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 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.
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!’
Fast facts: Cardiac Arrhythmias
Gerry Kaye, Steve Furniss and Robert Lemery
Publisher: Health Press
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.
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
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.
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. Đorđevic, 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 peer-reviewed 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.
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 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.