Download The William Harvey lecture at ESC Congress 2016

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CardioPulse
doi:10.1093/eurheartj/ehw477
The William Harvey lecture at ESC Congress
2016
Prof Denise Hilfiker-Kleiner outlines the key role of interdisciplinary research in cardiovascular science using the example of STAT3 as she delivers the William Harvey
Lecture on Basic Science at ESC 2016 in Rome
STAT3 is a protein that plays a pivotal role in cardiac physiology and
pathophysiology.
Connected to different pathways and networks, it affects almost
every biological mechanism in the heart.
‘If you move STAT3 it basically moves the whole network’,
explains Professor Denise Hilfiker-Kleiner. ‘It is not the only gene in
the universe of cell biology that has such a key function, but it seems
quite essential for many different aspects of the heart including stress
response, survival, growth, inflammation, metabolism, matrix composition and fibrosis, angiogenesis, contractile function, cell-to-cell communication, regeneration, and many more’.
Through the William Harvey Lecture on Basic Science at ESC
2016 in Rome entitled ‘Renaissance of signalling modules: The role of
STAT3 in the cardiac pathophysiology’, she will offer an introduction
on signalling modules from today’s perspective; summarize the nature
of STAT3, its regulation and biological roles; and the role of STAT3 in
the heart with regard to development and aging.
Prof Hilfiker-Kleiner, who is Dean of Research of the Hannover
Medical School (MHH) and leads the Department of Molecular
Cardiology within the Department of Cardiology and Angiology of
the MHH, will further explain contrary roles of STAT3 in tumour
cells and in the heart with regard to cardio-toxic treatments and
Cardio-Oncology; and provide insights into the role of STAT3 in
pathophysiologic conditions.
And significantly, she will focus on an area she has gained global
renown for by summarizing the central role of STAT3 for protection
of the maternal heart and its relation to Peripartum cardiomyopathy
(PPCM).
Prof Hilfiker-Kleiner, who has long-standing experience in analysing signalling pathways in cardiac cells relevant for cardiac physiological and pathophysiological, explained: ‘What makes it so interesting
to work with this protein is that there are thousands of different
aspects you can study—everything from development to ageing,
physiological stress factors, having ischaemia, infarction, cardiotoxicity, and also neuro-hormones’.
‘With almost every single thing that happens to the heart, STAT3
plays a role.’
She felt it was a great honour to be chosen to deliver the William
Harvey lecture at ESC 2016 and see the cardiology community
appreciate and acknowledge her work in cardiovascular science.
‘It means a lot to me as a basic scientist (biologist) to be chosen to
present my work at the world’s biggest medical congress on cardiovascular disease’, she added.
Acknowledging the role of her former mentor Prof Helmut
Drexler from Hannover and Prof Karen Sliwa—her close collaborator in her work with PPCM, she also paid tribute to the contribution
of English physician William Harvey (1578–1657), who is acknowledged as the first to describe the systemic circulation and properties
of blood being pumped to the brain and body by the heart.
‘William Harvey was a genius’, said Prof Hilfiker-Kleiner. ‘He was a
great observer and a critical researcher, who founded the modern
view of the cardiovascular system by stating that the blood is circulating through the veins.’
‘But he was much more; he was a talented physician as well as a
great biologist and physiologist.’
Inspired by Harvey, she sees an affinity to the 16th century physician and his work.
She continued: ‘Maybe there are some parallels in the way he conducted his research; always carefully planning experiments, using positive and negative controls, believing his eyes and data when he was
sure he had carefully planned and conducted his experiments, no
matter if his findings were contradicting common views’.
There are, she suggests, further parallels in that he was also a
developmental biologist making an important contribution in the field
of embryology and epigenetics.
As a developmental biologist and geneticist, who later switched to
medical research, Denise Hilfiker-Kleiner sees her work as continuing
the tradition he began almost four centuries ago.
Today, a major focus of her research lies in understanding pathophysiology’s of the cardiovascular system associated with pregnancy,
with a second focus on myocardial ischemia and Cardio-Oncology.
During her early career at the University of Zurich’s Department of
Classic and Molecular Genetics and Developmental Biology, and at the
Department of Biology, Emory University, Atlanta, Georgia, her main
discovery was the novel way the maternal environment determines
the sex of a developing house fly embryo and together with her husband Andreas Hilfiker, showed for the first time the important role of
histone modification for transcriptional control in higher eukaryotes.
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It was on joining the lab of Prof Drexler at the MHH that she started
to specialize in signalling pathways important for the development of
cardiac pathophysiology’s, with a special focus on STAT3 signalling.
An observation made was the clear gender difference with females
being more tolerant to low STAT3 levels than males, except in pregnancy and STAT3 turned out to be a critical molecule for protection
of the maternal heart against the Peripartum-related stress.
Her group discovered that at least one of the major pathophysiological mechanisms of PPCM involved unbalanced oxidative stress
that promotes proteolytic cleavage of the nursing hormone prolactin
in a strongly anti-angiogenic 16 kDa form that impairs cardiac angiogenesis and leads to heart failure.
Blocking prolactin with the Dopamine 2D receptor agonist bromocriptine successfully prevented PPCM in mice and in a high risk
PPCM collective with subsequent pregnancies.
Denise Hilfiker-Kleiner explained that her collaboration with
Karen Sliwa over PPCM began with a chance meeting and a casual
conversation in an airport lounge.
Karen Sliwa was seeing in patients what Denise Hilfiker-Kleiner
was observing in mice models.
‘We were convinced that the mice were showing more or less the
same PPCM phenotype that she saw in patients so we started a
bench-to-bedside approach and soon figured out that bromocriptine
is playing a major role in this setting.’
First publishing their findings in 2007, clinical trials with Karen Sliwa
followed.
A Fellow of the ESC and past chair of the ESC Working Group on
Myocardial Function, Denise Hilfiker-Kleiner is a founding member of
the study group on PPCM and of the translational research group of
the Heart Failure Association of the ESC, a core PI of the REBIRTH
Excellence Cluster at the MHH and the lead scientist and organiser
of the multicentre clinical trial on the efficacy of bromocriptine in
PPCM, funded by the German Federal Ministry of Education and
Research.
Mark Nicholls
[email protected]
doi:10.1093/eurheartj/ehw478
An airport meeting that led to bromocriptine
use in peripartum cardiomyopathy
Prof Denise Hilfiker-Kleiner speaks about a chance meeting that helped tackle peripartum cardiomyopathy (PPCM), with Mark Nicholls
It was a chance meeting, yet one which helped unlock the mysteries
of a cardiac condition affecting thousands of pregnant women.
The casual conversation in an airport lounge took place between
South African cardiologist Karen Sliwa and Andres Hilfiker, a biologist
now specialising in tissue engineering, who relayed it to his wife
Denise Hilfiker-Kleiner.
That led to a close collaboration between the two women, which
in turn significantly advanced the knowledge and awareness of PPCM
and as a consequence helped save many lives.
Today, Professor Denise HilfikerKleiner—now Dean of Research of the
Hannover Medical School (MHH) and who
leads the Department of Molecular
Cardiology within the Department of
Cardiology and Angiology of the MHH—is
widely-recognized for her work on PPCM.
From initial work studying transcription
control of insects, she joined the lab of
Professor Helmut Drexler at the MHH in
1996 where she specialized in signalling pathways important for the development of cardiac pathophysiologies,
with a special focus on STAT3 signalling.
A clear gender difference with females being more tolerant to
low-STAT3 levels than males except in pregnancy as observed, with
STAT3 turning out to be a critical molecule for protection of the
maternal heart against the peripartum-related stress.
Together with Prof Drexler, she started to elucidate the pathophysiological mechanism of postpartum cardiomyopathy using mice