Stephan Baldus / Martin Mollenhauer / Volker Rudolph - B 2

Inflammatory pathways propagating ventricular arrhythmia - the role of myeloperoxidase for postischemic pro-arrhythmic remodeling

Abstract

Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain potentially lethal cardiac arrhythmia, which are provoked by acute myocardial ischemia and chronically following myocardial scar formation. So far, alterations in myocardial Ca2+ handling, disturbances of intercellular signaling and ventricular fibrosis are considered key events for this disease.
Despite the fact that leukocytes, in particular polymorphonuclear neutrophils (PMN), are abundantly found in the infarct and periinfarct region of the ventricle, a connection between the innate immune system and the ventricle´s susceptibility to arrhythmia remains unclear. We have previously observed that leukocyte-derived myeloperoxidase (MPO), a heme enzyme sequestered by PMN abundantly found in ischemic myocardium, is propagating fibrosis within the atria, thereby facilitating the onset of atrial fibrillation.
Using an array of transgenic mouse and cell culture models as well as in-vivo and ex-vivo electrophysiology we aim to analyze the role of MPO in ventricular proarrhythmic remodeling. We plan to characterize the role of this enzyme in modulating the function of Ca2+/Calmodulin kinase II (CaMKII) in myocytes, the integrity of connexins and the role of MPO in the development of ventricular scar formation.
Given the recent preclinical efforts in the developing specific inhibitors for MPO, the current project will help to point towards a potentially novel treatment strategy for this disease in humans.

Clinical/medical relevance and sustainability in disease understanding

Ventricular tachycardia after ischemic heart disease is a major cause of mortality in western countries, with sparse treatment options. The herein proposed study will investigate the importance of myeloperoxidase (MPO) for ventricular proarrhythmic remodeling following myocardial infarction in mice. This might become therapeutically relevant in the prospect of applying pharmacologic MPO-inhibitors in clinical practice and pinpoint towards MPO as a potential prognostic target in VT development.


Prof. Dr. med. Stephan Baldus

Dept. III of Internal Medicine

Prof. Dr. med. Stephan Baldus

Principal Investigator B 2
Executive Board Member

stephan.baldus@uk-koeln.de

Work +49 221 478 32512

Fax (Work) +49 221 478 32512

Heart Center Dept. III of Internal Medicine
Kerpener Str. 62
50937 Cologne

http://herzzentrum.uk-koeln.de/de/kardiologie

Publications - Stephan Baldus

Link to PubMed


Dr. rer. nat. Martin Mollenhauer

Dept. III of Internal Medicine

Dr. rer. nat. Martin Mollenhauer

Co-Principal Investigator B 2

martin.mollenhauer@uk-koeln.de

Heart Center University Hospital Cologne
Kerpener Str. 62
50937 Cologne

Publications - Martin Mollenhauer

Link to PubMed


Prof. Dr. med. Volker Rudolph

Dept. III of Internal Medicine

Prof. Dr. med. Volker Rudolph

Co-Principal Investigator B 2

volker.rudolph@uk-koeln.de

Work +49 221 478 32495

Fax (Work) +49 221 478 32400

Heart Center University Hospital Cologne
Kerpener Str. 62
50937 Cologne

http://herzzentrum.uk-koeln.de/de/kardiologie/forschung/ag_rosenkranz

Publications - Volker Rudolph

Link to PubMed

Group Members

Martin Mollenhauer (PhD)
Tanja Rudolph (MD)
Kai Friedrichs (MD)
Matti Adam (MD)
Dennis Mehrkens (MD)
Anne-Kathrin Schätzle (MD)
Jürgen Konradi (MD)
Kashish Manchanda (PhD student)
Charlotte Kaltwasser (cand. med.)
David Muders (cand. med.)
Simon Geißen (cand. med.)
Martin Toubartz (cand. med.)
Max Lange (cand. med.)
Jan Gesenberg (cand. med.)
Matthias Berlin (cand. med.)
Johanna Schneider (cand. med.)
Christina Schroth (Technician)
Christina Kerkenpaß (Technician)
Iris Berg (Study nurse)