Stephan Baldus / Martin Mollenhauer / Volker Rudolph - B 2

Summary

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.      

Introduction

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). 

Perspectives 

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.