1. health and fitness
2. disease

Heart News
Volume 11, Number 1, 2003
and
views
www.ishrworld.org
the news Bulletin of the International Society
for heart research
contents
Past Truth & Present Poetry . . 1
In Memoriam Peter Harris . . . . . 3
22.
F rom M olecular B iology to the B edside
M
President's Letter . . . . . . . . . . . . . 4
Report from S. Verma . . . . . . . . . 5
Brisbane 2004 . . . . . . . . . . . . . 8
Report from H. Sommerschild 10
Janice Pfeffer Lecture . . . . . . . . . 12
Biosketches of Fellows . . . . . . . . 13
Meetings Calendar . . . . . . . . . .15
www.editorialmanager.com/jmcc/
for online submission
of manuscripts
OLECULAR biology has
taken over biological
sciences. In some respects,
its application to clinical
medicine has been dis–
appointing. Yet, molecular
biology has recently led the
way to therapeutic tri–
umphs, resulting in the
successful treatment of a
series of hitherto lethal
conditions. For us inter–
ested in problems of the heart
and circulation, these suc–
cesses are relevant, not only because all
biological sciences are interconnected,
but because heart disease may be
secondary to some of these primary
disorders.
In 1960, Nowell and Hungerford, two
physicians at the University of Penn–
sylvania, discovered a chromosomal
abnormality in the cells of patients with
leukemia and suggested that it may play
a role in the etiology of the leukemia.
This abnormally small chromosome 22
was named the Philadelphia chromosome
for the city in which it was discovered.
The Philadelphia chromosome was the
first specific mutation to be associated
with cancer. Initially this malformed
chromosome 22 was thought to represent
a deletion of a large portion of the
chromosome long arm; however, in the
early 1970s with the development of
chromosome banding techniques, Janet
Rowley showed that the
Philadelphia chromosome
results from a reciprocal
translocation between
chromosomed 9 and 22,
t(9;22). Her studies indi–
cated that most of the long
arm of chromosome 22 was
translocated onto the long
arm of chromosome 9 and
a small distal portion of
chromosome 9 was translocated to
chromosome 22 forming the Philadelphia
chromosome.
Molecular characterization of the
chromosome translocation breakpoints
and subsequent identification of the
genes involved clarified the connection
between the chromosome abnormality
and leukemia. Most of the c-ABL protooncogene is translocated from chromo–
some 9 to a position within the middle
portion of the BCP (breakpoint cluster
region) gene on chromosome 22. The cABL gene is a cellular homologue of the
v-ABL gene of Ableson murine leukemia
virus; it speficies a protein with tyrosine
kinase activity that plays a role in normal
(continued on page 2)
1
the
news bulletin of the international society for heart research
hematopoiesis. The normal c-ABL
proto-oncogene becomes activated or
oncogenic when some of its aminoterminal (N-terminal) amino acids are
removed which has the effect of
releasing the ABL kinase from its normal
regulatory constraints. The BCR-ABL
hybrid gene formed from the chromo–
some translocation removes the Nterminal ABL sequences and replaces
them with BCR sequences resulting in a
constitutively active ABL kinase and
unwanted and uncontrolled cell growth.
The Philadelphia chromosome was
first identified in patients with chronic
myelogenous leukemia (CML). It is now
known to occur in almost 100% of CML
patients. It also has been identified in
about 5% of children and 30-40% of
adults with acute lymphocytic leukemia.
Transcription of the hybrid BCR-ABL
gene in CML produces an 8.5-kb fusion
transcript that encodes a 210-kDa hybrid
protein, the activated tyrosine-specific
kinase. This BCR-ABL fusion oncogene
is able to transform primary hemato–
poietic cells in culture and induce
hematopoietic neoplasms in mice. In
ALL the BCR-ABL rearrangement often
produces a shorter fusion transcript and
hybrid fusion protein (185 to 190kDa).
Tyrosine kinases are important in the
regulation of numerous key cellular and
developmental processes as they serve
as growth factor receptors and as
transducers of intracellular commu–
niations. The chimeric tyrosine kinase
proteins resulting from gene fusions
such as the BCR-ABL fusion represent
novel, tumor-specific products and as
such are ideal targets for new molecular
therapeutic strategies.
It is not surprising that progress in
the field of molecular therapeutics
depended on discoveries from basic
research and on development of new
technologies. First, chromosomal
abnormalities were found by kario–
2
typing. Later, tools of molecular
genetics such as situ hybridization,
gene amplification and DNA se–
quencing, identification of fusion
transcripts, immunoblotting, measure–
ment of kinase activity, and anti–
proliferative assays were developed.
Finally, it was the clinician and the
pharmacologist who developed the
therapeutic implications of these
fundamental discoveries.
The clinical success depended on the
successful inhibition of tyrosine kinase.
This was first demonstrated in vitro by
groups from the Ciba-Geigy (now
Novartis) Company and by workers at
the University of Oregon who tested
several compounds of the 2-phenyl–
aminopyrimidine class. One compound
(imatinib mesylate) exhibited specific
inhibition at the submicromolar level.
This molecule, also known as Gleevec
or ST1571, binds in the active site of the
ABL tyrosine kinase and prevents the
binding of ATP. The compound showed
efficacy and safety in patients with
CML, and many patients treated with
this compound went into complete
remission, a remarkable therapeutic
triumph. In fact, initial trials with this
drug were so successful that Gleevec
received the fastest FDA approval of
any drug in history (2 months).
Tyrosine kinases also play a role in
the etiology of the idiopathic hyper–
eosinophilic syndrome (HES). This
disease has relevance to the cardiologist
as it is frequently accompanied by heart
disease. This syndrome also results from
the presence of a tyrosine kinase which
is susceptible to the specific inhibitor
imatinib mesylate (Gleevec). The cardiac
manifestations of HES result from
eosinophilia infiltration of the myo–
cardium (Loeffler syndrome), resulting
in acute necrosis, followed by throm–
bosis, and finally by myocardial fibrosis.
As in CML, patients with HES can go
into complete remission when treated
with the tyrosine kinase inhibitor. These
results represent a triumph of the
combination of fundamental and clinical
studies.
There has been much discussion
about the application of molecular
biology and genetics to the bedside.
Here we have a brilliant example that
such an application is feasible. This
should give us hope that a combination
of molecular biology and clinical
medicine can find therapeutic ap–
proaches to incurable diseases.
Selected publications:
Buchdunger E, Zimmermann J, Mett H et al.
Inhibition of the Abl protein-tyrosine kinase
in vitro and in vivo by a 2-phenyl–
aminopyrimidine derivative. Cancer Res
1996; 56: 100-4.
Klein A de et al. A cellular oncogene is
translocated to the Philadelphia chro–
mosome in chronic myelocytic leukemia.
Nature 1982; 300: 765-7.
Druker B, Talpaz M, Resta D et al. Efficacy
and safety of a specific inhibitor of the
BCR-ABL tyrosine kinase in chronic
myeloid leukemia. New Engl J Med 2001;
344: 1031-7.
Konopka JB et al. An alteration of the
human c-ABL protein in K562 leukemia
cells unmasks associated tyrosine kinase
activity. Cell 1984; 37: 1935.
Rowley JD. Biological implications of
consistent chromosome rearrangements in
leukemia and lymphoma. Cancer Res 1984;
44: 3159.
Weller PF, Bubley G. The idiopathic
hypereosinophilic syndrome. Blood 1994;
83: 2759-79.
I am grateful for the constructive help
of Dr Faye Eggerding.
Richard J Bing, M.D.
Volume 11, Number 1, 2003
P
ETER HARRIS was an influential
international statesman in car–
diology. He was at the forefront of the
revolution in biomedical research that
started more than 40 years ago and
paved the way for radical new treatments
that are now taken for granted in most
branches of medicine.
A science scholar at King’s College,
London, UK, Harris trained in medicine
at Kings College Hospital, qualifying in
1946. During house appointments at
King’s and the Brompton Hospital, he
obtained his MD in 1951, winning the
university gold medal and a PhD in
1955. That was followed by a 2-year
Nuffield Fellowship at the Bellevue
Hospital and Columbia University, New
York, USA. On his return to the UK, he
was appointed lecturer, in 1957, and
reader in medicine, in 1962, at Birm–
ingham University.
His career, which was dedicated to
exploring the cardiovascular system and
the origins of heart disease, can be
viewed as three chapters. During the
1950s and early 1960s, he was in the
mainstream of research, and used
established methods of haemodynamic
measurements to explore cardiac output
and pulmonary blood flow and the
metabolism of the heart muscle. In the
process, he compiled an immense body
of knowledge that was the basis for The
Human Pulmonary Circulation, the first
of his definitive texts, co-authored with
Donald Heath, a colleague then at
Birmingham. He maintained that since
so many of the methods of garnering
cardiovascular data in research into the
circulation and valve disease had
passed into routine clinical inves–
tigations, the catheter laboratory should
be supported by the National Health
Service rather than be a drain on
university funds. The argument was
also a signal to the second stage of his
career when his research into the heart
muscle turned to experiments at the
cellular and molecular level.
His view that a better understanding
in memoriam
Peter Harris
1923 - 2002
(self-portrait)
of heart disease probably lay in a more
intimate knowledge of the physiology
and biochemistry of abnormalities of
the heart muscle coincided, in 1966, with
a decision of the British Heart Foun–
dation to create its first chair in
cardiology. Harris was given the chance
to follow his vision when he was
appointed the first Simon Marks
Professor of Cardiology at the Cardio–
thoracic Institute and Director of the
Institute of Cardiology, in the University
of London. Initially there were some
shortcomings; his brave new world
consisted of one room with a secretary
and technician. But the fortunes of the
unit improved, with support from the
Medical Research Council and the
Wellcome Trust, and at new premises
on Wimpole Street it became a magnet
for a formidable team of scientists
working on the underlying biochemistry
and physiology of heart disease.
Today’s holder of the Simon Marks
Chair of Cardiology, professor Philip
Poole-Wilson, says that as well as
developing his own interests in heart
disease, Harris trained and encouraged
many scientists and clinical cardiol–
ogists who now hold leading posts
around the world.
In 1970, Harris organised a meeting of
the European section of an international
study group for research in cardiac
metabolism, which resulted in the
publication of one of the most influential
works on cardiology: Calcium and the
Heart. The study group was also the
forerunner of the International Society
for Heart Research, which, in 1986,
created the prestigious Peter Harris
Award for Achievement in Research.
The third element to Harris’s career
involved his fascination with the
evolution of the cardiovascular and
related systems, and love of travel. In a
series of essays in 1983, he traced the
way that the origins of clinical heart
failure might lie in ancient reflexes. And
expeditions to the Andes and Himalayas
raised questions in his mind about the
long-term adaptation in llamas, yaks,
other animals, and people to their
environment. His study of the right
ventricle of the heart and the blood flow
to the lungs of yaks showed they had
adapted genetically to high altitude by
eliminating the vasoconstrictor re–
sponse due to reduction of oxygen; and
a study of crossbreeds, the dzo and
stols, revealed that this characteristic
was inherited as a simple autosomal
dominant.
In 1988, Harris described a new
disease in man at altitude occurring
widely in Tibet, sub-acute infantile
mountain sickness. It affected infants
born at low altitude and brought to live
in a place higher up. He believed the
syndrome illustrated his view of the
evolutionary processes involved in the
development of the circulation to
promote the survival of the species.
Away from the laboratory he was a
talented musician and artist, and he
showed a leaning toward satirical
writing. His wife Francesca survives
him.
Reprinted with permission from Elsevier
(The Lancet 2003; 361: 1231).
3
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news bulletin
of the
international society
for
heart research
P resident s l etter
Strength in Numbers
I AM WRITING to you from post-war America. We continue to see the aftermath
of the terrorist attacks of 9-11 play itself out on the world stage. Our staunchly
conservative government is asserting itself like no other in recent memory. As a
result, historically strong alliances are being strained by President Bush’s new
America-first policy. What kind of world order will emerge from all of this is anyone’s
guess. The ISHR was contacted in April to see if we wanted to join the coalition of
the willing but we politely declined. As it turned out, coalition forces had more than
enough cardiac biochemists to accomplish their mission in Iraq without us.
The terrorist threat has already claimed one ISHR casualty. The Australasian section’s meeting originally
scheduled for Bali had to be canceled in the aftermath of the terrorist bombing there. It has been rescheduled to
meet in Melbourne August 7-9, 2003. Otherwise, this year’s meetings schedule seems to be proceeding on schedule.
Fortunately, none of our meetings is scheduled for regions with a SARS travel advisory. I just returned from a
meeting in Japan. Although SARS has not yet spread to Japan, all Asian travelers are nervous. When my Delta
flight landed in Narita (Tokyo) it pulled in between two Chinese airliners. I tried to hold my breath until I cleared
customs. The direct result of the Asian SARS scare was very empty aircraft both coming and going. It was great
for those traveling in coach but one wonders how long the airline industry can keep flying with so many empty seats.
Leslie Lobaugh, the ISHR’s executive secretary, has been hard at work with the section secretaries to get
an accurate census of our worldwide membership. At the time of this writing we have 2576 active members. The
number is somewhat fluid because we receive new applications through the web site almost every day. The
breakdown is Australasian: 91, Chinese: 373, European: 746, Indian: 44, Japanese: 406, Latin American: 69 and North
American: 847. Leslie had gone through the international database and cleared out all of the inactive members. We
are constantly updating our membership information to keep it as accurate as possible. However if you move, get
a new email address or phone number we have no way to know unless you contact us and let us update your listing.
Please take a minute and go to www.ishrworld.org and look at your contact information in the membership directory
to see if it is current.
We use the ISHR database for email communications with the membership. This includes the latest PDF
version of this publication, HEART NEWS AND VIEWS, along with meetings announcements and other important
information. Every time I send out a mailing I get about 10 bounced emails (email addresses that are no longer valid).
We have no choice but to erase those from the database. Please get your current email address to us so we can
keep you abreast what is happening in the ISHR. Send us updates.
As the saying goes, there is strength in numbers, and that certainly holds true for the ISHR. At 2576 members
we still remain the worlds largest organization devoted solely to heart research. Nevertheless there are thousands
of potential members still not in our organization. The Basic Cardiovascular Sciences council of the American Heart
Association has nearly twice that many members. Granted, that includes a large number of vascular biologists who
might not see the ISHR as their primary affiliation, but there are still many cardiac researchers who are not members.
Please ask your colleagues and students if they are members. If they are not, urge them to consider joining the
society. By the way, most sections have a very attractive student rate. A membership form can be found at
www.ishrworld.org.
James M. Downey
4
volume 11, number 1, 2003
C - r eactive p rotein i ncites
a therothrombosis
Atherosclerosis and its complications represent the most common cause of
death in Western societies. Over the past few years we have witnessed a
paradigm shift in our understanding of the underlying principles of athero–
sclerosis. This new view supports the concept that inflammation is the central
orchestrator of atherosclerotic lesion formation, progression, and eventual
rupture.1,2 Chronic inflammation results in endothelial dysfunction, and
facilitates the interactions between modified lipoproteins, monocyte-derived
Subodh Verma, M.D., Ph.D.
macrophages, T cells and normal cellular elements of the arterial wall inciting
early and late atherosclerotic processes. This paradigm has fueled
exponential interest in evaluating inflammatory markers of atherosclerosis, of
which high sensitivity C-reactive protein (CRP) has emerged as one of the
most important. As such, the inflammatory marker CRP is one of the most
powerful independent predictors of myocardial infarction, stroke, and vascular
death in a variety of settings, with prognostic value extending across various
ethnic groups, and in men and women in different age groups.3-6 More
recently, elegant work by Ridker and colleagues has demonstrated that CRP
may be a better predictor of future cardiovascular events than LDL-cholesterol,
and that baseline CRP evaluation adds prognostic value to conventional
Framingham risk assessment.7 The link between CRP and atherosclerosis
was initially suggested to be that of a “surrogate biomarker” vs a mediator of
atherosclerosis. This view has been recently revisited; with observations
suggesting that CRP has a direct effect to promote atherosclerotic processes
and endothelial cell inflammation. In this report our data are summarized,
which suggests that CRP functions as a powerful proatherogenic factor, in
addition to a risk marker of atherosclerotic and metabolic events.
Effects of CRP on Endothelial Cell
Activation and Angiogenesis
A growing body of evidence im–
plicates CRP as a direct mediator of
endothelial dysfunction. First, CRP at
concentrations known to predict
vascular events, directly upregulates
endothelial cell adhesion molecules,
such as ICAM-1, VCAM-1 and Eselectin.10-15 These adhesion molecules
play a key role in the facilitating
leukocyte-endothelial interaction, an
early step in atherogenesis. Once the
Dr Subodh Verma was the winner of
the Young Investigators Award
competition at the XXIV American
Section Meeting (Madison, WI; July
24-27, 2002).
leukocytes adhere to the dysfunctional
endothelium, CRP promotes the release
of MCP-1, a key chemoattractant
chemokine, which facilitates leukocyte
transmigration through the endo–
thelium.10,11 Third, CRP directly promotes
the release of potent endotheliumderived contracting factors, such as
endothelin-1 (ET-1) from endothelial
cells.10 ET-1 is not only one of the most
potent vasoconstrictors currently
known, but also appears to be a mediator
of CRP-induced upregulation of ad–
hesion molecules and MCP-1. 10 More
important are observations demon–
strating the ability of CRP to directly
quench the production of nitric oxide
(NO) from the endothelium. 16,17 NO is
the key endothelium-derived relaxing
factor, which plays a pivotal role in the
maintenance of vascular tone and
reactivity. In addition to being the main
determinant of basal vascular smooth
muscle tone, NO acts to negate the
actions of potent endothelium-derived
contracting factors such as angiotensinII (Ang-II) and ET-1 and serves to inhibit
platelet and leukocyte activation and
maintain the vascular smooth muscle in
a non–proliferative state. Human
recombinant CRP, when incubated with
human endothelial cells at concen–
trations demonstrated to predict vas–
cular events, potently inhibits both
basal and stimulated NO release, in part
via destabilizing endothelial nitric oxide
synthase (eNOS) transcript.16 In ad–
dition, CRP inhibits the eNOS protein
expression, and the downstream effector
of NO, cyclic GMP. 16 By virtue of
inhibiting eNOS expression and NO
release, CRP blocks NO-dependent
processes, such as angiogenesis. 16
When studied in vitro, using both
scratch-wound assays, and endothelial
cell migration studies, CRP consistently
inhibits angiogenic responses, in a NOdependent fashion. Angiogenesis is a
key compensatory mechanism in
chronic ischemia, and the ability of CRP
to inhibit angiogenesis has important
clinical implications for patients with
coronary artery disease. Endothelial
cell apoptosis is an important contributor
in lesion formation, propagation and
eventual rupture. Through inhibiting
NO production, CRP facilitates endo–
thelial cell apoptosis, uncovering yet
another proatherogenic and proin–
flammatory phenotype. 16 Recent evi–
5
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of the
dence also implicates CRP as a direct
promoter of CD14-induced endothelial
cell activation. 18 In addition to the
aforementioned effects of CRP on
endothelial cell adhesion molecules,
and vasoactive hormone release, CRP
functions to upregulate the tran–
scription factor NFκB (unpublished
observations) NFκB has been implicated
as a key mediator of atherosclerosis.
The majority of proinflammatory genes
expressed in endothelial cells during
the initial phase of lesion formation and
in response to inflammatory mediators
are dependent on NFκB activation.
Recent evidence suggests that CRP
directly increases the degradation of
IκB-α and subsequently activates the
NFκB pathway in endothelial cells
(unpublished observations). The pro–
atherogenic effects of CRP on endo–
thelial activation are exaggerated in the
hyperglycemic milieu,19 suggesting an
important mechanistic link between
hyperglycemia, endothelial dysfunction
and cardiovascular disease. Lastly,
patients with elevated levels of CRP
have been shown to elicit impaired
endothelium-dependent vasodilatation,
suggesting that CRP may be a useful
clinical tool for endothelial vaso–
motion.20
Effects of CRP on Macrophage
LDL-Uptake
Uptake of LDL by macrophages is an
important process contributing to
plaque progression. Recent evidence
suggests that CRP directly promotes
native LDL-uptake into macrophages, a
process that is ET-1 dependent, and
inhibited during co-incubation with the
ETA/B receptor blocker, bosentan.10,21
Effects of CRP on Fibrinolytic
Parameters
Endothelial cells are the major source
of plasminogen activator inhibitor-1
(PAI-1) and PAI-1 serves to inhibit
endogenous fibrinolysis, promoting
atherothrombosis and progression of
6
international society
acute coronary syndromes. Recent
evidence suggests that incubation of
human coronary artery endothelial cells
with CRP results in a time- and dosedependent increase in secreted PAI-1
antigen, PAI-1 activity, intracellular
PAI-1 protein, and PAI-1 mRNA. 22
Effects of CRP on Vascular Smooth
Muscle Cells and Angiotensin
Receptor Regulation
Ang-II is one of the most important
proinflammatory molecules, capable of
promoting diverse proatherosclerotic
processes at the level of the endo–
thelium, and vascular smooth muscle.
The majority of Ang-II is produced
locally, and mediates inflammatory and
atherosclerotic actions via the angio–
tensin type 1 receptor (AT1-R). The AT1R is a key atherosclerotic switch
facilitating Ang-II induced reactive
oxygen species production, VSM
migration, proliferation, and vascular
remodeling. Given the central impor–
tance of AT1-R in the development and
clinical course of atherosclerosis, we
recently evaluated the effects of CRP
on AT 1 -R and associated patho–
physiological processes.23 CRP potently
upregulates AT1-R mRNA and protein,
and increases the number of AT1-R
binding sites in VSM cells.23 This effect
is not related to a change in AT1-R
mRNA stability, since the half-life of
AT1-R transcript was similar following
incubation with actinomycin-D. Addi–
tionally, in VSM cells in vitro, CRP
markedly stimulated cell migration and
proliferation, with an effect approaching
75% of that noted with the protypical
stimulant PDGF.23 The effects of CRP on
VSM cells appear to be closely related
to the expression of AT1-R, since they
were inhibited by losartan, an angio–
tensin receptor blocker. CRP also
augmented Ang-II-induced VSM cell
migration and proliferation, further
supporting a functional relationship
between CRP and Ang-II in mediating
VSM cell pathology. In VSM cells, CRP
for
heart research
increased basal ROS production, and
potentiated the effects of Ang-II on
ROS formation. These effects were also
inhibited by losartan, indicating that
increased CRP-mediated ROS formation
in VSM cells was related, in part to
increased AT 1-R expression. Lastly, in
an in vivo model of carotid balloon
angioplasty, CRP exposure facilitated
AT 1 -R expression, with resultant
increases in neointimal formation, VSM
migration and proliferation, and pro–
moted collagen and elastin production,
key matrix proteins in the vessel wall.
These effects were attenuated by
angiotensin receptor blockade with
losartan. Therefore, CRP exerts direct
proatherosclerotic effects at the level of
the VSM (in addition to the endothelium)
in part, via increased AT 1-R expression
and signaling.23 No effect of CRP was
found on AT2-R, which may be vasculo–
protective in certain settings. Likewise,
we did not observe an effect of CRP on
Ang-II release.
Effects of CRP on Bone Marrow
Derived Endothelial Progenitor Cells
Postnatal neovascularization is a
process that is vital to the compensatory
physiologic response in chronic isch–
emia. Myocardial ischemia provides a
potent stimulus to angiogenesis and
the subsequent development of col–
lateral vasculature that maintains and/
or revitalizes cardiac tissue. The
mobilization and differentiation of bonemarrow derived endothelial progenitor
cells (EPCs) has recently been shown to
be important in this process of neo–
vascularization.24 In fact, recent evi–
dence suggests that EPCs contribute to
over 25% of endothelial cells in newly
formed blood vessels. More recently,
the number and migratory activity of
circulating EPCs has also been shown
to inversely correlate with risk factors
for coronary artery disease. 25 In this
vein, recent work suggests that EPCs
incubated with human recombinant CRP,
at concentrations known to predict
volume 11, number 1, 2003
adverse vascular outcomes, exhibited
decreased survival and increased
apoptosis.26 This reduction in EPC cell
number was dose dependent, and at a
CRP concentration of 20µg/mL, there
was an approximate 80% reduction in
cell number at seven days. Additionally,
EPCs incubated with human recom–
binant CRP exhibited decreased ex–
pression of EC specific markers Tie-2
and EC-specific Lectin indicating an
effect of CRP to inhibit EPC differ–
entiation.26 CRP also caused a significant
decrease in EPC eNOS mRNA expression
after 24 hours of incubation. These
observations extend the proatherogenic
effects of CRP, beyond the endothelium
and VSM, to the bone marrow, and the
systemic response in chronic ischemia.
Conclusions
A growing body of evidence impli–
cates CRP as a powerful risk marker for
diverse cardiovascular and metabolic
diseases. Initially, this association was
suggested to be a surrogate one,
wherein CRP functioned to highlight
increased levels of vascular inflam–
mation, and in this fashion identify
patients at heightened risk of athero–
thrombosis. This dogma has been
recently revisited, with observations
from our group and others suggesting
that CRP functions as a direct partaker
in lesion formation, and directly
uncovers a proatherosclerotic and
proinflammatory phenotype. Thus, CRP
may not just be a marker of athero–
sclerosis and coronary events, but also
a mediator of this disease because it
contributes to the substrate underlying
lesion formation, plaque rupture, and
coronary thrombosis. The CRP-athero–
sclerosis story is nothing short of a
self-fulfilling prophecy.
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24. Szmitko PE, Fedak PWM,Weisel RD et
al. Circulation (in press)
25. Hill JM, Zalos G, Halcox JP et al. N Engl
J Med 2003; 348: 593-600.
26. Verma S, Kuliszewski MA, Mickle DAG
et al. Can J Cardiol 2002; 18 (Suppl. B):
325.
Subodh Verma, M.D., Ph.D.
Toronto, Ontario, Canada
Human C-reactive protein (CRP) elicits direct proatherogenic and proinflammatory effects.
CRP, at concentrations known to predict diverse vascular events, directly quenches endothelial
cell nitric oxide (NO) production via destabilizing eNOS transcript. Via decreasing NO release,
CRP inhibits angiogenesis, and stimulates endothelial cell apoptosis. In a synchronous fashion,
CRP stimulates the release of the potent endothelium-derived contracting factor, endothelin-1
(ET-1), which in part, is responsible for CRP-induced upregulation of adhesion molecules
ICAM-1 and VCAM-1. CRP potently upregulates MCP-1 release, a key chemoattractant
chemokine responsible for leukocyte transmigration. Recent studies suggest that CRP also
promotes NFκB upregulation in endothelial cells. At the level of the VSM, CRP promotes AT1R upregulation, and stimulates VSM migration, proliferation, and neointimal formation while
concomitantly increasing reactive oxygen species production. CRP also inhibits endothelial
progenitor cell survival and apoptosis and stimulates PAI-1 production (not shown in this
diagram). In this fashion, CRP functions as an active participant in lesion formation, and hence
is mechanistically linked to atherosclerosis.
7
the
news bulletin
of the
international society
for
heart research
Brisbane
XVIII world congress International Society for heart research
and the
52nd Annual S cientific meeting of the cardiac society
of Australia & new zealand
Cardiology bench to bedside: the science and the practice
7-11 a ugust 2004
brisbane convention & exhibition centre Brisbane Queensland Australia
Dates to remember:
Deadline for Abstracts:
February 29, 2004 (How could
anyone forget this date?)
Deadline for Young Investigator Grant
applications:
February 29, 2004
Notification of acceptance of abstracts:
March 29, 2004
Deadline for hotel registration:
May 31, 2004
CPT 2004:
July 31-August 6, 2004
Pre-conference satellites:
Iguazú Falls (Argentina/Brazil)
August 1-3, 2004
Melbourne (Australia)
August 3-5, 2004
ISHR2004:
Saturday, August 7 to Wednesday,
August 11, 2004
CSANZ 2004:
August 8-11, 2004
Post-conference satellites:
Hong Kong (China)
August 13-15, 2004
Kruger National Park (South Africa)
August 13-15, 2004.
FOR MANY OF US, setting MCQ is a way of life. Try this
one:
What are the major advantages for members of the
ISHR?
A.
It is the only international society focussing on
cardiovascular research
B.
It is the society behind the well-respected Journal
of Molecular and Cellular Cardiology
8
C.
It publishes HEART NEWS AND VIEWS, now in
full colour
D.
It holds triennial scientific conferences, with the next
being in Brisbane
E.
All of the above.
What is the prize for the correct answer?
Simple – free access to the web-site for the Brisbane meeting
at www.heart2004.com !
THE LOCAL ORGANISING COMMITTEE has been working
to bring you symposia which will demonstrate the advances
in cardiovascular research since Winnipeg.
One major problem has been to cut down the 130 or so
symposia suggestions to the 40 timeslots that we have
allocated.
This has now been done and, by the time you read this, all the
symposia chairpeople will have confirmed their involvement
and we will be finalising the speakers.
The breadth of the topics is astounding and evidence that
cardiovascular research remains one of the key research areas
in biomedical sciences.
Further, this research is international – so the ISHR is the
appropriate place to present new studies.
We hope to have the initial program on the web-site in August
or September to show you what you can expect to hear in
Brisbane.
THE ISHR has always emphasised young researchers and,
once again, there will be financial assistance for young
investigators to allow them to present their work in Brisbane.
The details are already on the web-site even though the
deadline is February 29 th, 2004, the same date for all
abstracts.
I will be applying to other funding bodies to increase the
funds available for young investigators – so please send in
your excellent applications to reinforce my contention that
this congress will attract the best young researchers from
around the world.
volume 11, number 1, 2003
The Story Bridge crossing the Brisbane river framing Brisbane's Central Business District
THERE HAS ALSO BEEN a lot of progress on planning the
world congress of Clinical Pharmacology and Therapeutics
which will run from the Sunday to Friday preceding our
meeting at the same venue. More details can be found at
www.cpt2004.com .
One highlight of CPT2004 will be a symposium on the Friday
morning on the Pharmacology of Cardiac Protection, to be
chaired by Jim Downey and myself.
Another highlight will be a Thursday afternoon symposium
on Drugs & Arrhythmias: Causes & Cures to be chaired by
Terry Campbell.
Keep checking the CPT web-site for more details! There will
be day registrations available to CPT2004 for ISHR members
to allow us to participate.
OUR CONGRESS will be integrated with the annual
scientific meeting of the Cardiac Society of Australia and
New Zealand.
Registration for either meeting will allow complete access to
all sessions of both societies.
As the motto for the meeting suggests, this will allow the
emphasis of the interrelationships between cardiovascular
science and practice.
ANOTHER IMPORTANT REASON to come to Brisbane is to
see the unique flora and fauna of Australia. The State of
Queensland is a major tourist destination in Australia as we have
the Great Barrier Reef, tropical rainforests, fantastic beaches, the
great Outback and much more. Why not take time to see this part
of the world? Check out the links to discover Brisbane or
Queensland on either the CPT or ISHR meeting web-sites.
Further, Brisbane is only a short flight away from the wonders
of New Zealand – examples are the volcanic areas of Rotorua
and ski-ing in the Alps of the South Island as August is winter
in the southern hemisphere. Then there are the tropical
paradises of Fiji, New Caledonia, Samoa and many others. Is
there a better way of spending your vacations in 2004?
THE SATELLITES are also progressing and we will be posting
details of the scientific programs within the next few months.
Details on the locations are already available on the web-site
– the next thing is for you to make the decision on which one
or more satellites you want to participate in!
See you in Brisbane in August next year!
Lindsay Brown, Ph.D.
9
the
news bulletin
of the
international society
for
heart research
R EPORT ON THE F IRST ISHR -ES/
S ERVIER R ESEARCH F ELLOWSHIP
After completing my medical studies I started work in basic medical research
in 1995 with Arnfinn Ilebekk and Knut Arvid Kirkeböen at the Institute for
Experimental Medical Research at Ullevål University Hospital in Oslo. We
studied the protective role of endogenous adenosine in an isolated piglet
heart model of global zero-flow and low-flow ischemia (acute hibernation).
This led to a PhD in 1999. In a short period of postdoctoral research in my
previous laboratory in Oslo, we started to work with the intriguing
phenomenon of myocardial preconditioning (PC) in anaesthetized pigs. At
this time a group at the Karolinska Institute in Stockholm/Sweden, lead by
Bertil Fredholm and Guro Valen was starting to look into the specific role of
adenosine receptor subtypes in PC of genetically engineered mice. After
some contact we decided to try and work together on this project. We wrote a
grant proposal and were very honoured to be awarded the first ISHR-ES/
SERVIER Research Fellowship in 2001. This made it possible for me to have
a one-year postdoc position at the Karolinska Institute from august 2001 to
august 2002. The results of this collaboration are presented below, as well
as some background information about adenosine and PC.
The History of Adenosine,
Preconditioning and Adenosine in
Preconditioning
Studies of adenosine in the cardio–
vascular system began in 1929 with the
discovery by Drury & Szent-Györgyi
that extracts from various tissues
containing adenosine produced brady–
cardia, hypotension and coronary
vasodilatation.1 That adenosine also
exerted direct cardioprotective effects
on the myocyte itself was discovered in
1985 by Ely and coworkers. 2 They
showed enhanced recovery of function
and higher postischemic ATP levels in
hearts treated with adenosine, and
proposed that adenosine served as an
intracellular substrate to enhance
salvage resynthesis of ATP during
reperfusion. Since then, cardioprotec–
tive effects of adenosine have been
extensively investigated, including the
importance of adenosine in the phe–
nomenon of myocardial precondi–
Dr Hilchen T. Sommerschild was in
2001 the recipient of the first ISHRES / SERVIER Fellowship.
10
tioning.
The term ischemic “preconditioning”
(PC) was introduced to describe the
phenomenon that myocardium exposed
to short periods of reversible ischemia
possess an increased tolerance to a
subsequent longer lasting ischemic
period.3 Protection induced by ischemic
preconditioning has a bimodal dis–
tribution: an early phase (early PC) and
a delayed phase (delayed PC). 4,5
Additionally, myocardial PC can be
evoked by systemic stimuli such as
anisomycine, or by preconditioning of
other organs. 6,7 These phenomena
represent adaptive and protective
responses to ischemia, but differences
in time courses of protection as well as
target organ may indicate different
underlying mechanisms.
Several endogenously produced
substances have been implicated as
triggers of this response. Since 1993 it
has been known that transient exposure
to exogenous adenosine or agonists
can mimic early PC against infarction.810
Endogenous adenosine initiates and
mediates early PC against infarction in
most species.8 The role of adenosine in
Hilchen T. Sommerschild, M.D.
delayed PC has been investigated, and
it is probably involved in protection
against infarction, as transient ex–
posure to adenosine 11 or adenosine
agonists12-15 induces delayed PC against
infarction. Adenosine may also be
involved in protection by remote PC.16
Despite massive experimental evi–
dence for the beneficial effects of
adenosine during ischemia and reper–
fusion, it is not used in the treatment of
patients with acute coronary ischemia.
The reason is that administration of
exogenous adenosine can cause sys–
temic side effects, such as hypotension,
bradyarrhythmias and induction of
“coronary steal” if a critical coronary
stenosis is present. 17 When given
intravenously to humans, adenosine
causes vasodilatation with increased
sympathetic activity, additionally it may
cause discomfort with facial flushing,
headache, chest pain and dyspnoea.17,18
Moreover, rapid degradation in the blood
makes continuous intravenous - or
possibly intracoronary infusion nec–
essary to obtain a sustained effect on
the myocardium. Hence, the role of the
five known adenosine receptor subtypes
(A1, A2a, A2b, A3, A4) and the effect of
corresponding selective agonists in
cardioprotection is of crucial importance.
Study of the Role of Adenosine
Receptor Subtypes in PC at the
Karolinska Institute
The main aim of our project was to
clarify the role of adenosine A1receptors and A3-receptors in PC. The
Karolinska Institute provided very good
volume 11, number 1, 2003
opportunities to investigate this in mice,
and has a very good international
reputation as an excellent research
institution. One group there lead by
Guro Valen has established mouse heart
perfusion since 1998. Furthermore,
another group lead by Bertil Fredholm
has produced a mouse deficient of the
adenosine A1 receptor, and had
available mice lacking the A3 receptor
produced elsewhere. The mouse geno–
me has been characterized, and the
genetically engineered mouse may be a
powerful tool to unravel the mysteries
of gene function, thus potentially
providing new insight into cardio–
vascular physiology and pathophysi–
ology (and other organ/cell systems, of
course!). However, the mouse is small
and studies of physiology are partic–
ularly demanding in that species,
requiring more sophisticated equipment
and handling than larger species.
The Role of the Adenosine A1
Receptor in Remote, Delayed
Preconditioning
The first experimental series I entered
into concerned a putative role of the
adenosine A1 receptor in remote,
delayed preconditioning. The model was
established by a previous PhD student,
Shinichi Tokuno, who found that mice
with severe atherosclerosis due to
apolipoproteinE/LDL receptor defi–
ciency had spontaneous ischemic
events in their hearts and brains.19 When
hearts of these animals were isolated
and subjected to global ischemia, heart
function was improved and infarct size
reduced compared with hearts of noninfarcted mice. This finding could be
mimicked by inducing brain ischemia
through bilateral occlusion of the
internal carotid arteries 24-36 hours
earlier in wild type mice, but not in mice
deficient in the inducible nitric oxide
synthase gene (Tokuno et al. 2002). I
wanted to study a possible role of the
adenosine A1 receptor in this model
through using mice without the A1
receptor. To characterize adenosine
release, microdialysis probes were
placed in the brain and the femoral artery
before carotid artery ligation, and
microdialysates collected for meas–
urement of adenosine and its meta–
bolites. Adenosine and its metabolites
increased locally in the brain as well as
in the circulation after carotid artery
ligation. Thereafter other mice were
subjected to the same preconditioning
protocol, and their hearts isolated to
study function and infarct size after
induced global ischemia. We found that
A1 receptor knockout mice as opposed
to their wild types could not be protected
by remote, delayed preconditioning. We
studied whether this may be due to
influence on mitogen activated protein
kinase (MAPK) phosphorylation during
ischemia and reperfusion through serial
sampling of hearts during perfusion,
ischemia, and reperfusion, protein
extraction, and immunoblotting with
phosphospecific antibodies against
ERK1/2, JNK, and p38 MAPK. However,
although both ERK1/2 and p38 were
phosphorylated during reperfusion after
global ischemia, there was no clear-cut
modification by remote, delayed pre–
conditioning, and no marked difference
between wild-type and knock out. Thus,
we concluded that although remote,
delayed preconditioning signals
through adenosine using the adenosine
A1 receptor, signalling to MAPK may
not be important for myocardial pro–
tection at the stage of organ effects
(manuscript submitted).
The Role of the Adenosine A3
Receptor for Classic
Preconditioning
Due to slow breeding of the A1
receptor knock outs, I could not pursue
studies in those mice as I would have
wished. Instead I switched to the
adenosine A3 receptor knockouts,
where the primary target was to study
whether these mice could be precon–
ditioned by classic preconditioning of
the isolated heart before induced global
ischemia. Wild types achieved infarct
reduction and functional improvement
after classic preconditioning, but this
effect was lost in mice deficient of the
A3 receptor which tended towards being
protected against ischemic injury. We
are currently supplementing these data
with gene array studies, where I collected
hearts of preconditioned or control
perfused wild type and knockout mice
serially during preconditioning, isch–
emia, and reperfusion for analysis with
the Affymetrix chip. PhD student
Jiangning Yang is currently analysing
the data to identify families of genes
which may be up- or downregulated,
which may provide new insights into
the possible signal transduction path–
ways of the adenosine A3 receptor in
ischemic preconditioning (manuscript
in progress).
Other Projects
During my stay in Stockholm I was
also involved in a study attempting to
clarify if and how adenosine signals to
nuclear factor kappa B with the aid of a
luciferase reporter mouse. That was a
study of highly surprising findings,
which is still ongoing. It may become
something rather exciting, or may end in
the Journal of Irreproducible Results.
Conclusion
Studies of genetically engineered mice
support an important role of adenosine
receptor subtypes for preconditioning
triggering, and may provide us with new
insights into the mechanisms and signal
transduction of this effect. I learned
many new aspects of integrative mouse
physiology and signal transduction
analysis during my stay at the Karo–
linska Institute, and thank SERVIER for
the opportunity.
References
1. Drury AN, Szent-Györgyi A. J Physiol
(Lond) 1929; 68: 213-37.
2. Ely SW, Mentzer RM, Lasley RD et al.
11
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news bulletin
of the
J Thorac Cardiovasc Surg 1985; 90:54956.
3. Murry CE, Jennings RB, Reimer KA.
Circulation 1986; 74: 1124-36.
4. Downey JM, Cohen MV. Adv Exp Med
Biol 1997; 430: 39-55.
5. Yellon DM, Baxter GF, Garcia-Dorado D
et al. Cardiovasc Res 1998; 37: 21-33.
6. Gho BC, Schoemaker RG, van den Doel
MA et al. Circulation 1996; 94: 2193-200.
7. Zhao TC, Taher MM, Valerie KC et al.
Circ Res 2001; 89: 915-22.
8. Downey JM, Liu GS, Thornton JD.
Cardiovasc Res 1993; 27: 3-8.
international society
9. Downey JM, Cohen MV, Ytrehus K et al.
Ann NY Acad Sci 1994; 723: 82-98.
10. Jong JW de, de Jonge R, Keijzer E et al.
Pharmacol Ther 2000; 87: 141-9.
11. Meldrum D, Cleveland Jr JC, Rowland
RT et al. Am J Physiol 1997; 273: H725-33.
12 Baxter GF, Pharms MR, Marber MS et
al. Circulation 1994; 90: 2993-3000.
13. Heads RJ, Punn A, Yellon DM. J Mol
Cell Cardiol 1996; 28: A47.
14. Baxter GF, Yellon DM. J Cardiovasc
Pharmacol 1997; 29: 631-8.
15. Dana A, Jonassen AK, Yamashita N et
al. Circulation 2000; 101: 2841-8.
for
heart research
16. Takaoka A, Nakae I, Mitsunami K et al.
J Am Coll Cardiol 1999; 33: 556-64.
17. Ogilby JD, Heo J, Iskindrian AS.
Cardiovasc Res 1993; 27: 48-53.
18. Mubagwa K, Mullane K, Flameng W.
Cardiovasc Res 1996; 32: 797-813.
19. Tokuno S, Hinokiyama K, Tokuno K et
al. Atherosclerosis, Thrombosis and
Vascular Biology 2002: 22: 995-1001.
Hilchen T. Sommerschild, M.D.
Oslo, Norway
The Janice Pfeffer
Distinguished Lecture
IN DECEMBER 2002 the International Section created a named lecture that will
be an important part of ISHR World Congresses and the North American Section
meetings. The lecture is named after the late Janice Pfeffer in honor Janice’s
contributions to scientific knowledge. At the time of her untimely death Janice was
a leader in the study of myocardial remodeling and heart failure. It is the intent of
this lecture to honor her memory and to recognize all that she has done for her field.
The Janice Pfeffer distinguished lecture will be held at each World Congress of
the ISHR. In the non-Congress years, the endowers have asked that the lecture be held at the annual meeting of
the North American Section to which Janice belonged. The speaker, however, will be selected from the entire
membership of the Society. This lecture is intended to be a high profile event and should be scheduled as a keynote
plenary lecture. The International Council will select the speaker. The topic of the lecture will be in the field of
remodeling, heart failure and/or hypertrophy but the content should be chosen to be of broad interest to the
cardiovascular community. The speaker will be reimbursed for travel expenses, and will receive a plaque and a
$ 1,000 honorarium. He/she will be announced in the Journal of Molecular and Cellular Cardiology, and featured
in HEART NEWS AND VIEWS, and on the ISHR website.
The International Council believes this initiative is another example of the continuing growth of the ISHR as
a professional Society, and brings us on a par with other major societies. As always, your comments/suggestions
are welcome. Please write to rbolli@louisville.edu.
This award is funded by generous contributions from: F. Hoffman-LaRoche Ltd, AstraZeneca LP, Bristol Myers
Squibb Co, Genzyme Biosurgery, Novartis Pharmaceuticals Corporation, Scios Research Group, and the Michael
and Keri Whalen Foundation.
The 2003 Janice Pfeffer Distinguished Lecture will be delivered by Dr Piero Anversa (Valhalla, NY) during the
XXV Annual Meeting of the North American Section (June 28 - July 1, 2003; Mystic, Connecticut).
12
volume 11, number 1, 2003
Peter H. Sugden
We continue publishing brief biosketches of the 82
Founding Fellows of the ISHR.
For a complete list of the Founding Fellows, see HEART
NEWS AND VIEWS 2001;9(1):8
Biosketches of Robert B. Jennings, James R. Parratt,
Michiel J. Janse, David J. Hearse, Glenn A. Langer, David
A. Eisner, Roberto Bolli, Arnold M. Katz, Litsa Kranias,
Michihiko Tada, Gerd Heusch, Howard E. Morgan, HeinzGerd Zimmer, James M. Downey, Kenneth D. Philipson,
Makoto Nagano, R. John Solaro, Edward G. Lakatta,
Richard A. Walsh, Masao Endoh, Laszlo Szekeres, Derek
M. Yellon, Guy Vassort and Edward Carmeliet have already
been published in HEART NEWS AND VIEWS
2001;9(1):9-10; 2001;9(2):5-6; 2002;10(1):10-11 and
2002;10(3):9.
Current appointment: Professor of Cellular
Biochemistry (personal chair), NHLI
Division, Faculty of Medicine, Imperial
College London, UK.
Career: BA, MA, DPhil (Biochemistry),
Oxford Univ., UK. Postdoctoral: Dept.
Physiol., Vanderbilt Univ, Nashville, USA;
Dept. Clin. Biochem., Oxford Univ., UK.
Research interests: Intracellular signaling
especially regulation of intracellular events by protein
phosphorylation and dephosphorylation This developed from an
initial interest in metabolic regulation. Mitogen-activated protein
kinase cascades and their roles in cardiac physiology and pathology,
especially in the hypertrophy of the cardiac myocyte and its
responses to cytotoxic stresses. Regulation of transcription and
translation by protein phosphorylation. Endothelin and Gq proteincoupled receptor signaling. Small G proteins (Ras and Rho families).
Non-professional achievements: In the long distance running arena,
England International (marathon, personal best 2 h 18 min). Winner,
London-Brighton 54 mile race (1987) and many other ultramarathon
races; p.b. for 50 miles, 5 h 1 min (1985).
Interests: Alcohol (especially beer and the wines of Bordeaux), travel
(especially in Europe), Reading Football Club (soccer), cricket
(Warwickshire CCC), eating out in France and Spain, The (London)
Times crossword puzzle, commercial aviation, boring people with
my running experiences.
Most admired scientist: Sir Howard (later Lord) Florey, who was
awarded the Nobel Prize in 1945 (with Fleming and Chain) for the
discovery and development of penicillin.
Saul Winegrad
Richard J. Bing
ISHR member since 1973.
Current position: Professor of Physiology,
School of Medicine, University of
Pennsylvania.
Training: B.S. Chemistry, M.D. Uni–
versity of Pennsylvania; Intern, Peter Bent
Brigham Hospital; NIH; University College
London.
Honors: Guggenheim Fellowship,
Fogarty Fellowship twice, Award of Merit, AHA
Major research interests: Intracellular and transmembrane
movements of Ca in activation and regulation of contraction of
striated muscle; regulation of cardiac contractility by posttranslational changes in myofibrillar proteins; regulation of cardiac
contractility and filament integrity by myosin-binding protein
C; chemical signaling between heart and coronary vessels in
matching contractility to blood flow.
Representative publications: Calcium flux and contractility in
guinea pig atria J Gen Physiol 1962;45:371.Autoradiographic
studies of intracellular Ca movements in frog skeletal muscle J
Gen Physiol 1965;48:455. Cyclic nucleotide regulation of the
contractile proteins in mammalian cardiac muscle. J Gen Physiol
1980;75:283. Cardiac endothelial cells modulate contractility of
rat heart in response to oxygen tension and coronary flow. Circ
Res 1993;72:1044. Alteration of myosin cross bridges by
phosphorylation of myosin-binding protein C in cardiac muscle.
Proc Natl Acad Sci 1996;93:8999.
Most admired scientist: Andrew Huxley.
Relaxation: traveling, photography, music.
First President of the ISHR and, along
with Dr Lionel Opie, founding editor of
the J Mol Cell Cardiol.
Current Post: Professor of Medicine,
Univ. of Southern California, and Director
of Experimental Cardiol., Huntington
Medical Research Institute, Em. Visiting
Associate, California Inst. of Technology.
Qualifications: Univ. of Bern; Carlsberg
and Rockefeller Institutes, Johns Hopkins Univ.. Honorary degrees
from Johns Hopkins Univ., Univ. of Bologna, German Acad. of Med.
Research emphasis: Cardiac metabolism, coronary microcirculation,
congenital heart disease, myocardial infarction, heart transplantation,
coronary blood flow, etc.
Publications: Two books, 450 research papers.
Representative research papers: Metabolism of the human heart: II.
Studies on fat, ketone, and amino acid metabolism. Am J Med 1954;
16:504-15; Metabolism of the heart. Acta Cardiol 1955;10:1-14;
Measurement of coronary blood flow in man. Circulation 1960;
22:1-3; The acute effects of alcohol on the human myocardium. Am
J Cardiol 1966;17:804-12; A new method of measuring coronary
blood flow in man. JAMA 1968;205:277-80; Mitrocirculation of left
atrial muscle, cerebral cortex and mesentery of the cat: A comparative
analysis. Circ Res 1982;50:240-9; Inducible nitric oxide synthase
activity in myocardium after myocardial infarction in rabbit. Biochem
Biophys Res Commun 1994;205:1671-80; Nitric oxide, prostanoids,
cyclooxygenase, and angiogenesis in colon and breast cancer. Clin
Cancer Res 2001;7:3385-95.
Most admired scientist: Homer W. Smith.
Relaxation: Music.
13
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of the
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heart research
Ketty Schwartz
Richard L. Moss
ISHR member since 1977. Secretary
General ISHR-European Section 1992-98.
Current positions: Vice-President of the
Board of Governors of the National Inst.
for Health and Medical Research (Inserm);
President of the Scientific Council of the
French Muscular Dystrophy Association
(AFM); Member of the Scientific Council
of the French Network of Génopoles.
Training: Universities of Paris V and XI; Pasteur Institute.
Research interests: The molecular mechanisms that regulate the
function of cardiac and skeletal muscles in both the normal and
pathological states.
Major research contributions: Demonstration that the myocardium can
modify its molecular phenotype depending upon its work conditions
(isomyosins, isoactins and calcium-ATPase of the sarcoplasmic
reticulum). Development of genetic cardiology through the study of
cardiomyopathies and muscular dystrophies, with the discovery of
cardiac myosin binding protein C and lamin as disease-causing genes.
Development of cell therapy of the failing heart and participation to the
first phase 1 and 2 world human trials using myoblasts.
Publications: Over 350 refeered articles Science Citation Index most
cited paper: Three myosin heavy-chain isozymes appear sequentially
in rat muscle development. Nature 1981;292:805-9 (524 citations)
Positions in scientific organizations and honors: 35 national or
international committees; Head of the French Research Directorate,
’01-’02; Knight of the Legion of Honor; Officer of the National Order
of Merit; Silver Medal of the National Center of Scientific Research.
Most admired scientist: Marie Curie
ISHR-NA Section: Member of Council
since 2000; Chair, Local Organizing
Committee, 24th Annual Meeting, 2002;
President Elect 2003-2006.
Current position: Chair of Physiology,
Director of Cardiovascular Research
Center, University of Wisconsin-Madison.
Training: PhD Physiology & Biophysics,
University of Vermont; post-doctorate,
Boston Biomedical Research Institute.
Research interests: Regulation of contraction and contraction kinetics
in striated muscle, mechanisms of myosin function, contractile
dysfunction in heart failure.
Summary of research: Myocardial contraction is influenced by the
properties of myosin and regulated by Ca2+, accessory proteins, and
myosin binding to thin filaments. To assess protein function in
working skinned myocytes, we acutely extract endogenous regulatory
proteins and replace them with alternate forms, e.g., extraction of
MyBP-C accelerates contraction kinetics, while extraction of TnC
reduces the cooperativity of force development. We use gene knockouts/ins together with acute biochemical replacements of proteins to
distinguish mechanisms of cardiac phenotypes in these animals, i.e.,
changes in the specific protein or secondary compensatory
mechanisms.
Representative articles: (1) Hypertrophic cardiomyopathy in cardiac
myosin binding protein C knockout mice. Circ Res 2002;90:594. (2)
Cross-bridge interaction kinetics in rat myocardium are accelerated by
strong binding of myosin to the thin filament. J Physiol 2001;530:263.
Avocations: Reading, fishing, applied oenology.
NORMAN R. ALPERT
ISHR member since 1970. Organized
American Section meetings in 1981 and
1992. Editor J Mol Cell Cardiol (1992-98).
Training: Columbia University (Phys–
iology and Biophysics).
Current position: Professor, Department
of Molecular Physiology and Biophysics,
University of Vermont College of
Medicine.
Positions in scientific organizations: President, Cardiac Muscle
Society (1981-82); President, American Physiological Society
Cardiovascular Section (1988-89); Vice President and Member of
Board of Directors of the International Academy of Cardiovascular
Sciences (1996-present).
Research: Our studies are currently directed at uncovering the
molecular basis of heart failure in NYHA Class III and IV failing
human hearts (mitral regurgitation and dilated cardiomyopathy). We
demonstrated a depression in myofibrillar ATPase activity, an
increase in the cross-bridge force-time integral, a marked depression
in calcium cycling and a blunting of the force-frequency relationship.
In FHC failure we showed that L908V and R403Q propelled actin
filaments faster than controls (in vitro motility assay) and that this
could be accounted for by a decrease in attachment time (single
molecule laser trap measurements).
Favorites: Playwright, Bernard Shaw; Author, Richard Feynman;
Composers, George Gershwin, Harold Arlen; Lyricists, Lorenz
Hart, Ira Gershwin, E.Y Harburg; Musicians, Yo Yo Ma (classical),
Miles Davis (jazz); Personal Activities, sailboat racing, tennis,
swimming.
14
2003 outstanding investigator
prize of the ishr
Dr Issei Komuro of the Department of Cardiovascular
Science and Medicine, Chiba University Graduate
School of Medicine, Chiba, Japan, has been selected as
the winner of the 2003 Outstanding Investigator Prize
of the International Society for Heart Research.
The award will be presented during the XX Meeting
of the Japanese Section that will be held in Tokyo,
Japan, on November 22-24, 2003.
The Outstanding Investigator Prize recognizes
cardiovascular scientists who have made major
contributions to our understanding of cardiovascular
disease and are internationally regarded as leaders in
their field.
volume 11, number 1, 2003
ISHR MEETINGS CALENDAR
Australia.
August 7-9, 2003.
XXVII Meeting of the Australasian Section: "New Science at the Heart of New Therapies".
Enquiries: Dr S. Pepe, The Baker Heart Research Institute, Melbourne, Australia.
Melbourne,
Tel. +61 3 8532 1310; Fax +61 3 8532 1314;
E-mail spepe@baker.edu.au; Website www.baker.edu.au/ishr
August 16-18, 2003.
XII Meeting of the Latin American Section.
Buenos Aires, Argentina.
Centro de Investigaciones Cardiovasculares, Facultad de Medicina, 60 y 120, 1900 La Plata, Argentina.
Enquiries: Dr A. Mattiazzi,
Tel./Fax +54 221 483 4833; E-mail
ramattia@atlas.med.unlp.edu.ar or aral@sinectis.com.ar
August 30 - September 3, 2003.
XXV Congress of the European Society of Cardiology.
Vienna, Austria.
Enquiries: E-
mail webmaster@escardio.org; Website www.escardio.org
November 9-12, 2003.
Scientific Sessions of the American Heart Association.
Association, Meetings and Councils, 7272 Greenville Avenue, Dallas, TX 75231.
Orlando, FL.
Enquiries: American Heart
Tel. +1 214 706 1543; Fax +1 214 373 3406; E-mail
scientificconferences@amhrt.org; Website www.americanheart.org
November 22-24, 2003.
XX Meeting of the Japanese Section.
Tokyo, Japan.
Enquiries: Dr S. Mochizuki, The Jikei University
School of Medicine, Division of Cardiology, Department of Internal Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
E-mail m_seibu@jikei.ac.jp
August 7-11, 2004.
XVIII World Congress of the International Society for Heart Research.
ISHR 2004 Congress, PO Box 164, Fortitude Valley QLD 4006, Australia.
Brisbane, Australia.
Enquiries:
Tel. +61 7 3854 1611; Fax +61 7 3854 1507; E-mail heart2004@
ozaccom.com.au; Website www.heart2004.com
XII XII Meeting of the Latin American Section
Buenos Aires, Argentina
August 16-18, 2003
Schedule
Symposium:
Ischemic heart disease - Emerging concepts
President:
Dr Raul Domenech Lira (Chile)
Moderator:
Dr Ricardo J. Gelpi (Argentina)
Conference:
President:
Dr Hernan Gomez Llambi (Argentina)
Speaker:
Dr Richard Walsh (USA)
Cardiac hypertrophy and failure: Molecular causes vs consequences
President:
Dr Jorge Ponce-Hornos (Argentina)
Speaker:
Dr Evangelia Kranias (USA)
Phospholamban: A key regulator of myocardial contractility
Symposium:
Frontiers in cardiac basic research - Genetic approaches to the comprehension of
cardiovascular disease
President:
Dr Luis Folle (Uruguay)
Moderator:
Dr Alberto Crottogini (Argentina)
Conference:
President:
Dr Liliana Grinfeld (Argentina)
Speaker:
Dr Horacio Cingolani (Argentina)
Blockade of Na+/H+ exchanger as a therapeutic strategy
Mini Course: Molecular biology - Basic concepts and their application in cardiac pathologies
I. Introduction to molecular biology
II. Molecular Biology in the cardiology practice - Present and future
Director:
Dr Gladys Chiappe de Cingolani (Argentina)
http://latin.ishrworld.org
15
the
news bulletin
of the
international society
HEART NEWS AND VIEWS
is published thanks to
an educational grant from Servier
a private French pharmaceutical company committed
to therapeutic advances in cardiovascular medicine as
well as other key therapeutic areas. We have successfully
developed products in the field of cardiovascular diseases
(ischemic heart disease, hypertension, and heart failure),
as well as in other major therapeutic fields. A number of
landmark studies like PROGRESS, EUROPA, PREAMI, PEP,
and HYVET are being conducted with our support.
The dynamism of our research is ensured by consistent
allocation of as much as over 25% of the annual turnover
of the Group to search for new molecules and develop
their therapeutic applications.
Servier supports a number of
important projects in the field
of cardiology, such as the
Education and Training
Programs of the European
Society of Cardiology.
2003
Servier is also the founding
father of The European
Cardiologist Journal by Fax
&
n
io
at
and Dialogues in
m
m
Infla
ry Disease
Coronary Arte
Cardiovascular Medicine,
a quarterly publication
with a worldwide
circulation edited by
Roberto FERRARI and David J. HEARSE.
Dialogues discusses in a comprehensive way issues from
the cutting edge of basic research and clinical cardiology.
ber 2
Volume 8 Num
•
The forthcoming issue, devoted to
INFLAMMATION & CORONARY ARTERY DISEASE
will feature articles by:
P. Libby, C. Kluft, A. Maseri
and J. Danesh
For further information on
Dialogues in Cardiovascular Medicine please contact:
Mr Thierry Hénane - Servier International
192 avenue Charles de Gaulle - 92578 Neuilly-sur-Seine Cedex - France
or webmaster@servier.com
16
for
heart research
H EART N EWS AND V IEWS
is the official News Bulletin of the
International Society for Heart
Research and is published every
fourth month.
Editor
T.J.C. Ruigrok
Utrecht, The Netherlands
E-mail t.j.c.ruigrok@xs4all.nl
Deputy Editor
C.M. Bloor
La Jolla, CA, USA
E-mail cbloor@ucsd.edu
Editorial Board
R.A. Altschuld
Columbus, OH, USA
R. Bolli
Louisville, KY, USA
Secretary General
R. Ferrari
Ferrara, Italy
President Elect
F. Kolár
Prague, Czech Republic
European Section
X.Y. Li
Beijing, China
Chinese Section
A. Mattiazzi
La Plata, Argentina
Latin American Section
S. Pepe
Melbourne, Australia
Australasian Section
T. Ravingerova
Bratislava, Slovak Republic
A.-M.L. Seymour
Hull, UK
C. Steenbergen
Durham, NC, USA
American Section
N. Takeda
Tokyo, Japan
K.K. Talwar
New Delhi, India
Indian Section
R.A. Walsh
Cleveland, OH, USA
Editor-in-Chief, JMCC
K.T. Weber
Memphis, TN, USA
Y. Yazaki
Tokyo, Japan
Japanese Section
Desk Editor
B.J. Ward
London, UK
Editorial Office
Markt 13
3961 BC Wijk bij Duurstede
The Netherlands.
Tel.: +31 343 597 555
Fax: +31 343 597 510