Download Chagas` disease and its toll on the heart

CardioPulse
European Heart Journal (2009) 30, 2063–2072
doi:10.1093/eurheartj/ehp277
Chagas’ disease and its toll on the heart
Chagas’ disease (American Trypanosomiasis) is a tropical disease
caused by the protozoan Trypanosoma cruzi. In natural conditions,
infection with T. cruzi occurs in early infancy. About 15 days after
infection, fever, lymphadenopathy, hepato-splenomegaly, and
subcutaneous oedema ensues. This acute stage lasts about a
1 month, and then the patients appear to fully recover.
After about 2 months, a positive serology appears, but no
evidence of organ disease exists. However, about 20 years later,
some 30% of infected patients develop chronic Chagas’ heart
disease and 10% develop gastrointestinal (G-I) tract diseases
(megaesophagus and megacolon). The remaining 60% are asymptomatic but have positive serology. ‘This unusual clinical course of
Chagas’ is still poorly understood, and the pathogenesis is undetermined in spite of numerous studies’, says Dr Bestetti.
The parasite is transmitted to humans through the faeces of a
sucking bug popularly known as ‘barbeiro’ (barber in English),
which sucks on the face of sleeping persons and defecates on
the skin or in the eye mucosa.
causing the initial disease. This is the commonest route of
transmission.
Another important route of infection is contaminated blood
donation. ‘This is under control in Brazil, but not in all countries
of South America’, he says. ‘Because of international migration,
centres for blood donation in developed countries should be on
the alert for this problem’.
Placental transmission in infected mothers occurs but the impact
of this mode on public health is unknown.
Oral transmission of T. cruzi is unusual, but recently occurred in
Brazil via sugar cane juice, which is very popular. The bugs can be
ground together with sugar cane bundles, releasing parasites into
the juice which are then absorbed from the G-I tract.
Chagas’ disease affects virtually all countries of South America,
but more commonly infects people in rural areas who have poor
quality housing, made of adobe and not covered by cement. ‘The
vector hides in the cracks during the day emerging at night to
suck on the sleeping victims’.
Collection of barbeiros captured in Lassance at the time of
Carlos Chagas, Courtesy of Claudio Adriano, Director,
Carlos Chagas Memorial, Lassance, Brazil
Adobe house in Lassance 2008
The faeces contain plenty of parasites, which penetrate the skin or
mucosa, entering the blood stream to spread throughout the body,
Additionally, people’s cats, dogs, and chickens are sucked on and
infected by ‘barbeiros’, replacing the armadillo, the natural
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
A heart disease caused by a protozoan affecting millions of people in
South America was discovered 100 years ago by Carlos Chagas (see
Box 1). It is the leading cause of heart failure in endemic areas, while
prevention and treatment still have a long way to go. J. Taylor
delivers the story from Reinaldo B. Bestetti, MD, PhD, FESC, Head
of Cardiology and Cardiovascular Surgery, Hospital de Base,
Faculdade de Medicina de São José do Rio Preto, Brazil.
2064
reservoir of the parasites. Dr Bestetti says: ‘Chagas’ disease is a
consequence of poverty, and not related to age, race, etc.’
Box 1 Carlos Chagas
Back in Lassance he saw a cat with an eye infection similar to
that in the monkey. Fifteen days later, on 14 April 1909, he
examined a child with fever and generalized lymphadenopathy,
the owner of the diseased cat. Chagas discovered uncountable
T. cruzi in the blood of this child. A new human disease had
been discovered.
By 1920, he and his team had discovered the vector, the
aetiological agent, the reservoir, the intermediate host, the
acute stage, and clinical aspects of the chronic stage, particularly cardiac involvement leading to chronic heart failure and
sudden cardiac death, and the potential role of autoimmunity
in the pathogenesis of the chronic stage.
More importantly, by living in the Brazilian backland, he
foresaw the scourge that this disease could be for Latin
America. Throughout his life, Chagas emphasized the need for
governmental action to control the new disease by replacing
poor houses by houses made of brick covered with cement.
A new phenomenon in the transmission of Chagas’ is occurring
where there is Amazon deforestation. Infected ‘barbeiros’ fly to
poor quality ‘urban’ houses and transmit the disease to urban
residents.
According to the World Health Organization, about 11 million
people are carriers of Chagas’ in South America, and another
100 million are at risk of acquiring the disease. Because of international migration, estimates are that 720 000 people with
Chagas’ disease live outside South America in the USA, Australia,
Europe, Canada, and Japan.
Most at risk are those living in poor conditions in rural areas
where Chagas’ is endemic, people who receive blood from an
infected patient, and the children of infected mothers.
What can be done for patients? ‘Mega-oesophagus and megacolon are treated surgically with good results’, says Dr Bestetti. Clinical manifestations of Chagas’ cardiomyopathy are atypical chest
pain, thrombo-embolism, A-V blocks and arrhythmias, and the
main problem of chronic heart failure, and sudden cardiac death
(Box 2).
Box 2 Mechanism of heart failure
and arrhythmias
In the chronic stage, the parasite virtually disappears from the
myocardium and a mononuclear cell infiltrate ensues, releasing
cytokines, and replacing myocardial cells by fibrosis. Thrombosis in the coronary microvasculature produces myocardial
ischaemia.
The myocardial parasympathetic ganglion cell count is
reduced, preceding left ventricular systolic dysfunction. Autonomic imbalance may induce coronary microvascular vasoconstriction, aggravating myocardial ischaemia. Resulting apoptosis
and/or necrosis is followed by marked confluent myocardial
fibrosis throughout the myocardium.
‘By acting in concert, such abnormalities lead to an
irreversible ventricular remodelling, thus producing chronic
heart failure’, says Dr Bestetti. ‘The fibrosis with myocardial
inflammation probably account for the bad prognosis of
Chagas’ heart failure compared with that of non-Chagas’
heart failure’.
The disseminated fibrosis along with myocardial inflammation
brings about multiple re-entry foci throughout the myocardium
that predispose to the development of life-threatening ventricular arrhythmias. ‘It is noteworthy that about 20% of Chagas’
patients have spontaneous ventricular fibrillation not preceded
by ventricular tachycardia, which contrasts with other types of
cardiomyopathy, and perhaps explains the high frequency of
sudden cardiac death observed in Chagas’ patients’.
There is no treatment for chagasic chest pain.
Thrombo-embolism is successfully treated with anticoagulants,
bradyarrhythmias with a pacemaker, and ventricular tachyarrhythmias with metoprolol, amiodarone or implantable cardioverter
defibrillators (ICD).
Chronic heart failure is treated similar to non-Chagas’ heart
failure, with diuretics, digoxin, beta-blockers, and ACE inhibitors.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
Carlos was a medical researcher at the Manguinhos Institute, in Rio
de Janeiro, with some expertise in combating malaria epidemics. In
1907, at the age of 28, he was sent to Lassance, a small city in the
Brazilian hinterland, to combat another malaria epidemic.
By examining the local inhabitants, he noticed a great number
of very young patients with arterial pulse abnormalities and
sudden cardiac death, cerebral palsy, and massive goitre. One
night, he was shown an insect that inhabited cracks in the walls
of poor houses during the day and sucked the face of people
while sleeping. By examining the intestine of such insects, he
observed several protozoans with the epimastigote forms, he
supposed, could transmit disease to humans. He sent the
sucking bugs to the director of Instituto Manguinhos, Oswaldo
Cruz, to perform an experiment in monkeys testing the hypothesis that such protozoans would be able to transmit diseases.
Some days later, Chagas came back to Rio de Janeiro and
noticed that one animal had an eye infection. Blood analysis
revealed a new protozoan, which was named Trypanosoma
cruzi in honour of Oswaldo Cruz.
CardioPulse
2065
CardioPulse
to be effective in decreasing serology in children, and for this
reason has been recommended that children should also be
treated with it. Work has yet to be done to achieve a universal
cure of the disease.
For the chronic stage, Dr Bestetti says the main challenge is to
discover the pathogenesis of Chagas’ cardiomyopathy. ‘Today,
the pathogenesis of the disease has been ascribed either to the
persistence of T. cruzi in myocardial tissue or to autoimmunity/
microvascular spasm/parasympathetic denervation interplay. If persistence of the parasite is proved to be the cause of the disease,
then treating patients at the chronic stage with benznidazol or
other parasiticide drug may change the natural history of the
disease’. Despite uncertainties in the pathogenesis of the disease,
a randomized trial testing the efficacy of benznidazol in Chagas’
heart disease is currently underway.
In addition, says Dr Bestetti, drugs proven to prolong life in
non-Chagas’ disease heart failure should formally be tested in
randomized trials in Chagas’ disease heart failure.
He adds: ‘Finally, randomized studies would be necessary to
assess the role of ICD for primary and secondary prevention of
sudden cardiac death, except for those at high-risk where an
ICD is vital’.
Chagas discovery was immensely appreciated in Europe, where
he received the Shaudinn Prize in 1912. However, he and his work
were fiercely attacked in Brazil and Argentina, the most important
criticism being that the disease had no socio-economic
importance.
In 1920 he was nominated for the Nobel Prize but Dr Bestetti
says, it has been speculated that the rejections influenced the
Karolinska Institute such that it did not award Chagas. ‘This is
why we are asking for justice with a posthumous Nobel Prize
to Carlos Chagas, who made the most complete discovery of a
disease, never seen in the realm of biomedical research’.1
Reference
1. Bestetti RB, Martins CA, Cardinalli-Neto A. Justice where justice is due: a posthumous Nobel Prize to Carlos Chagas (1879 –1934), the discoverer of American
Trypanosomiasis (Chagas’ disease). Int J Cardiol 2009;134:9–16.
Cardiology practice Guidelines of the European
Society of Cardiology
The constant update of existing guidelines and preparation of new topics is a huge
undertaking for the ESC. Emma Wilkinson talks to guidelines committee member
Professor Christian Funck-Brentano about how it is all organized and how the
process is being and can be improved.
A recent article in the Journal of the American Medical Association
[2009;301(8):831 – 841] raised some difficult questions about
the evidence-base used to formulate modern cardiology guidelines. An analysis of the American College of Cardiology and
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
But Dr Bestetti says: ‘Prognosis is worse for Chagas’ heart failure,
20% 1-year mortality, versus 8% in non-Chagas’ failure, despite
similar treatment’.
In patients with malignant ventricular dysrrhythmias (VT deteriorating into VF), ICD may avert sudden cardiac death which
affects up to 37% of a community-based cohort.
Heart transplantation is a valid option for patients with
end-stage cardiomyopathy.
Dr Bestetti says: ‘We have transplanted 4 patients in their twenties
and one at the age of 18 died whilst waiting for a heart transplant’.
He suggests that this poor prognosis could be because
pharmacological agents have never been tested in a randomized,
double-blinded controlled trial on patients with Chagas’ chronic
heart failure. ‘We have to extrapolate data obtained in non-Chagas’
disease patients on the assumption that we will obtain the same
benefit’, he says. ‘Prevention of chronic heart failure might be
accomplished with proper treatment by introducing b-blockers
in the early stages of the disease’.
Patients with only positive serology usually have the same life
expectancy as non-Chagas’ disease patients. Patients with only
electrocardiographic abnormalities have a slight decrease in life
expectancy, whereas patients with heart failure have a marked
decrease in survival, only about 30% live 5 years after symptoms
have appeared. ‘We estimate that overall life expectancy for
Chagas’ disease patients is 50 years in Brazil, 30% lower than for
the general population’, says Dr Bestetti.
Chagas’ disease presents unique challenges for prevention and
treatment. For prevention, Dr Bestetti believes that the main
challenge is to provide good housing for the population, as
recommended by Carlos Chagas 100 years ago. ‘However, I am
sure that this will not be possible for political reasons’, he says.
Spraying insecticide on the walls of poor quality houses may be
of value in controlling the disease, and the other big challenge is to
control deforestation, mainly in the Amazon region. Dr Bestetti
says: ‘Vaccination against this disease seems not to be on the
horizon in the near future’.
Benznidazol is effective in treating the acute stage of the disease.
In the chronic stage, one randomized trial has shown benznidazol
2066
American Heart Association guidelines over the past two
decades showed that recommendations in current clinical practice guidelines are largely developed from lower levels of evidence or based solely on expert opinion. Recommendations
for which there is no conclusive evidence are also becoming
more common.
Christian Funck-Brentano, director of the Clinical Investigation
Center at St Antoine and Pitié-Salpêtrière University Hospitals,
Paris, France, has been a member of the European Society of
Cardiology (ESC) Committee for Practice Guidelines (CPG)
CardioPulse
the guideline development process takes two to three years it’s
a fairly constant process and it can be quite a lot of work’, he
adds.
ESC CPG
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
since 2006 and he agrees that the JAMA paper raises some important questions. ‘It said that most guidelines were based on Grade
C evidence so we’re moving from recommendations made on
very strong evidence to a situation where the content of
most guidelines increasingly refer to less evidenced-based
recommendations’.
This becomes a problem when authorities view guidelines as
definitive models of care, then use them to determine reimbursement policies. ‘This is a big issue. Most recommendations are there
to be discussed, especially as guidelines are for population-based
decisions not individual patient decisions’.
But, he says there are problems with guidelines and guideline
development that must be addressed if they are to be useful to
practising clinicians. In no particular order, these include taking
on board balancing points of view of experts and non-specialists,
better management of pressure from various sources, including
academics, industry, and public health experts, and careful consideration around extrapolation of data from sub-groups into the
general population, as well as better dissemination of the
completed guidelines.
These are all issues being actively addressed by the CPG,
under the lead of Prof. Alec Vahanian from Bichat University
Hospital, but these efforts must be put in context with the
vast amount of work it takes to keep the ESC guidelines up to
date. ‘There is a list of guidelines that have been produced in
the past and the first issue is “do we need to update these guidelines”. The CPG itself discusses the need to update old guidelines
and there must be new events, new clinical trials, techniques, or
controversies that signal the need to update. A constitutional
group can also asks the CPG for an update and this is usually
the source of extensive discussion as you don’t want to update
too often or update on the basis of a single clinical trial’, says
Brentano.
Recently the CPG agreed to update guidelines on diabetes and
cardiovascular disease in the diabetic patient. ‘On average the
guidelines are updated every four years, which means that as
New guidelines can be proposed by internal staff or by national
societies although many areas are now covered and completely
new topics are becoming less common.
‘All these examples are clinical practice guidelines. The old
guidelines that were prepared 5– 10 years ago, for example on
beta-blockers, will not be updated. We want guidelines to be
practical on medical topics not specialist technology guidelines’,
he says.
Conflict of interest is an obvious and ongoing problem within
guideline development and something that the CPG are trying to
tackle. When a topic is ready for updating or a new guideline is
being developed, the CPG has to work out who to include in the
task force from a list of recommendations from national societies
and professional organizations. ‘The way the task forces are constituted influences the guidelines and one of the things we are
keen to avoid is having too many specialists—you want people
such as GPs involved’, says Brentano. ‘The second issue is you
have to get a disclosure of conflict of interest’. Recent literature
has shown that guidelines can be biased through the membership
of the task force. Conflict of interest is a difficult issue because it
relies on how intellectually honest people are.
‘I think you have to report every potential conflict of interest
even if you don’t think it’s a conflict of interest and this is not
only with industry—it can also be government related. For
example, different health systems have different reimbursement
systems which may effect the recommendation you make. With
defibrillators, Germany implants many and they are reimbursed
but in France for the past decade, until recently there were not
reimbursed. And this is a possible influence’.
Years ago, Prof. John Camm from St Georges Medical School,
London, suggested introducing a ‘passport system’ to standardize
the reporting of conflict of interest. Although this passport has
never seen the light of day, the ESC is hoping to produce an
electronic form for collecting conflict of interest information
using these principles. ‘We are still working around this and it is
a very hot issue’, says Brentano.
The main role of the CPG is to give direction to the
task forces they have selected to update or create ESC
guidelines. The first job of the chairman of each group is to
CardioPulse
accessible directly by all. That has almost doubled the number of
downloads’, says Brentano.
In addition to website access to the guidelines, there are
pocket guidelines (paper and PDA) and slide-sets, which are
often given away at meetings or by national societies. ‘We ask
each national society to formally endorse the guidelines. They
can translate them, and we have formalised the way this is
done. We are still working on having a nationally identified
person who is in charge of being the contact person for any
issue related to dissemination of guidelines in each of our
member countries’.
There are also issues around how the national societies publicise the ESC documents, as in theory they are supposed to link
directly to the ESC website. ‘We want to avoid guideline PDFs
being downloaded directly from national society websites, so,
e.g. if you go on the Finnish society website the link brings you
to the ESC. At the ESC you have all the updates and other
related materials so we would rather have people access the documents that way. We are also working with national societies on
their implementation programmes. The Spanish Cardiology
Society is very strong in this field and pushes their clinicians to
follow the guidelines’.
He says that when a guideline is published it can be difficult
to envisage how it will be received, and there is always the
concern of guideline fatigue. ‘It’s like having a movie and not
knowing how many people will go to see it. But you know
with some things, for instance if you publish a guideline on
heart failure, people will jump on it. One of the more surprising
ones was the guideline on valvular heart disease which has
been extensively downloaded although it is a more specialized
topic’.
And practicality is always a key concern for the ESC. ‘We are we
are concerned about readability and are not quite sure how
people use the information. For example, the hypertension guideline is a 60–70 page document and the question is how practical
that is when most patients with hypertension are being followed
by GPs’.
He would like to see more education and training on how to put
the expert opinion available in guidelines into practice. ‘One of the
problems is that physicians tend to see guidelines as a bible and
that’s not what guidelines are meant to be—they are there to
help direct your care of a patient’.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
prepare an outline on the structure of the guidelines and what
will be covered. For each of these sections the chairman
selects a member of the task force to carry out the literature
search.
Once the guideline process is complete, all members of
the CPG (and a selection of external reviewers) are sent
the final document for review and ultimately for publication
approval. This process is confidential and ends with a single
document of all reviewers’ comments, which is returned to
the task force for clarification before the completed
guidelines can be published. ‘It’s a complex process and it is a
fairly safe process in that so many people view the guidelines
before they are published. The conflict of interest problem is
answered by the amount of people who have a say—it would
be very difficult for one person to influence the outcome’, he
says.
Ironing out problems with conflict of interest is not the only
step being taken by the CPG to improve the guideline process
and the final product. They are also keen to make the guidelines
more practical and accessible through such measures as the whittling down of guidelines from two, to one shorter and more
concise document. ‘It used to be a full text guideline—80 pages
long and unreadable—not marvellous from a practical point of
view so now we limit the guideline to an “executive summary”
style document. More recently—the ones to be published this
year—we have asked that for each recommendation of Grade I
that the reference is attached to it as, by definition, if it is Grade
I you need to produce the evidence’, he says.
‘The other thing we have formally asked for is 10 –15 key points
that summarise the guidelines to try to make them more practical.
For example, if you look at heart failure guidelines you have key
points that can be read very rapidly to get up to date. We have
also created a section called gaps in evidence, a summary of the
things we don’t know about yet but would like to know more
about. These gaps in evidence may push further research on
these missing points’.
Then there is the question of how best to publicize the
guideline. ‘The first thing which we have worked a lot on is to
avoid having access to the guidelines behind a login. Before, you
had to register with the ESC website and many people stopped
at that stage even though this was a free process. After many
discussions on how to open the door the guidelines are now
2067
2068
CardioPulse
Reduced negative surface charge on arterial
endothelium of diabetic patients may account
for accelerated atherosclerosis: new evidence
presented by Gustav Born
Long retired, Prof. Born is still actively involved in research. At a
recent symposium held in Krakow, Poland, in memory of his
close friend, the late Prof. Sir John Vane FRS (Nobel Laureate,
1982), he presented a paper on the possible role of electrostatic
forces in atherogenesis and in the microcirculation.
Prof. Born (left) with John Vane
John Vane and Gustav Born were lifelong friends and research
associates, first in the 1950s in Oxford, and later at the Institute
of Basic Medical Sciences at the Royal College of Surgeons in
London, which Born directed from 1960.
Prof. Born (centre with glasses) his research group, and on
his left John Vane, in the Royal College of Surgeons foyer,
London, in the 1960s
He says he can remember Vane bursting into his office one day in
1971 after spending the weekend writing about the release of
prostaglandin mediators from the lung, saying: ‘I think I know
how aspirin works: it inhibits prostaglandin biosynthesis’. By
evening, Vane had carried out the first experiment and within a
few days had the necessary evidence to support his idea, for
which—together with the discovery of prostacyclin—he received
the 1982 Nobel Prize for physiology or medicine (shared with
Bengt Samuelsson and Sune Bergström).
In 1986, the two colleagues worked again in the same place, viz.
the William Harvey Research Institute, a remarkable centre set up
by John Vane in 1986 in the Charterhouse Square campus of St
Bartholomew’s Hospital Medical College, London. Here, having
retired from the Wellcome Foundation, Vane gathered around
him a group of scientists investigating the pharmacology of inflammation and of cardiovascular disease. Prof. Born, who had retired
from his chair at King’s College London, was one of them and like
most of the others he was self-funded. Now aged 87, he still has an
office and a secretary at the William Harvey, which enables him to
continue active research.
Currently, he is engaged on two very different projects, one
concerning a possible role of the negative electrostatic charges
on the inside surfaces of arteries. The idea came from earlier
work in which he showed that electrostatic repulsion rather than
prostacyclin prevents platelets from adhering in intact blood
vessels. He comments: ‘In the 1980s we showed that the insides
of arteries have extraordinarily high densities of free negative
charges, due to sialoproteins and proteoglycans. In fact, the
surface of the arterial endothelium has much higher densities
than other cell surfaces. Dr Wulf Palinski and I also showed that
if you reduce the charge on the surface of the endothelium,
blood flow through the microcirculation is significantly impeded’
[J Physiol 1989;419:169 –176]. An obvious hypothesis is that
there is electrostatic repulsion between negatively charged endothelium and red blood cells.
‘Atherogenesis involves the passage of negatively charged lowdensity lipoprotein from the blood into the arterial wall. We
have shown that removal of sialic acid groups from the arterial
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
With a lifetime’s research behind him, Professor Gustav Born MD, FRCP, FRS,
and his colleagues have come up with evidence that the early onset of heart attacks
and strokes in diabetics could be accounted for by reduced electrostatic repulsion
between the cholesterol-carrying particle in the blood and arterial walls. He talks to
Barry Shurlock, PhD, about this new work and about the other research that still
occupies his waking days.
2069
CardioPulse
endothelium with the selective enzyme neuraminidase accelerates
the process (dermatan sulphate may have the opposite effect)’.
First aggregometer
Cartoon image of possible effect of endothelial charge on
LDL uptake
Prof. Rena Yarom in Israel showed that in diabetic rats, the charge
on arterial endothelium is significantly reduced. If both these
observations applied in man, they could explain why people with
Type 2 diabetes tend to get heart attacks significantly earlier
than non-diabetics. Prof. Born and Prof. Michael P. Frenneaux,
MD, Professor of Cardiology at the University of Birmingham,
UK, have now obtained clinical evidence that the negative charge
density on the arterial endothelium of diabetic patients is indeed
lower than in non-diabetic controls, implying that LDL can move
faster into arterial walls. In this work, which has been submitted
for publication, in Diabetes, charge densities were determined on
small samples of arteries to be used for coronary bypass grafts.
They were stained with cationized ferritin, and the negatively
charged sialic acid groups so-labelled were counted under the electron microscope.
Prof. Born’s long research career has been mainly concerned
with various aspects of cardiovascular disease, including years of
work on platelet aggregation, atherogenesis, and plaque fissure.
Now, in his 80s, he is undertaking research in a completely different field—namely, cancer. He recalls: ‘Some year ago I was reading
papers on metastatic cancers. I knew that certain organs are preferentially “chosen” by malignant metastases. And then I wondered
why metastases hardly ever grow in some other tissues, notably
muscle, which together makes up about 40% of body mass?’
He comments: ‘I did not anticipate that it would be used all over
the world’. The idea came from the work he had done for the
DPhil, when he used turbidimetric assays to determine ribonuclease activity in cell cultures. He was having a bad time with
that work, he says, and the man who ‘saved him’ was the head
of the Sir William Dunn School of Pathology at Oxford, Prof.
Howard Florey, MD, well known for his role in the development
of penicillin. Florey’s advice was not to take out patents for
‘advances of value in medicine’ such as the aggregometer. Prof.
Born still regards this as good advice. The two-page paper he published on LTA in Nature [1962;194:927– 29] was declared a Citation Classic by Science Citation Index. And the concept of
determining platelet aggregation by passing light through
platelet-rich plasma is still regarded as the ‘reference standard’
for diagnosing various platelet disorders and has not yet been
overtaken by newer technology [A.D. Mumford. J Thromb
Haemost 2009;7:673–675]
Much more important than the invention of the aggregometer
itself, which Prof. Born describes as a ‘banal idea’, was his contributions to the elucidation of the mechanism of platelet aggregation.
The aggregometer led to the discovery of secondary aggregation—
a feedback mechanism whereby platelets accelerate their own
clumping by producing ADP and thromoboxane-A2. Prof. Born
admits that he and his then co-worker the late Dr Michael Cross
missed this phenomenon in their earlier recordings and it was
left to his friend, Prof. Michael Oliver and Dr D.C. Macmillan in
Scotland, to make the discovery [J Atheroscler Res 1965;5:
440–444]. However, Prof. Born discovered the first aggregation
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
Intrigued by this idea he raised £100 000 from the Garfield
Weston Foundation and set out to find a collaborator. Dr David
Sassoon from the Mt Sinai Hospital in New York agreed to join
the project and has been working with tumour and tissue cells
at the Pitié-Salpêtrière Hospital, Paris. It is too early to talk
about their findings, according to Prof Born, who comments:
‘We have picked up some interesting differences from control
tissues and I am cautiously optimistic. If we can find out how
muscle protects itself from metastatic cancer, why not other
tissues?’
The two studies are typical of much of Prof. Born’s work—
simple, clear ideas with experiments to look into reasonable
hypotheses. One of his major contributions to cardiovascular
science was the invention in 1961—the year after he moved to
the Royal College of Surgeons—of a simple device for following
platelet aggregation. The first light transmission aggregometer
(LTA) was built in his departmental workshop in 1961 and is
now in a Museum.
2070
glorious period when Max Born introduced matrix mechanics and,
with his assistants, Werner Heisenberg and Pascual Jordan laid the
foundations of quantum mechanics, later receiving the Nobel Prize,
and teacher of nine other Nobel laureates! Born and Heisenberg
were both excellent pianists and Born junior remembers lying
under their Steinways whilst they played.
After Oxford, the career of Prof. Born was mainly based in
London and in a curious way shadowed that of William Harvey,
the discoverer of the circulation. He was appointed Vandervell
Professor of Pharmacology at the Royal College of Surgeons
from 1960 until 1973, when he moved to the University of
Cambridge, UK, as Sheild Professor of Pharmacology and fellow
of Gonville and Caius College, where William Harvey had
studied medicine as an undergraduate. But for Prof. Born the
move was unsatisfactory: he comments: ‘It just didn’t work’.
Within a few years he was back in London, as Professor of
Pharmacology at King’s College, where he ‘worked happily and
productively’. In 1986 he took up his present professorship at
the William Harvey Research Institute, which in 2000 merged
with St Bartholomew’s Hospital Medical College, London—
where, it so happens, William Harvey served as a physician and
made his great discovery.
Reynolds LA, Tansey EM. 2005. The Recent History of Platelets in
Thrombosis and Other Disorders, vol 23. Welcome Trust Centre for
the History of Medicine at UCL, pp 3–13. (This source cites many
of Professor Born’s publications.)
Thomas Woodtli an artist with medical motifs
A Swiss artist whose origins were as a
medical technician briefly describes
his works.
Initially, a medical technician was employed in different scientific
laboratories at the University Hospital of Basel; he later trained
professionally in graphic printing techniques. As a part-time
lecturer at Bern University of the Arts, he lead ‘The mapped
body’ project.
Pictorial language and artistic
concerns
In his paintings, Woodtli analyses and synthesizes the composition
of material and motifs. The artist is a subtle narrator and
derives considerable inspiration from the complexity of the
world around him. His former activities in various scientific
laboratories (diabetes, cardiology, and human genetics) as well
as strolling through major cities are his inspiration. It is the
fleeting moment that counts for him, the synchronous and
varied impressions affecting the different senses, which can
only be acknowledged individually as small parts of the
whole. Woodtli chooses themes that convey socio-critical
content. Spontaneous graphic notations and collage pieces
merge together in different layers so as to create a symbolic
meta level.
Thus, creation is symbolized as rising out of chaos and the
macrocosm formed from the microcosm. Picture fragments of
gene and cell structures, human organs (heart, kidneys etc.), and
microscope slides appear frequently.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
inhibitors [Clayton, S, Born GVR and Cross MJ. Nature
1963;200:138–139] and foresaw the most significant advance to
come from LTA, namely the discovery of drugs to prevent or
reduce thrombosis in myocardial infarction and stroke. In his
Nature 1962 paper he had speculated that ‘it is conceivable that
AMP or some other substance could be used to inhibit or
reverse platelet aggregation in thrombosis’. It was left to Dr
Harvey Weiss in New York and others to identify aspirin as the
‘other substance’ [Weiss HJ, Aledort LM, Lancet 1967;2:495–497;
Evans G et al. J Exp Med 1968;128:877–94], a few years before
John Vane elucidated its mode of action. Another benefit to flow
from LTA was the use of platelet aggregation inhibitors to
prevent thrombosis in cardiopulmonary bypass machines.
Prof. Born’s interest in platelets started when, as a Medical
Officer in the British Army, he was posted in 1946 near Hiroshima,
Japan, where a few months after the atom bomb had exploded
people were still dying from ‘unstoppable’ haemorrhage due to
thrombocytopenia. This was only a few years after he had qualified
in medicine at Edinburgh University, UK, where his famous father
Max Born (1882– 1970) was Tait Professor of Natural Philosophy.
Encouraged by Albert Einstein (who coined his adage ‘God doesn’t
play dice’ in a letter to Born père), the family had left Germany in
1933, when Prof. Born was only 11 years old. They had been
forced to leave by the introduction of Nazi antisemitic laws that
stripped Born senior of his Directorship of the Institute of Theoretical Physics at the University of Göttingen. It was a sad end to a
CardioPulse
2071
CardioPulse
experimenting, creativity, flexibility and openness to new ideas are
common to both’.
This short text by Peter Killer, an art critic from Olten, very well
describes another facet of Woodtli’s work.
‘Art is a lie that makes us realize truth, at least the truth that is
given us to understand’. Expressed by Picasso in 1923, this has
much to do with Woodtli’s work, which constantly raises the
questions: ‘What is reality?’ ‘What and how do we observe?’
‘How real is our observation?’ Woodtli gives clear, yet ambiguous, answers. Reality is too complex, multilayered, and contradictory and cannot be shown in concise and simple pictures.
Diffuse, complementary compositions with puzzle-like parts are
the theme and subject of his artwork and not just a style of
art for him.
In contrast to the second part of Picasso’s quotation which is
not usually cited ‘. . . at least the truth that is given us to understand’, Woodtli’s artwork deliberately ranges between the understandable and legible on the one hand and the intangible to be
guessed and guessable on the other.
In memoriam: Robert F. Furchgott
Robert Furchgott passed away on 19 May 2009, at the age of 92
years, after a full and admirable life. He was a giant, who has had
a profound impact not only on cardiovascular physiology and
pharmacology but on biological science in general.
Dr Furchgott was born in 1916 in Charleston (SC, USA). He
graduated in chemistry from the University of North Carolina at
Chapel Hill, and went on to obtain a PhD in biochemistry at
Now cracks a noble heart. Good night,
sweet prince, Let flights of angels
sing thee to thy rest.
William Shakespeare [Hamlet]
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
Woodtli’s art is freely created from everyday motifs. In his
many-facetted compositions, he tests and questions the
meaning of newspaper pictures, illustrations in scientific textbooks, or photos of people or situations. Together, they
reflect an encyclopaedic view of the artist’s outlook of the
world. The combination of painting and digital printing techniques has occupied the artist over a length of time. The
artist is fascinated by the clash of emotional intelligence and
technical image processing. Intuitively, he draws or paints a
line across the pictorial background either freehand or digitally.
His favourite materials are glass, stainless steel, or MDF boards.
Sketches and designs are first made on paper, cardboard, or
pieces of material. Everything is incorporated into the picture,
nothing is thrown away. Over the years, several hundred
diary pages have been filled. He sketches everyday events,
sometimes from memory, or scribbles notes, most of which
are then used for the new designs. ‘My writings concentrate
in an analytical and scientific way on the positive and negative
sides of humanity. To me, science and art have many similarities:
2072
prejunctional (presynaptic) effect of the cholinergic transmitter
on adrenergic nerve terminals. Those are but a few examples of
Dr Furchgott’s monumental contribution to pharmacology and
physiology.
Dr Furchgott was a prince in science. But he remained very
humble, open, and friendly. He was always ready to talk to
younger people, always had time to try to help them. He always
asked the right constructive question. He was not seeking recognition as for him, the excitement of science did not come from
receiving awards, but from understanding better, to be able to formulate the next hypothesis, to do the next experiment to prove or
disprove the previous interpretation. But, of course, recognition
came and the scientific community saluted his pivotal contributions
by granting him the highest signs of approval, the Albert Lasker
Award for Basic Medical Research in 1996, and the Nobel Prize
in 1998, to name but the most prestigious ones.
Dr Furchgott not only was an extraordinary researcher, but a
warm, loving human being. We remember his tender care when
Lenore was ill, and how he was consumed by her disease. We
remember how more recently, he protected Maggie. We remember how he always was willing to listen to the worries of his
friends, how he always tried to help. He was a good prince in
life. We will miss him.
Paul M. Vanhoutte
Hong Kong, 13 June 2009
CardioPulse correspondence: Dr Andros Tofield, Managing Editor CardioPulse, European Heart Journal. Email: [email protected]
People’s corner: New position
doi:10.1093/eurheartj/ehp291
.............................................................................................................................................................................
Professor Malte Kelm, FESC has been recently appointed to
Head, Department of Cardiology, Pulmonary Diseases,
Vascular Medicine, and Intensive Care at Heinrich Heine
University, Düsseldorf
Between 1986 and 1987 he completed his internship in the Department of Neurology at Cologne University
and was a research associate at the Laboratory for Vascular Ultrasound at the Max-Plank Institute for Brain
Research. From 1987 to 1989 he was a postdoctoral Fellow in the Department of Cardiovascular Physiology
at the Heinrich-Heine University in Düsseldorf with Prof. J. Schrader his scientific mentor. During this time he
was a visiting scientist to Prof. J. Pearson at the Clinical Research Centre, Vascular Biology Section, Kings College, London. Prof. Kelm
spent most of his clinical career (1989–2005) in the Department of Medicine, Division for Cardiology, Pulmonary Diseases, Vascular
Medicine, and Intensive Care, Heinrich-Heine University, Düsseldorf. During this time, he rose up the ranks from resident and Fellow,
to assistant and finally associate professor of Medicine and Vascular Medicine. From 1998 to 2005 he continued as a full professor for
Internal Medicine, Cardiology, and Vascular Medicine. In 2005 he was appointed Professor and Chairman, Department of Cardiology,
Pulmonary Diseases, Vascular Medicine, and Intensive Care, University Hospital Aachen, where he was until March 2009.
During his career he has won several prestigious awards including the Homburg Award, Walter Clawiter Award, Gerhard Hess
Fellowship, Albert Fränkel Award, and Arthur Weber Award. His interests include interventional catheterization and cardiac
imaging techniques. Furthermore, he has developed a profound expertise in the underlying mechanisms and therapy of coronary
micro- and macro-angiopathy with special focus on molecular mechanisms of endothelial dysfunction and nitric oxide pathways.
Outside of medicine, Prof. Kelm has a lovely wife and two sons that keep him busy. He enjoys yachting and is a passionate runner.
His favorite authors include Herman Hesse.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 22, 2016
Northwestern University. He was on the faculty of Cornell University from 1940 to 1949, and that of Washington University School
of Medicine from 1949 to 1956. He then became professor and
chair of the Department of Pharmacology at what eventually
became the State University of New York Downstate Medical
Center in Brooklyn (NY, USA), where he worked from 1956 to
1988. From 1989 to 2004, Dr Furchgott was professor of Pharmacology at the University Of Miami School of Medicine. A very
simple, exemplary academic career.
Dr Furchgott will obviously be remembered best for his seminal
discovery (published in 1980) of the obligatory role of endothelial
cells in, the in vitro vasodilator response to the cholinergic transmitter, acetylcholine, and for his proposal in 1986, that the mysterious
‘endothelium-derived relaxing factor’ (EDRF) is nothing else but
nitric oxide. Those of us who listened to him on that day of
1986 will never forget how he simply, step by step, explained
what the tissues in his organ chambers had told him, and why
EDRF had to be nitrous oxide. We are all aware of the fact that
this very proposal opened a totally new page in biology. But his
immense contribution started long before the endothelial saga!
His studies on drug-receptor interactions, in particular, his
concept of spare receptors and receptor reserve, have been
fundamental for our current understanding of how pharmacological agonists interact with cell membrane receptors. His quest for
understanding why acetylcholine causes vasodilatation in vivo
started many years before the discovery of the role of the endothelial cells, and lead to the description of the powerful
CardioPulse