Translational Research on Heart Failure and Arrhythmias

translational-research-heart-failureResearch overview

Heart failure, sudden death, and atrial fibrillation are often manifestations of cardiomyopathies and chronic cardiac damage. We study the effects of genetic factors for the development of heart failure, atrial fibrillation, and sudden death. We use molecular biology, imaging, and physiological techniques to identify mechanisms leading to these diseases, work on novel ways to develop and validate personalized approaches to diagnose and treat patients with these conditions, and test interventions in experimental models and in clinical trials.

Our research group

We use cellular and integrated physiological measurements, molecular biology, and imaging techniques to characterise heart function in transgenic models. These allow us to identify molecular mechanisms of cardiac dysfunction (e.g. in inherited cardiomyopathies) and help to delineate new therapeutic targets for personalized treatment of heart failure and arrhythmias.

Our group works closely with other research groups on campus and in the two major NHS trusts (UHB and SWBH) in Birmingham. We maintain research contacts with the German Atrial Fibrillation NETwork and with the Medical Faculty at the University of Münster, and collaborate with professional organisations and research networks in Britain and Europe. Together with these partners, we explore possibilities to translate new insights into hypotheses that can be tested in clinical trials and/or in biobanks, with the final goal to improve treatment of patients suffering from heart failure, atrial fibrillation, and/or to prevent sudden death using personalized approaches to diagnosis and therapy.

Current projects

  • Deciphering the genetic topology of atrial fibrillation
  • Understanding the function of pitx2 in the left atrium
  • Translating mechanisms of AF into new diagnostic and therapeutic modalities
  • Sodium channel dysfunction and its contribution to heart failure and arrhythmias
  • Understanding the relevance of desmosomal proteins for right heart function and failure
  • Improving outcomes by early rhythm control therapy in atrial fibrillation

Recent publications

Syeda F, Holmes AP, YuTY, Tull S, Kuhlmann SM, Pavlovic D, Betney D, Riley G, Kucera JP, Jousset F, de Groot JR, Rohr S, Brown NA , Fabritz L, Kirchhof P. 2016. PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers.  Journal of the American College of Cardiology. Vol. 68, issue 17, 2016, p. 1881-1894.

Ponomaryov T, Payne H, Fabritz L, Wagner DD, Brill A. 2017.  Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice. Circulation Research.

Kotecha D, Calvert M, Deeks JJ, Griffith M, Kirchhof P, Lip GYH, Mehta S, Slinn G, Stanbury M, Steeds RP, Townend JN. A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial. BMJ Open. 2017: DOI: 10.1136/bmjopen-2016-015099

Schnabel RB, Pecen L, Ojeda FM, Lucerna M, Rzayeva N, Blankenberg S, Darius H, Kotecha D, Caterina R, Kirchhof P. Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation. Heart, published on line February 2017.

Di Biase L, Callans D, Georg Haeusler K, Hindricks G, Al-Khalidi H, Mont L, Cosedis Nielsen J, Piccini JP, Schotten U, Kirchhof P. Rationale and design of AXAFA-AFNET 5: an investigator-initiated, randomized, open, blinded outcome assessment, multi-centre trial to comparing continuous apixaban to vitamin K antagonists in patients undergoing atrial fibrillation catheter ablation. Europace. 2017;19:132-8. doi:10.1093/europace/euw368 

Kirchhof P. The Future of atrial fibrillation management. Integrated care and stratified therapy. Lancet, published on line April 2017.

Syeda F, Kirchhof P, Fabritz L. PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol. Published on line 19 Feb 2017.

Syeda F, Holmes AP, Yu TY, Tull S, Kuhlmann SM, Pavlovic D, Betney D, Riley G, Kucera JP, Jousset F, de Groot JR, Rohr S, Brown N, Fabritz L, Kirchhof P. PITX2 modulates atrial membrane potential and reduced PITX2 potentiates the antiarrhythmic effects of sodium-channel blockers. J Am Coll Cardiol. 2016;68:59-72; doi: 10.1016/j.jacc.2016.07.766.

Ackers-Johnson M, Li PY, Holmes AP, O'Brien SM, Pavlovic D, Foo RS  A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Non-Myocytes from the Adult Mouse Heart. Circulation Research; 2016; 119(8):909-20.

Fabritz L, Guasch E, Antoniades C, Bardinet I, Benninger G, Betts TR, Brand E, Breithardt G, Bucklar-Suchankova G, Camm AJ, Cartlidge D, Casadei B, Chua WW, Crijns HJ, Deeks J, Hatem S, Hidden-Lucet F, Kaab S, Maniadakis N, Martin S, Mont L, Reinecke H, Sinner MF, Schotten U, Southwood T, Stoll M, Vardas P, Wakili R, West A, Ziegler A, Kirchhof P. Expert consensus document: Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment. Nat Rev Cardiol. 2016;13:230-7.

Kirchhof P, Fabritz L. Can biomarkers balance stroke and bleeding risk? Lancet. 2016;10.1016/S0140-6736(16)30121-0 

Shantsila E, Haynes R, Calvert M, Fisher J, Kirchhof P, Gill PS, Lip GY. IMproved exercise tolerance in patients with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation rationale and design of the IMPRESS-AF randomised controlled trial.BMJ Open. 2016;6:e012241.

Ezekowitz MD, Pollack CV, Sanders P, Halperin JL, Spahr J, Cater N, Petkun W, Breazna A, Kirchhof P, Oldgren J. Apixaban compared with parenteral heparin and/or vitamin K antagonist in patients with nonvalvular atrial fibrillation undergoing cardioversion: Rationale and design of the EMANATE trial. Am Heart J. 2016;179:59-68.

Oto E, Okutucu S, Katircioglu-Ozturk D, Guvenir HA, Karaagaoglu E, Borggrefe M, Breithardt G, Goette A, Ravens U, Steinbeck G, Wegscheider K, Oto A, Kirchhof P. Predictors of sinus rhythm after electrical cardioversion of atrial fibrillation: results from a data mining project on the Flec-SL trial data set. Europace. published on line July 2016.

Holmes AP, Yu TY, Tull S, Syeda F, Kuhlmann SM, O'Brien SM, Patel P, Brain KL, Pavlovic D, Brown NA, Fabritz L, Kirchhof P. A Regional Reduction in Ito and IKACh in the Murine Posterior Left Atrial Myocardium Is Associated with Action Potential Prolongation and Increased Ectopic Activity. PLoS One. 2016;11:e0154077.

Kotecha D, Manzano L, Krum H, Rosano G, Holmes J, Altman DG, Collins PD, Packer M, Wikstrand J, Coats AJ, Cleland JG, Kirchhof P, von Lueder TG, Rigby AS, Andersson B, Lip GY, van Veldhuisen DJ, Shibata MC, Wedel H, Bohm M, Flather MD, Beta-Blockers in Heart Failure Collaborative G. Effect of age and sex on efficacy and tolerability of beta blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ. 2016;353:i1855

Haeusler KG, Kirchhof P, Heuschmann PU, Laufs U, Busse O, Kunze C, Thomalla G, Nabavi DG, Rother J, Veltkamp R, Endres M. Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS): Rationale and design of a prospective randomized multicenter study. Am Heart J. 2016;172:19-25.

Holmes AP, Kirchhof P. Pitx2 Adjacent Noncoding RNA: A New, Long, Noncoding Kid on the 4q25 Block. Circ Arrhythm Electrophysiol. 2016;9, published on line 25 January 2016.

Kirchhof P, Tal T, Fabritz L, Klimas J, Nesher N, Schulte JS, Ehling P, Kanyshkova T, Budde T, Nikol S, Fortmueller L, Stallmeyer B, Muller FU, Schulze-Bahr E, Schmitz W, Zlotkin E, Kirchhefer U. First Report on an Inotropic Peptide Activating TTX-Sensitive, "Neuronal" Sodium Currents in the Heart. Circ Heart Fail 2015; 8: 79-88.

Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD, on behalf of the Beta-Blockers in Heart Failure Collaborative G. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384: 2235-2243.

Yu TY, Syeda F, Holmes A, Osborne B, Dehghani H, Brain KL, Kirchhof P, Fabritz L. An automated system using spatial oversampling for optical mapping in murine atria. Development and validation with monophasic and transmembrane action potentials. Prog Biophys Mol Biol; 2014;115:340-8.

Pavlovic D The role of cardiotonic steroids in the pathogenesis of cardiomyopathy in chronic kidney disease. Nephron Clin Prac; 2014; 128(1-2):11-21. 

For full publication lists see:

Staff

Principal Investigators
Professor Paulus Kirchhof
Dr Larissa Fabritz 
Dr Davor Pavlovic
Dr Dipak Kotecha 

Postdoctoral Researchers
Dr Winnie Chua
Dr Claire Hepburn
Dr Andrew Holmes
Dr Lisa Fortmeller - at University of Münster, Germany

PhD Students and Clinical Research Fellows
Dannie Fobian
Sian-Marie O’Brian
Yanish Purmah
Jawad Qamar
Chris O’Shea
Syed Akbar
Simon Wells
Victor Cardoso

Research Technicians
Syeeda Nashitha Kabir
Clara Apicella

Former Group Members
Sebastian Fischbach
Sarah Hopkins
Marcel Kemper
Stefan Kuhlmann
Pushpa Patel
Dr Genna Riley
Dr Ewa Truchanowicz
Dr Eleni Vloumidi
Sabina Yasin
Ting Yu Yue
Dr Fahima Syeda
Dr Samantha Tull