Österreichische Kardiologische Gesellschaft Jahrestagung 2018
Featured Poster Session 1
Novel regulators of cardiomyocyte proliferation
and regeneration in mouse and human
T. Schuetz, T. Dolejsi, M. Adamowicz-Brice,
C. Morgan, T.
J. Aitman, J.
Department of Internal Medicine III, Cardiology, Innsbruck
Medical University, Innsbruck, Austria
Centre for Genomic and Experimental Medicine, University of
Edinburgh, Edinburgh, United Kingdom
Imperial College, National Heart and Lung Institute, Faculty
of Medicine, London, United Kingdom
Institute of Molecular Biotechnology of the Austrian Academy
of Sciences, Vienna, Austria
e adult m
ammalian heart has little regen-
erative capacity after myocardial infarction (MI) while neonatal
mouse hearts regenerate without scarring or dysfunction. How-
ever, the underlying pathways and responsible coding and non-
coding transcripts are poorly dened.
e sought to derive insights into the pathways
regulating neonatal development of the mouse heart and car-
diac regeneration post-MI.
Methods and Results:
erforming RNA-seq on neonatal
mouse hearts through the rst 10 days of postnatal life revealed
changes in the coding and non-coding transcriptome after neo-
natal MI, with evidence of essentially complete healing by P10.
Over two thirds of each of the mRNAs and microRNAs that were
dierentially expressed in the post-MI heart were also dieren-
tially expressed during normal postnatal development, suggest-
ing a common regulatory pathway for normal cardiac develop-
ment and post-MI cardiac regeneration.
We selected exemplars of miRNAs that were implicated
in our data set as regulators of cardiomyocyte proliferation.
Several of these showed evidence of a functional inuence
on mouse cardiomyocyte cell division. In addition, a sub-
set of these microRNAs, miR-144-3p, miR-195a-5p, miR-451a
and miR-6240 showed evidence of functional conservation in
Promising targets of the coding transcriptome were vali-
dated in neonatal mice in-vivo using a rAAV9 mediated knock-
down system. Candidates like Igf1r, Myl9, Lamc2 and Spp1 were
conrmed as potentially important players in the process of
neonatal cardiac regeneration.
sets of mRNAs and miRNAs that we report
here merit further investigation as gatekeepers of cell division
in the postnatal heart and as targets for extension of the period
of cardiac regeneration beyond the neonatal period. Results
of rAAV9 mediated knock-down experiments furthermore
strengthen the validity and relevance of our screening results in
the process of neonatal cardiac regeneration.
Repeated remote ischemic conditioning preserves
systolic left ventricle function and increases
NRG-1 expression following myocardial infarction
P. M. Pilz, M. Lang, O. Hamza, I. Fonseca- Gonçalves,
M. Inci, B. Podesser, A. Kiss
Center for Biomedical Research, Ludwig Boltzmann Cluster
for Cardiovascular Research
Medical University Vienna, Vienna, Austria
dverse left ventricle (LV) remodelling fol-
lowing myocardial infarction (MI) plays a key role in the pro-
gression of congestive heart failure (HF). Recombinant human
Neuregulin-1 (rhNRG-1) has been demonstrated to have both
anti-brotic and anti-inammatory eects. Chronic admin-
istration of rhNRG-1 markedly improved LV ejection fraction
(LVEF) and coronary microcirculation in patients with HF.
Repeated remote ischemic conditioning (RIC) is considered as
a potential clinically approach to improve cardiac function fol-
lowing MI, however the mechanisms are not fully elicited.
e aim of the pr
esent study was to (1) clarify the
eects of a brief period of RIC on LV hemodynamic function
and coronary ow (CF) and (2) to assess the expression of NRG-
1, ErbB2/3/4 expression following MI.
Methods: Male Sprague-Dawley rats were subjected to per-
manent left coronary artery (LCA) occlusion and allocated to
ee groups: (1) MI (n
13), (2) MI+RIC (
10) and (3) c
group (Sham, n
ithout LCA occlusion and without RIC).
Repeated RIC was started at the 3rd day after MI once a day for
5 days by 3 cycles of 5 min of unilateral hindlimb ischemia and 5
min of reperfusion. Cardiac functional parameters were assessed
by transthoracic echocardiography at baseline and at days 3
and 8 following MI. Coronary ow (CF) and LV systolic pressure
(LVSP) were evaluated on an isolated erythrocyte-perfused work
ing heart model at day 8 following MI. e alterations in CF pri-
marily reect alterations in coronary resistance, allowing evalua-
tion of microvasculature function in this experimental setup. e
ession of plasma level of NRG-1 was measured by ELISA and
mRNA expression of ErbB2/3/4 was accessed by RT-qPCR.
hort term duration (5 days) of RIC enhanced LVEF
as compared to MI group (63
on day of 8th fol
lowing the induction of MI, p
= 0.074). is was accompanied by
preserved LV systolic function in rats with RIC as compared with
MI (LVESD: 5.9 ± 0.06
and 6.4 ± 0.2
= 0.064). Results
were obtained from the isolated working heart system showed
that CF and LVSP were markedly enhanced in rats with RIC as
compared to MI (CF: 4.3
heart weight and
g vs 119
4; mm H
< 0.01, respectively).
Both plasma and tissue expressions of NRG-1 were signicantly
elevated by RIC in comparison to MI group (plasma: 10.6
µg/ml and L
V tissue: 0.53
Similarly, the mRNA expression of ErbB2/3/4
showed at least partly signicant dierences between the groups
± 0.2 vs. 2.08 ± 0.4 1/18S, p
< 0.05; ErbB3: 1.07 ± 0.3 vs.
± 0.4 1/18S, p
< 0.05; ErbB4: 0.46 ± 0.12 vs. 0.64 ± 0.23 1/18S;
n.s.) in LV tissue samples, taken from the infarcted zone.
Conclusions: RIC preserves systolic LV function and mark-
edly enhances basal CF following MI in rats. ese results were
accompanied by with a marked increase in NRG-1 levels in
plasma and myocardial tissue samples indicating enhanced
cardioprotection. erefore, repeated remote RIC is a potential
therapeutic approach for improved post-MI remodelling.