Download Biomarkers, genomics, telemetry, computational biology, and zebrafish

European Heart Journal (2014) 35, 57–62
doi:10.1093/eurheartj/eht494
Biomarkers, genomics, telemetry, computational
biology, and zebrafish: will one of these solve
the problems of post-myocardial infarction
heart failure?
Interventional cardiologist Dr Daniel Wagner, FESC in Luxembourg,
is determined to find an answer to the problem of heart failure after
myocardial infarction, and is researching a wide variety of approaches,
reports Barry Shurlock PhD
Any interventionist who puts in a stent, sees a strong recovery, and
then watches the patient decline with heart failure wants to find a solution to the problem of pump function loss of a remodelled fibrotic
heart following acute myocardial infarction (AMI).
One who is determined to do so is Dr Daniel
Wagner MD, PhD, FESC, FACC, Director of
Cardiology at Luxembourg Central Hospital,
Luxembourg. It would not be the first time
that someone in one of the smallest countries
of Europe had surprised the world (think of
Andreas Grüntzig in Switzerland!), but he is
fully aware of the scale of the challenge.
He first became interested in the problem during a 5-year fellowship at the University of Pittsburgh in the USA, where he
trained as an interventionist and carried out research with Prof.
Arthur M. Feldman MD, PhD (now Executive Dean of the
Temple University School of Medicine, Philadelphia, PA, USA),
who headed the Division of Cardiology and the Cardiovascular Institute. Dr Wagner said: ‘The hypothesis was, that cytokines in the
heart were part of the pathophysiology of heart failure and that
adenosine may modulate cytokines in the heart. We worked on
isolated cardiac cells, explanted cardiac tissue and rat models. It
didn’t quite work out, but the end result was that adenosine is
an interesting way of limiting cytokine production and I still
believe it may be an important strategy to limit the development
of heart failure’.
Now established back in his native Luxembourg, he did his basic
medical training in Germany, at the Giessen University Medical
School and then specialized in internal medicine at the Max Planck Institute, Bad Nauheim, near Frankfurt, and the University of Munich.
Then he moved to Belgium, to work for a PhD at the De Duve Institute
in Brussels. Outlining his work since returning to Luxembourg in 1999,
he said: ‘When I came back we had no basic research at the hospital, and
a very small lab which I had to develop. As an interventionist I wanted to
fix patients’ problems, but not just on the table! I wanted to give them a
good outcome for many years. So, we decided to focus on identifying
patients who after an AMI have problems of left-ventricular remodelling and risk death from heart failure. We wanted to identify them early
and seek to prevent further development.’
Daniel Wagner & Group, in front of a network
of microRNAs at Henri Tudor Public Research
Centre Luxembourg
Dr Wagner and his group therefore set up a database of post-AMI
individuals and recorded a wide range of biological and genomic variables from blood samples and other clinical sources. After 6 years
they have 1000 individuals registered, of which about 20% have
died from HF and sudden death. This has enabled the team to
search for key correlates. He said: ‘It’s tough, but we don’t just
want to find a biomarker, but a way to treat. We know that adenosine
has some effect and we became interested in possible effect of it on
MMP9 (matrix metalloproteinase 9) in cells. Working with colleagues
at the University of Nancy we have shown, in rats and mice, some
effect of adenosine, but it is mild. We also have explored the possible
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
58
role of some polymorphisms of MMP9, but unfortunately our database is not big enough. We are therefore expanding it by working
with a number of other major centres – in Leicester, Maastricht,
Basel and Paris. We are especially interested in the potential for transcriptonomics and computational biology to find connections
between genes and proteins that will help to elucidate the pathophysiology of heart failure. We hope to identify biomarkers for
post-AMI heart failure from the 1000 or so forms of micro-RNA,
small pieces of RNA that circulate and can easily be measured in
blood’.
The long-term aim of Dr Wagner and his group is to identify new
therapeutic pathways for heart failure and associated problems, including ways of countering fibrosis, so-called ‘reactive fibrosis’. In collaboration with workers at the University of Liège they hope to find
clues to limiting fibrosis of the heart from studies of zebrafish, which
are regarded as a useful model for cardiac physiology, yet have a tiny
heart, only 0.5 mm in size.
CardioPulse
He has also been exploring the use of telemetry as a means of monitoring heart failure patients at home. The work was done in collaboration with the Henri Tudor Public Research Centre, Luxembourg,
named after a celebrated engineer who developed the first lead-acid
battery (and ironically died of lead poisoning). Dr Wagner said:
‘Using measurements of the relationship between pulse transit time
and blood pressure we hoped to be able to identify patients at risk
of congestion, and thereby avoid hospitalization. The problem was
that the measures acted differently from patient to patient and we
were not able to show that the changes were clinically meaningful in
the limited trial we could carry out –only a few dozen patients - and
we couldn’t find the funding for a larger trial’.
Despite these setbacks, he is determined to find ways of improving
the lot of patients with heart failure following AMI. He said: ‘my
mentor Art Feldman always said: “You can’t do interventional cardiology and basic research at the same time”, but I’m determined to do
so – it keeps me busy and young!’
Book Review
Fast facts: Cardiac Arrhythmias
Gerry Kaye, Steve Furniss and Robert Lemery
Publisher: Health Press
2nd edition
ISBN 978-1-908541-25-3
Paperback Pages: 148
During the last three decades our understanding of cardiac
arrhythmias has significantly improved. While, initially, invasive
electrophysiology procedures were mainly diagnostic, arrhythmia
treatment primarily consisted of pharmacotherapy and pacemakers. Later, the use of catheter-based percutaneous ablation of
cardiac rhythm disturbances has led to a paradigm shift in this
field. As our knowledge about arrhythmias has grown rapidly in
recent years, many books on this topic have been published.
However, many of them have been at great length.
The second edition of Fast Facts: Cardiac Arrhythmias continues
the concept of the first edition and meets the need for a concise,
easily understandable, and clinically useful summary of cardiac
arrhythmias, contributing to a better understanding of the basic
principles, diagnosis, and state-of-the-art treatments The highlights
of this pocket book consist of an easy-to-remember classification of
cardiac arrhythmias, a clear description of symptoms, and vivid illustrations. The updated and clinically useful chapter on atrial fibrillation is surely an enrichment and covers the most important
developments in diagnosis and management, including information
on recent clinical trials involving the novel oral anticoagulants, and
recent guidelines from North America and Europe. Again, the last
chapter is dedicated to cardiac pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization devices, which
remain cornerstones in the treatment of bradyarrhythmias,
ventricular tachyarrhythmias, and heart failure with extensive electrical dyssynchrony.
Of note, this book is not written to provide in-depth information
for electrophysiology procedures or to present exhaustive information about basic science in electrophysiology. Therefore, advanced
readers looking for more detailed knowledge will soon realize that
the pocket book format does not allow a disquisition on the topics
addressed. As an electrophysiologist, I really appreciate this pocket
book which is reasonably priced and which I can recommend to
medical students, general practitioners, nurses, technicians, and
young cardiologists caring for patients with cardiac arrhythmias.
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CardioPulse
Long-distance cross-country skiers at increased
risk of arrhythmias
The risk of developing atrial fibrillation or bradyarrhythmias was
greater among skiers who completed a higher number of races and
with a faster finishing time relative to other participants
Photo Vasaloppet
Cross-country skiers who take part in one of the world’s most challenging ski races, the 90 km Vasaloppet in Sweden (the Vasaloppet is
the world’s oldest, longest, and largest cross-country skiing race), are
at an increased risk of developing arrhythmias, according to a study of
nearly 53 000 race participants recently published in the European
Heart Journal. 1
Dr Kasper Andersen, a cardiologist at Uppsala
University Hospital, Uppsala, Sweden and his
colleagues, identified 52 755 cross-country
skiers who had completed the Vasaloppet
between 1989 and 1998, and followed them
through to 2005.1 During this follow-up period,
919 participants (1.74%) experienced some
form of arrhythmia.
Atrial fibrillation (AF), the most frequent, occurred in 681 skiers.
After adjusting for age, education, and occupation, there was a 29%
increased risk of AF among skiers completing five or more races compared with those completing only one; there was a 20% higher incidence of AF for those with the fastest finishing times compared
with the slowest, although this finding was not statistically significant.
Bradyarrhythmias occurred in 119 skiers. After adjusting for age,
education, and occupation, the risk more than doubled (110% increase) among those who completed five or more races compared
with those who completed one. There was a tendency for the risk
to increase with faster finishing times.
The study found that those who completed five or more races in a
period of 10 years had a 30% higher risk of developing any arrhythmia
than those who did one race only. Similarly, skiers who had the fastest
finishing time relative to the other participants also had a 30% higher
risk of developing any arrhythmia in subsequent years.
‘The skiers in our study are as a group healthier than the general
population. We have previously shown that besides higher leisure
time physical activity, the participants in Vasaloppet smoke less,
have lower fat and higher fibre consumption and better physical
and mental health than the general population. Actually the participants have about half the mortality than the general population.
This is probably not only because of the training level of the participants, but also because the participants need to be healthy to even
consider participating in the race’.
Photo Vasaloppet 2011
The study was important because there have only been a few
smaller studies of the effects of endurance exercise on heart
rhythm disturbances and they have tended to look at people who
are less physically active, or compared very sedentary people with
those who were very active.
Andros Tofield
Reference
1. Andersen K, Farahmand B, Ahlbom A, Held C, Ljunghall S, Michaëlsson K, Sundström J.
‘Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study’. Eur
Heart J 2013;34:3624 –3631.
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CardioPulse
Heart and blood vessels
The Journal of the Cardiology Society of Serbia, Heart and Blood
Vessels, has been published continuously for 2 years
This journal’s origins are in the former Yugoslavia where, as Cardiology, it was successfully printed from 1980 to 2003 through the
efforts of Prof. Ivan Lambic and his associate Prof. Velibor Obradovic.
All cardiologists in Yugoslavia published their works in this journal.
The publications served for studies in cardiology and cardiovascular medicine as well as as references for the authors in their careers to
academic titles. The turbulent events that affected the area contributed to a diminished enthusiasm for regular journal printing.
The publishing of a journal can only be maintained if there is an
enormous amount of enthusiasm of top-quality persons. Cardiology
in Serbia has always had extraordinary and charismatic teachers, clinicians, and scientists, who contributed significantly to publishing practice and culture, including academics and distinguished professors
such as V. Arnovljevic, B. Ðordevic, J. Slavkovic, I.Papo, V. Kanjuh,
D. Boskovic, A. Popovic, and particularly our most cited cardiologist
professor Srecko Nedeljkovic (e.g. ‘Seven countries study’).
The change of name from Cardiology to Heart and Blood Vessels was
more symbolic than substantial and it marked a new beginning, a revitalization, and broadening of the scope of cardiovascular medicine
from bench to bedside. This was brought about by a well-known generation of cardiologists born in the late 1950s to early 1960s and the
talented generation born in the 19701980s. The enthusiasm for
volunteer work and determination for success were the most efficacious driving forces for the revival of the national journal.
Heart and Blood Vessels is published quarterly and includes peerreviewed original manuscripts, review articles from national and international experts, case reports, and cardiovascular images. In addition,
the journal has successfully published Serbian translations of the ESC
Guidelines, as well as important articles such as Almanac 2011, first
published in Heart, and some important ESC documents.
The journal also publishes all relevant information and notifications on activities, forthcoming congresses, and meetings of the Cardiology Society of Serbia, and the European Society of Cardiology.
Finally, the journal publishes abstracts from National congresses in
special supplement issues.
All issues are printed and delivered to .800 members of the Cardiology Society of Serbia and are also available on the official website
of our society www.uksrb.org. Our journal is a member of the European Editorial Network.
The editorial staff of Heart and Blood Vessels includes a national
Editorial board not only of cardiologists, but also basic scientists
dedicated to cardiovascular medicine, as well as paediatricians, and
cardiac and vascular surgeons. In addition, there is an international editorial board of prominent cardiologists such as William Wijns, Eugenio
Picano, Antonio Colombo, Osamu Katoh, Jumbo Ge, George Sianos,
and others. We understand that the editorial staff is only a partial guarantee for a journal’s success; the main responsibility and credit for
success belongs to those who send their works to the journal.
The goals of the journal are to improve its structure with more original and educational articles, include more young cardiologists in the
production of the journal, gain regional visibility, improve connections with the European Journal Network, and ultimately, achieve
international citation indices.
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CardioPulse
Controversies in acute cardiovascular care:
cardiogenic shock
Arguments for and against the statement: ‘There is still an indication
for intra-aortic balloon pump in cardiogenic shock’
Protagonist view: Doron
Zahger (Israel)
Cardiogenic shock remains the main cause of
hospital mortality in patients with acute myocardial infarction (MI). The pathophysiology involves
both reduced cardiac output and increased filling
pressures which, especially in the presence of
ongoing ischaemia, create a vicious cycle of progressive haemodynamic
deterioration.
The intra-aortic balloon pump (IABP) has been recognized for
decades as a powerful bedside tool to achieve augmentation of
cardiac output and coronary perfusion and reduction of filling pressures, without the increase in oxygen consumption which usually accompanies the use of inotropic agents, an increase poorly tolerated
by the ischaemic myocardium. Use of the IABP in cardiogenic
shock is supported by many small studies and registries as well as
by the experience of many physicians caring for these critically ill
patients. However, until recently no major randomized trial has
assessed the role of the IABP in this setting.
The recently published IABP-SHOCK II trial was the first relatively
large randomized trial to assess the effects of the balloon pump in
patients with post-MI cardiogenic shock. To the surprise of most
experts, including the authors, the study failed to show a benefit on
mortality by this intervention. Other, secondary efficacy measures
were similarly neutral.
While this study undoubtedly mandates reconsideration of the
balloon pump in cardiogenic shock, a number of concerns should
be kept in mind. The study was neutral and did not suggest harm
by counter pulsation, raising the possibility of benefit in some
subgroups.
Indeed, younger patients in the balloon pump arm seemed to
benefit from the intervention. The event rate in this study was
lower than expected and the study might therefore have been underpowered to detect the effect it was planned to detect. About 40% of
patients in this trial had undergone cardiac arrest and resuscitation
and required therapeutic hypothermia, suggesting that they were admitted in coma. These patients may have sustained severe cerebral
and organ damage not amenable to counter pulsation. Whether
patients who are not comatose might benefit is unclear. Importantly,
86% of patients in the study received the balloon pump after primary
PCI. However, there may still be an important benefit in selected
patients. More studies and data are needed to identify whether
subgroups exist that may benefit.
It is clear, therefore, that the IABP can no longer be recommended
for all patients with cardiogenic shock. However, there may still be an
important benefit in selected patients. More studies and data are
needed to identify whether subgroups exist that may benefit.
Contra view: Holger
Thiele (Germany)
Since 1968 the IABP has been the most widely
used support device in cardiogenic shock.
Intra-aortic balloon pump support has been
described to improve diastolic blood pressure,
thereby improving coronary perfusion and, by its afterload reduction
properties, myocardial oxygen consumption is reduced, leading to a
modest increase in cardiac output of 0.5 L/min.1 However, the majority of trials investigating haemodynamic IABP effects had no
control group, which is important to weigh the results of these
haemodynamic trials.1 In a small randomized trial in 40 patients, no
significant differences between IABP and control were observed in
detailed haemodynamic monitoring.2 Interestingly, there was a significant increase in cardiac power output, a haemodynamic parameter correlating well with mortality,3 in both groups, indicating that
any initial haemodynamic improvement might be more influenced
by revascularization as well as fluid and inotropic optimization than
by IABP effects. In addition, there was no effect on blood pressure
in the IABP-SHOCK II trial, which randomized 600 cardiogenic
shock patients to IABP or control.4
Therefore, the major question is how does this translate into a clinical outcome?
Until recently, there were only registry trials for IABP support in
cardiogenic shock, which were summarized in a meta-analysis.5 In
conjunction with fibrinolysis or no reperfusion, there was a mortality
benefit, whereas there was a 6% risk of mortality increase if IABP was
used in conjunction with primary PCI.5 Based on this insufficient and
conflicting evidence, American and European guidelines recently
downgraded IABP use for cardiogenic shock from a class I to a class
IIa and IIb recommendation.6 – 8 It is important to note that these
recommendations were downgraded not on the basis of randomized
controlled clinical trials.
In the IABP-SHOCK II trial, altogether 600 patients with cardiogenic shock complicating acute MI with early revascularization
were randomized to either IABP support or conventional optimal
medical treatment alone.9 There was no reduction in the primary
endpoint 30-day mortality.
Several subgroups were also evaluated and there was no benefit
for any of the subgroups studied. Intra-aortic balloon pump
support also did not result in a reduction in the length of ICU treatment or in catecholamine dosing. Also, serum lactate was not altered
62
by IABP support in comparison with control. This trial led to a multitude of discussions and many believed that, at longer follow-up, a potential benefit of IABP support might be observed. However, the
recently published results did not show any benefit on mortality at
the 12-month follow-up, confirming the negative 30-day findings.10
Taken together, there is no evidence that IABP support can
improve relevant haemodynamic parameters or alter the clinical
outcome of patients in cardiogenic shock. Although we have been
used to it for over five decades, we should stop using a device that
has properties of a mechanical placebo.
CardioPulse
6.
7.
8.
References
1. Scheidt S, Wilner G, Mueller H, Summers D, Lesch M, Wolff G, Krakauer J,
Rubenfire M, Fleming P, Noon G, Oldham N, Killip T, Kantrowitz A. Intra-aortic
balloon counterpulsation in cardiogenic shock. Report of a co-operative clinical
trial. N Engl J Med 1973;288:979–984.
2. Prondzinsky R, Unverzagt S, Russ M, Lemm H, Swyter M, Wegener N, Buerke U,
Raaz U, Ebelt H, Schlitt A, Heinroth K, Haerting J, Werdan K, Buerke M. Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized
IABP shock trial. Shock 2012;37:378 –384.
3. Fincke R, Hochman JS, Lowe AM, Menon V, Slater JN, Webb JG, LeJemtel TH,
Cotter G. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004;44:
340 –348.
4. Thiele H, Zeymer U, Neumann F-J, Ferenc M, Olbrich H-G, Hausleiter J, Richardt G,
Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J,
Böhm M, Ebelt H, Schneider S, Schuler G, Werdan K. Intraaortic balloon support
for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287–1296.
5. Sjauw KD, Engstrom AE, Vis MM, van der Schaaf RJ, Baan J Jr, Koch KT, de Winter RJ,
Piek JJ, Tijssen JGP, Henriques JPS. A systematic review and meta-analysis of
9.
10.
intra-aortic balloon pump therapy in ST-elevation myocardial infarction: should
we change the guidelines? Eur Heart J 2009;30:459 –468.
O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA,
Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM,
Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ,
Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX. 2013 ACCF/AHA
Guideline for the management of ST-elevation myocardial infarction: a report of
the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation 2013;127:e362 –e425.
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Valgimigli M, Van’t Hof A, Widimsky P, Zahger D. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569 –2619.
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Dunning J, Elia S, Kappetein P, Lockowandt U, Sarris G, Vouhe P, von Segesser L,
Agewall S, Aladashvili A, Alexopoulos D, Antunes MJ, Atalar E, Brutel de la
Riviere A, Doganov A, Eha J, Fajadet J, Ferreira R, Garot J, Halcox J, Hasin Y,
Janssens S, Kervinen K, Laufer G, Legrand V, Nashef SA, Neumann FJ, Niemela K,
Nihoyannopoulos P, Noc M, Piek JJ, Pirk J, Rozenman Y, Sabate M, Starc R,
Thielmann M, Wheatley DJ, Windecker S, Zembala M. Guidelines on myocardial
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Thiele H, Zeymer U, Neumann F-J, Ferenc M, Olbrich H-G, Hausleiter J, de Waha A,
Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R,
Lauer B, Böhm M, Ebelt H, Schneider S, Werdan K, Schuler G. Intraaortic balloon
counterpulsation in acute myocardial infarction complicated by cardiogenic shock.
Final 12-month results of the randomised IntraAortic Balloon Pump in cardiogenic
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3 September 2013.
CardioPulse contact: Andros Tofield, Managing Editor. Email: [email protected]