiology 2021. DOI: 10.1016/j.yjmcc.2021.02.006
• Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation. Naunyn-Schmiedeberg's Archives of Pharmacology 2020. DOI: 10.1007/s00210-020-01968-1
• Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Post-Operative Atrial Fibrillation. Circ Res 2020. DOI: 10.1161/CIRCRESAHA.120.316710
• Dysferlin links excitation-contraction coupling to structure and maintenance of the cardiac transverse-axial tubule system. Europace 2020. DOI: 10.1093/europace/euaa093
• cGMP signalling in cardiomyocyte microdomains. Biochem Soc Trans. 2019. DOI: 10.1042/BST20190225
• The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy. ESC Heart Failure 2018. 10.1002/ehf2.12378
• Profibrotic, electrical and calcium-handling remodeling of the atria in heart failure patients with and without atrial fibrillation. Frontiers in Physiology, section Cardiac Electrophysiology 2018. DOI: 10.3389/fphys.2018.01383
• Identification of optimal reference genes for transcriptomic analyses in normal and diseased human heart. Cardiovascular Research 2018. DOI: 10.1093/cvr/cvx182
• Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis. Arrhythm Electrophysiol Rev. 2016. DOI: 10.15420/aer.2016.8.2
• Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes. Basic Res Cardiol 2016. DOI: 10.1007/s00395-015-0525-2
• Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation. Basic Res Cardiol 2015. DOI: 10.1007/s00395-015-0505-6
• Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes. Cardiovasc Res 2015. DOI: 10.1093/cvr/cvv046
• Altered atrial metabolism: an underappreciated contributor to the initiation and progression of atrial fibrillation. J Am Heart Assoc 2015. DOI: 10.1161/JAHA.115.001808
• Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases. J Am Heart Assoc 2014. DOI: 10.1161/JAHA.114.000858
• Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol 2012. DOI: 10.1016/j.jacc.2012.01.060
• Sarcoplasmic reticulum and L-type Ca²⁺ channel activity regulate the beat-to-beat stability of calcium handling in human atrial myocytes. J Physiol 2011. DOI: 10.1113/jphysiol.2010.197715
• Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation. Biochem Biophys Res Commun 2011. DOI: 10.1016/j.bbrc.2011.05.113
• Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors. Eur Heart J 2011. DOI: 10.1093/eurheartj/ehq464

• Deutsche Forschungsgemeinschaft
• Heisenberg
• Gertraud and Heinz Rose Foundation
• Marie Curie Actions Intra-European Fellowships (IEFs)

• www.uke.de/forschung/forschungsschwerpunkte/cardiovascular-research-center-cvrc/forschung/ag-molina.html

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www.researchgate.net/profile/Cristina-Molina-3

orcid.org/0000-0003-3094-1568

“A healthy future demands an excellent science that focuses on humans” Why did we choose to start a scientific career? Why did we specialize in the research field we are in? The driving force in my career was to improve the life and well-being of humans. That was the reason for me to choose the cardiovascular field, the leading cause of death, and atrial fibrillation (AF) specifically, which is the most common cardiac arrhythmia and which highly affects the well-being of patients limiting their health-related quality of life. I have the vision that we can not only improve the health of humans with cardiovascular research, but that we can at the same time significantly reduce the impact of our research e.g. in animal testing. Therefore, I integrated the 3R (Refinement, Reduction, Replacement) approach, or as I would say the 4R (the above mentioned plus Responsibility) approach, into my research. 4R because we as leading scientists are responsible for educating and leading into a future that includes all aspects of a sustainable and responsible research into account. Having worked in Hamburg and seen first-hand the huge demonstrations against animal testing here has sharpened my vision that we also have to take into account, what the public expects from us and that we can always show that we proactively improve the current status. We have furthermore to breed a younger generation of scientists that are willing and capable of improving what we achieved.
Let me give you an insight on what path this thinking has led me so far: I am a 20 years experienced cardiac cellular electrophysiologist. During all these years, I not only built up my expertise in various areas, i.e. electrophysiology or Ca2+-handling and nanodomains, but also used my knowledge to develop my own methods creating an international visibility of my research. A prove of this visibility is my re-election as a nucleus member of the Working Group in Cellular Cardiac Electrophysiology in the European Society of Cardiology. I use patch-clamp, confocal Ca2+ imaging, fluorescence resonance energy transfer (FRET), immunostaining and molecular techniques to study the role of receptor-mediated modulation of ion currents, intracellular Ca2+-handling and second messengers in AF. During the last years, I was specially interested in cyclic nucleotides signaling and how phosphodiesterases (PDEs) can differentially affect cellular nanodomains in human atrial tissue and myocytes (HAMs). Many of these classical and state-of-the-art techniques require the isolation and culture of myocytes. But human myocytes die only few hours after isolation. This has been a problem over the past several decades for all the experts working in cardiac research and one of the main reasons to work with animal models. Animal experimentation in these cases was required. However, current alternative strategies for cardiac research and safety evaluation of drugs in the heart, such as hiPS-CMs or even animal models, have shown significant limitations, resulting in a low percentage of successful therapies when translated to patients. Thereby, during my career I worked with different strategies to develop more predictive, human-relevant preclinical approaches to solve this problem.
I achieved my PhD in Cell Biology with a summa cum laude in 2009 working at Sant Pau Hospital in Barcelona (supervisor: Dr. Leif Hove-Madsen), using patch-clamp techniques and confocal Ca2+ imaging in HAMs from patients with AF. I gained expertise in nanodomains during my first postdoc in France, at the laboratory of Dr. Rodolphe Fischmeister. There I developed my own isolation method which allowed me to transduce and culture, for the first time, HAMs and to monitor cAMP changes in these cells using FRET. I then provided evidence for PDE4 contribution to cytosolic cAMP dynamics in HAMs from sinus rhythm patients (Molina et al., JACC 2012). Afterwards, I obtained an IEF Marie Curie grant. I moved to Germany to deepen my knowledge in the field of AF with Prof. Dr. Dobromir Dobrev and Prof. Dr. Niels Voigt. Since 2018, when I got my group leader position at UKE in Hamburg, I improved the isolation/culture method for human myocytes in order to use it with any kind of cardiac human tissue, from cm to mm sized tissues, atrial or ventricular, from healthy or from diseased patients. Actually, many worldwide recognized experts collaborate with me for translating their research into a human model thanks to this technique (M. Zaccolo, Oxford University; J. Gorelik, Imperial College London; S. Sossalla, UKGM Giessen; VO Nikolaev, UKE).
My plans as a Professor at UKE with my own research team include using this isolation method 1) to transduce HAMs with FRET sensors in order to visualize cAMP, cGMP and CaMKII, 2) to genetically manipulate human myocytes in order to study genes of interest in cardiac diseases and validate gene therapies as a proof-of-concept, and 3) to establish a HAM computational model which includes PDE nanodomains and that will have the potential to predict drug-induced pro-arrhythmia risk.