Stephan Baldus / Martin Mollenhauer / Volker Rudolph - B 2

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


Ventricular tachycardia after ischemic heart disease is a major cause of mortality in western countries with sparse treatment options. This study investigates the importance of the leukocyte derived enzyme myeloperoxidase (MPO) for ventricular pro-arrhythmic remodeling following myocardial infarction in mice. We now could show that MPO contributes to the development of induced and spontaneous ventricular tachycardias (VT) by disrupting the homogenous ventricular conduction in two murine models of ischemic cardiomyopathy.      


Among the several mechanisms linked to ventricular arrhythmia induction following ischemic myocardial damage, electrical reentry has evolved as particularly important. It involves areas of functional conduction block, around which electrical conduction travels to leave the initially excited area enough time to regain excitability. A variety of structural and functional alterations have been suggested as underlying mechanisms: fibrosis, reduction and functional impairment of connexins and gap-junctions, and decreased ionic currents of Na+, Ca2+ and K+. In this regard MPO gains potential significance since:  a) MPO is secreted and lastingly activated following myocardial ischemia in the myocardium at risk and b) based on its prooxidant properties – MPO is potentially involved in structural and functional alterations yielding ventricular arrhythmia. 

Hererin, we subjected wild-type (WT) and MPO-deficient (Mpo-/-) mice to two models of ischemic cardiomyopathy and investigated the myocardial electrical remodeling.

MPO´s impact on VT inducibility 

WT- and Mpo-/- mice were subjected to 30 minutes of myocardial ischemia followed by 7 days of reperfusion (I/R) or permanent ischemia for 21 days (PI). Electrocardiographic recordings (ECG) and ventricular burst stimulation were performed with an intracardiac octapolar electrophysiological catheter (EPU). WT mice exhibited increased vulnerability to ventricular tachycardias (VT) (representative electrocardiograms in Figure 1A, B) as compared to sham-operated animals (WT sham) with respect to the number of VT episodes (Figure 1C) and the duration of VTs (Figure 1D). In comparison, Mpo-/- mice undergoing I/R (Mpo-/- I/R) or permanent ischemia (Mpo-/- PI) showed a significantly reduced vulnerability for VT episodes and duration (Figure 1C, 1D).

MPO and spontaneous VT development

To assess the spontaneous VT development after ischemic injury in vivo, telemetric transmitters were implanted and ECGs of WT and Mpo-/- mice were recorded after 24 hours of PI and additional challenge with isoproterenol. Here, Mpo-/- mice showed a significantly less frequent development of spontaneous VT as compared to WT animals (representative ECG traces are shown in Figure 2A). Furthermore, the probability of VT induction was lower, VT freedom was longer, VT number and mean time of VT episodes were lower (Figure 2B, C, D, E) revealing a significant role of MPO in the development of ventricular arrhythmias after myocardial ischemic injury.

MPO and left ventricular conduction

Inhomogeneous ventricular conduction after cardiac ischemic injury contributes to the development of VT. To reveal the role of MPO in electrical ventricular remodeling epicardial mapping studies in spontaneously beating hearts were performed by 32-multielectrode arrays in vivo. Mapping analyses revealed a disruption of conduction homogeneity in WT animals following I/R and PI, whereas in Mpo-/- mice electrical conduction was preserved in both models, as ascertained by respective differences in the inhomogeneity index, absolute inhomogeneity, the variation coefficient of local phase delays and the mean conduction velocity (Figure 3 C,D,E). 


The current data point towards an important causal role of MPO in myocardial electrical remodeling in two different murine models of ischemic injury. Ongoing experiments will disclose whether MPO also modulates Ca-homeostasis, ion channel function and cardiomyocyte-fibroblast coupling in mice subjected to ischemic injury. Moreover, underlying molecular mechanisms like CaM-kinase II- or matrix-metalloproteinase activation will be unravelled. Furthermore, the translational relevance of these findings shall be determined by using MPO-inhibitors in vivo and in vitro.     

Selected publications

Rudolph, V., Andrié, R. P., Rudolph, T. K., Friedrichs, K., et al. (2010). Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 16, 470-474 

Mollenhauer, M. et al. (2017) Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. Circ Res. 2017 Jun 23;121(1):56-70

Prof. Dr. Stephan Baldus

Dept. III of Internal Medicine / RG location

Prof. Dr. Stephan Baldus

Principal Investigator B 2
Executive Board Member

Work +49 221 478 32512

Fax (Work) +49 221 478 32512

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

Publications - Stephan Baldus

Link to PubMed

Dr. Martin Mollenhauer

Dept. III of Internal Medicine

Dr. Martin Mollenhauer

Co-Principal Investigator B 2

Work +49 221 478 87445

Heart Center University Hospital Cologne
Kerpener Str. 62
50937 Cologne

Publications - Martin Mollenhauer

Link to PubMed

Prof. Dr. Volker Rudolph

Dept. III of Internal Medicine

Prof. Dr. Volker Rudolph

Co-Principal Investigator B 2

Work +49 221 478 32495

Fax (Work) +49 221 478 32400

Heart Center University Hospital Cologne
Kerpener Str. 62
50937 Cologne

Publications - Volker Rudolph

Link to PubMed

Group Members

Tanja Rudolph (MD)
Kai Friedrichs (MD)
Anna Klinke (PhD)
Dennis Mehrkens (MD)
Senai Bokredenghel (MD)
Max Wißmüller (MD)
imon Braumann (MD)
Anne-Kathrin Schätzle (MD)
Karen Gerke (cand. med.
Charlotte Kaltwasser (cand. med.)
David Muders (cand. med.)
Simon Geißen (cand. med.)
Johannes Dohr (cand. med.)
Gülsah Duman (cand. med.)
Nam Guy Im (cand. Med.)
Lisa Remane (cand. med.)
Simon Grimm (Technician)
Christina Schroth (Technician)
Iris Berg (Study nurse)

Figure 1

Vulnerability to ventricular arrhythmias: Representative surface (top panel) and intracardiac (bottom panel) ECG recordings of electrical ventricular stimulation of WT and Mpo-/- mice after (A) ischemia and 7 days of reperfusion (I/R) and (B) 21 days upon permanent ischemia (PI). (C) Number of episodes of ventricular tachycardia (VT) and (D) total time of VT after I/R and PI. sham: n=4; WT / Mpo-/- I/R n=8/9; WT / Mpo-/- PI n=6/11. *=P<0.05, **=P<0.01, ***=P<0.001.

Figure 2

Analysis of ventricular tachycardia after 24 hrs of PI: (A) Representative ECG-traces recorded by telemetric investigations (for 2 hrs) before (lower panel) and after 24 hrs of PI and two isoproterenol injections (2 mg/kg BW) (upper panel) in WT and Mpo-/- animals. Analyses of (B) VT probability, (C) onset of VT, (D) mean number of VT episodes and (E) mean time of VT episodes in WT and Mpo-/- animals. n=10/10. *=P<0.05.

Figure 3

Epicardial mapping analyses: Representative maps of spontaneous conduction in the periinfarct region of WT and Mpo-/- hearts (A) after left ventricular ischemia and 7 days of reperfusion (I/R) and (B) 21 days upon permanent ischemia PI (from dark red to dark blue, bars indicate total time from first to last measurement within one heartbeat). (C) Inhomogeneity index, (D) absolute inhomogeneity, (E) variation coefficient of conduction of WT and Mpo-/- hearts. sham n=5; WT I/R / Mpo-/- I/R n=6/6; WT PI / Mpo-/- PI n=7/5. *=P<0.05, **=P<0.01, ***=P<0.001.