More studies linking the effect of antiplatelet drugs on platelet
function with clinical outcomes are urgently needed, a new review of
the field concludes [1].

The review, published in the November 6, 2007 issue of the Journal
of the American College of Cardiology, is written by a team led by
Drs Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore,
MD) and Richard Becker (Duke University Medical Center, Durham, NC).

In an interview with heartwire, Becker commented: ¡§This paper is
intended to be a state-of-the-art review of platelet-function tests.
While studies of patient responsiveness to antiplatelet therapies,
particularly aspirin and clopidogrel, have increased dramatically in
recent years, the relationship between ex vivo measurements of
platelet function and in vivo platelet reactivity and clinical
outcomes remain largely unknown. We need better studies linking
effects on platelets to clinical outcomes."

Becker explained that it was now well-known that there is a subset
of patients who do not respond to clopidogrel. ¡§That means that
they have a less-than-10% difference in platelet aggregation before
and after taking the drug. And we know that these patients are at
increased risk of cardiac events. But not all these patients will
experience an event, and we do not know that an increased dose of
clopidogrel will improve matters. So it is difficult to make
recommendations for these patients.¡¨

Large piece of the puzzle still missing

Becker says there is no case for measuring platelet aggregation on a
routine basis in heart disease patients at present. This is because
a large piece of the puzzle is currently missing. ¡§We know patients
with a low platelet response to aspirin or clopidogrel are at risk
of events, but we don¡¦t know whether increasing the dose of these
drugs will make a difference. The new drugs in development do have
less variability in platelet-function tests, but we don¡¦t know if
this will mean they are better or not. More potent drugs could be
good from an efficacy view, but they could also be bad in terms of
bleeding side effects. And platelet-aggregation tests at present
cannot give us this information," he noted.

¡§Our take-home message is that we need parallel investigations of
platelet response to antiplatelet drugs and clinical outcomes in the
same studies. Large clinical trials of antiplatelet drugs need to
include platelet substudies that are big enough to give solid
answers," he added. Becker advises that several platelet-aggregation
tests be performed as part of these studies, including light
transmission studies, aggregometry, and point-of-care tests, so that
each method can be compared to determine which one correlates best
with clinical outcomes. ¡§The field is advancing. We do have some
clues as to what is happening. But we now need to take it to the
next level to get answers," he says.

Assessing safety

Another issue addressed in the paper is that of trying to assess
safety from platelet-responsiveness studies. Becker commented: ¡§So
far, all the platelet studies have focused on identifying
hyporesponders--patients who do not show the required antiplatelet
effect of drugs such as aspirin and clopidogrel. But we have very
little data on the upper thresholds of platelet inhibition in terms
of safety. How much platelet inhibition is safe? We really have no
idea at the moment, and this is very important, particularly now as
new, more potent antiplatelet drugs are being developed. Some of the
new antiplatelet drugs inhibit platelet aggregation by about 80% to
90%. That is a very powerful effect. But we don¡¦t know from
platelet tests whether this is safe or not. We have to wait for
large clinical trials to tell us this.¡¨

Important data on prasugrel next week

The first major trial with one of the new agents--the TRITON-TIMI 38
trial comparing the new agent prasugrel (Daiichi Sankyo, Eli Lilly),
with clopidogrel in more than 13 000 ACS patients undergoing PCI--
is to be reported at next week¡¦s American Heart Association meeting
in Orlando. Lilly¡¦s share price has fallen in recent days on
speculation that the trial will show improved efficacy but increased
bleeding complications for prasugrel.

Which test?

In the paper, Gurbel et al outline the various methods for testing
platelet function, but they point out that ¡§a basic problem with
attempting to measure platelet function or drug-related inhibition,
let alone correlating it with clinical outcomes, is that no single
test encompasses the complexity of platelet biology and function."

They conclude: ¡§The measurement of platelet function and response
to pharmacological antagonists is inherently complex and confounded
by several methodological factors, making it difficult to correlate
results with clinical outcomes and, in turn, to use the results to
guide therapy. A major limitation that has hampered both knowledge
acquisition and translation to the clinical arena is the absence of
established investigative platforms and trials of sufficient size to
either support or refute hypothesis-generating observations from
small studies. The clinical-trials community, working closely with
platelet biologists, clinician-scientists, and the pharmaceutical
and device industries, must formulate an agenda, building on the
strengths of collaboration, to address an area of unmet clinical
need."

This work was supported by grants from Accumetrics, Lilly, Astra-
Zeneca, The Medicines Company, Sanofi-Aventis, and Bristol-Myers
Squibb. Gurbel has received grant support from AstraZeneca. Becker
has received research support from Bristol-Myers Squibb and The
Medicines Company. Other authors of the paper have consulted for or
received honoraria from AstraZeneca, Bristol-Myers Squibb, Sanofi-
Aventis, The Medicines Company, and Lilly.

1Gurbel PA, Becker RC, Mann KG, et al. Platelet function monitoring
in patients with coronary artery disease. J Am Coll Cardiol 2007;
50:1822¡V34.

Use of the appetite suppressants phentermine and sibutramine
(Merida, Abbott Laboratories) appear to have caused MI in two young
women, say Malaysian doctors [1]. Dr Shah M Azarisman (International
Islamic University, Kuantan, Malaysia) and colleagues report their
findings in a letter in the November 1, 2007 issue of the New
England Journal of Medicine.

Azarisman told heartwire that he believes these two cases are the
tip of the iceberg. "Anecdotally, there has been quite an increase
in the number of myocardial-associated adverse drug reactions
associated with appetite suppressants; it has been small talk around
the dinner table," he said. "There has also been some evidence from
[adverse drug reaction reports] with these kind of drugs reported to
our pharmacology colleagues," he added.

Azarisman said he would now like to see industry registries set up
to monitor these kinds of reactions to appetite suppressants.

All other causes of MI ruled out

Although appetite suppressants have been around for a number of
years in Malaysia, "they have only recently become more widely
obtainable," Azarisman explained. In fact, while phentermine is
available legally in Malaysia, sibutramine is not, because its
introduction was withheld in 2002 due to concerns about poor
tolerability. However, it is widely obtainable on the black market,
he noted.

Five years ago, in the US, sibutramine was lambasted by Public
Citizen, the Washington, DC–based consumer-advocacy group, which
called for the FDA to withdraw the drug from the market. Public
Citizen said sibutramine contributed to major cardiovascular
problems and was not particularly effective in aiding weight loss.
Of particular concern was the propensity for sibutramine to
significantly increase blood pressure and heart rate. At that time,
Abbott said the safety of sibutramine had been assessed in more than
12 000 patients in clinical trials. In placebo-controlled trials,
there was no increase in MI, congestive heart failure, cardiac
arrhythmias, or death in the sibutramine-treated patients as
compared with controls, the company noted.

Azarisman says the problems with sibutramine with regard to
hypertensive crises "are well-known and well-documented," but that
it is the association with MI that seems to be new and is of most
concern now.

The Malaysian doctors report on two otherwise-healthy young women
who had MI with acute ST-segment elevation The first, aged 35,
developed acute STEMI and hypotension following general anesthesia
for liposuction. She was a nonsmoker but was overweight (body mass
index 29), and she had undergone two previous liposuction procedures.

Cardiac biomarkers were elevated (creatine kinase 445 U/L; troponin
T 1.86 µg/L), and echocardiography revealed septal hypokinesia.
Results of coronary angiography were normal. The only medication she
reported using recently was phentermine, which she had taken
intermittently in the past and for three consecutive days before her
admission for this procedure.

The second patient was 24 years old and presented to the emergency
room with severe, recurrent retrosternal chest pains. The ECG showed
acute inferior MI. Peak levels of serum creatine kinase and troponin
T were 3450/L and 4.25 µg/L, respectively. Results of coronary
angiography were normal. This patient was also a nonsmoker and had
no other illnesses. The only medication she reported taking was
sibutramine for the previous three months. In both patients, the ECG
showed complete resolution within 24 hours.

The doctors investigated and ruled out all other possible causes of
MI, including cocaine abuse, viral myocarditis, aortic dissection,
hypercoagulable states, and autoimmune vasculitis.

"The absence of any attendant cardiovascular risk factors and the
negative results of other studies led us to conclude that the use of
appetite suppressants was responsible for the MI in each of the two
patients," they conclude.

Industry registry needed

Azarisman told heartwire that although there hasn't been long-term
follow-up on these two women, they have not come back complaining of
any recurrent problems. They were advised to stop taking appetite
suppressants.

He added that there has only been one prior report of MI associated
with appetite suppressants, and this was with phenylpropanolamine
(Dexatrim, Chattem). This was a case report plus a review of seven
other cases of myocardial injury associated with the same drug
[2]. "I suspect that is why the New England Journal of Medicine
accepted our correspondence," he told heartwire.

He believes that this issue needs investigating and that perhaps a
registry could be set up to monitor such events. "We really need to
get down and work with industry on this," he noted.

Azarisman SM, Magdi YA, Noorfaizfan S, et al. Myocardial infarction
induced by appetite suppressants. N Engl J Med 2007; 357: 1873-1874.
Pilsczek FH, Karcic AA, and Freeman I. Case report: Dexatrim
(phenylpropanolamine) as a cause of myocardial infarction. Heart
Lung. 2003; 32:100-104. Abstract

A new study suggests diffusion-weighted imaging (DWI) may help to
differentiate between patients who will have a good vs a poor outcome
among those who remain comatose after a resuscitated cardiac arrest.

Researchers led by Christine Wijman, MD, PhD, from the Stanford
Stroke Center, Stanford University, in Palo Alto, California, found
that patients who had good and poor outcomes could be differentiated
by the temporal and spatial profile of quantitative brain absolute
diffusion coefficient (ADC) values between 24 hours and 5 days after
cardiac arrest using DWI.

"It appears that [magnetic resonance imaging] MRI can certainly
identify the most severely affected patients fairly easily, but
whether it's going to be predictive in a prospective data set would
need to be validated," Dr. Wijman told Medscape Neurology &
Neurosurgery. "We would not recommend ¡X now, at least ¡X making a
decision to withdraw life support based on this, but I do think that
MRI may be a very promising additional prognostic tool in these
patients."

Their findings were presented at the 132nd Annual Meeting of the
American Neurological Association.

Accurate Prediction of Outcome

Approximately 350,000 cardiac arrests occur each year in the United
States, and as many as half of these can be resuscitated
successfully, the authors write. To date, only 10% to 30% of these
patients have good neurologic recovery, although this is expected to
improve with the use of therapeutic hypothermia, they note.

Currently available prognostic indicators identify only about one-
third of poor-outcome patients reliably. This has been further
hampered recently by the more widespread use of hypothermia as a
standard of care in the United States. Patients are sedated for the
first 24 hours, and sedation may last even longer if the liver or
kidneys are damaged, inhibiting clearance of these medications, said
Dr. Wijman, "so we've sort of lost our window for getting serial
neurologic examinations or using [electroencephalography] EEG at
least up to 36 hours."

MRI has been shown to be more sensitive for detecting hypoxic brain
injury than computerized tomography, for example, which can be
unremarkable unless the brain injury is very severe, she said. DWI,
in particular, is "exquisitely sensitive" in detecting early ischemic
changes, she noted.

Previous pathology studies had suggested that susceptibility to
hypoxic injury differs by brain region. In this study, the
researchers set out to look at spatial and temporal differences in
susceptibility to changes on DWI in comatose post¡Vcardiac arrest
patients and to see whether differences in these patterns of
quantitative brain ADC values could differentiate those with good
outcomes, defined as those who were alive at 3 months, and those with
poor outcomes. Poor outcome was defined as death, the bilateral
absence of cortical responses by somatosensory evoked potentials,
clinical evidence of brainstem dysfunction after 72 hours, or in a
vegetative state after 1 month.

Regional and Temporal Differences

This substudy is part of an ongoing pilot project funded by the
American Heart Association looking at the utility of MRI and a
variety of serum biomarkers in these patients. A total of 35 patients
with 42 scans were included; 20 scans in 18 good-outcome patients and
18 scans in 15 poor-outcome patients, all acquired within 8 days of
the arrest. Patient MRIs were then compared with those from 14 normal
controls.

The researchers found both regional and temporal differences in the
quantitative ADC patterns in patients with good vs poor outcomes.

"The differentiation between patients with good and poor outcomes by
MR imaging seems to be time dependent over the first week and to be,
to some extent, also regionally different ¡X in other words, some
areas are more affected than others," Dr. Wijman said.

"The main ones affected are the gray matter ¡X the cortical
structures and the deep gray nuclei ¡X more so than the corona
radiata and the internal capsule, which are white-matter structures,"
she added. In the white-matter structures, it appeared that there
were some changes in the poor-outcome group as well, but these seemed
to be more gradual and delayed compared with changes in gray-matter
structures.

Specifically, they reported that in good-outcome patients, the mean
ADC values of the cortical structures were higher than controls at
nearly all time points starting at 24 hours after the arrest. The
opposite pattern was seen in the cortex of those with poor
outcome, "with early, marked restricted diffusion in all 4 structures
between 49 and 120 hours after the arrest," the authors write.

In the hippocampus, good-outcome patients showed increased
diffusivity starting with early scans at 24 hours that continued
through 192 hours. Poor-outcome patients showed no significant
difference in diffusivity from controls in this structure.

Deep gray-matter structures showed increased diffusivity at 49 to 96
hours among good-outcome patients that continued through 120 hours in
the putamen, they note. "In contrast, in the poor-outcome group, the
putamen showed restricted diffusion as early as 25 to 72 hours
following cardiac arrest," the authors write. "When compared with the
decrease in mean ADC values seen in the cortical structures, the
decrease in these structures was more modest."

Finally, in good-outcome patients, white-matter structures, including
the corona radiata and the internal capsule, showed milder,
facilitated diffusion occurring later than in gray-matter
structures. "Only ADC values of the corona radiata were significantly
higher, but not until 49 to 96 hours, and this was carried out to 192
hours," they write. In the poor-outcome patients, restricted
diffusion was also less severe and more delayed in the white-matter
structures compared with the gray matter.

Others Investigating This Modality

David M. Greer, MD, from Massachusetts General Hospital, in Boston,
who was not involved with this study, said his group is also studying
the use of DWI at their institution for this purpose. They plan soon
to publish findings in their own series of patients. "It's a very
good modality to study hypoxic-ischemic brain-injured patients, but
we're still scratching the surface of what exactly it will mean in
terms of prognostication," he told Medscape Neurology & Neurosurgery.

The authors report no conflict of interest. The study is supported by
the American Heart Association Scientist Development Award and the
Katherine McCormick Fund for Women.


132nd Annual Meeting of the American Neurological Association:
Abstract #T-124. Presented Tuesday, October 9, 2007.

¡§The much-needed alternative to drug-eluting stents may not be the
next-generation drug-eluting stents.¡¨ Such was the message conveyed
here yesterday at the TCT 2007 meeting by Dr Robbert de Winter
(Academic Medical Center, Amsterdam, the Netherlands).

DeWinter presented preliminary results from TRIAS HR, the first
randomized comparative study between the prohealing Genous
bioengineered R stent (OrbusNeich, Wanchai, Hong Kong) and Boston
Scientific¡¦s first-generation Taxus paclitaxel-eluting stent.

At 30-day and six-month follow-up, the prohealing Genous stent
displayed efficacy similar to Taxus in high-risk restenosis patients.

The single-center, single-blind study included 193 patients at high
risk of restenosis, defined as patients who had diabetes mellitus,
small vessels (<2.8 mm), long lesions (>20 mm), or chronic total
occlusions. Of the patients treated, 98 received a Genous
bioengineered R stent, while 95 received a Taxus paclitaxel-eluting
stent.

There were no significant differences in death or MI between the two
groups. There were more instances of non¡Vtarget-vessel
revascularization in the Taxus arm (14% of patients) than the Genous
arm (3.2%). The level of acute thrombosis was lower in the Genous
arm, and there was no evidence of subacute or late-stage thrombosis.
In the Taxus arm, the acute-thrombosis levels were slightly higher
and there was also evidence of both subacute and late-stage
thrombosis.

At six-month follow-up, 44% patients treated with a Genous stent
were on clopidogrel, compared with 73% treated with the Taxus stent.

So how does Genous differ?

The Genous stent relies on the use of naturally circulating
endothelial progenitor cells (EPCs), which are produced in the bone
marrow and are involved in the repair of blood vessels. Genous is
coated with an antibody that attracts the EPCs to the surface of the
stent and allows for a layer of endothelium to form around the
device.

In the discussion following de Winter¡¦s presentation, Dr Cindy
Grines (William Beaumont Hospital, Royal Oak, MI) said that the
trial results were promising in that the Genous stent requires a
shorter treatment of clopidogrel and seems to reduce the risk of
stent thrombosis. She did voice concerns about the size of the
patient sample, however, stating that it needed to be expanded.

According to deWinter, his team has started enrolling patients in
the multicenter, multiarm TRIAS study in Europe to address this
issue. The trial will compare bare-metal stents and drug-eluting
stents with the Genous stent across 50 centers and will include 1250
patients.

¡§Genous is a very promising, innovative device with a wide range of
applications for physicians and many benefits to patients,¡¨
deWinter said. ¡§The results of our pilot study fully support our
rationale for the large-scale TRIAS study that will compare Genous
with both drug-eluting and bare-metal stents.¡¨

Selective use of transesophageal echocardiography (TEE) appeared to
be as effective at preventing embolic events as routine use in a
cross-Canada study looking at use of the procedure prior to left
atrial ablation for atrial fibrillation (AF) [1]. The survey-based
study was presented at the Canadian Cardiovascular Congress 2007.

The results indicate a potential cost-effectiveness issue with
routine use, noted Dr Damian Redfearn (Queen's University, Kingston,
ON) in his presentation of the data. The study was undertaken to
assess the use of TEE across Canada as well as to determine the
prevalence of left atrial clot identified by routine or selected use
and to compare the different practices across the country,
correlating them with cerebral thromboembolic events.

Cross-country checkup

A survey was emailed to 10 Canadian electrophysiology centers that
practice left atrial ablation for AF.

Retrospective analysis on data from all 10 centers revealed a total
of 2225 cases of AF, with a median of 110 per center, or roughly 55
per year. The great majority--80%--of cases were paroxysmal AF. TEE
was performed in a total of 1194 cases. Routine TEE was performed in
996 patients. A total of 16 left atrial clots were identified
(prevalence of 1.25%).

Eleven cerebroembolic events were observed, nine with previous
negative TEE. At an incidence of 0.49%, the rate of thromboembolic
complications is low, observed Redfearn. No difference was seen in
the rate of embolic complications between routine TEE (six of 996
cases) and selected TEE (five of 1190 cases), and there were no
reported complications from TEE use.

Although he feels a more comprehensive analysis is needed before
talking of clinical impact, he doesn't foresee a change in practice.
¡§The images and the subjective experience of colleagues are such
that, if they do routine TEE, they're resistant to change,¡¨ he
noted, adding that his center performs routine TEE.

Redfearn DP. Transesophageal echocardiography (TEE) prior to atrial
fibrillation: A Canada Atrial Fibrillation and Complex Ablation
Alliance (CAFCAA) study. Canadian Cardiovascular Congress 2007;
October 22, 2007; Quebec City, QC.

Reducing LDL cholesterol to levels considerably below current
recommended targets appears to provide greater protection in
patients with established atherosclerotic disease, according to US
and German researchers.

In the September 1st issue of the American Journal of Cardiology,
Dr. John C. LaRosa of The State University of New York Health
Science Center, New York and colleagues note that the conducted a
post-hoc analysis of data from a clinical trial of atorvastatin.

More than 10,000 subjects with coronary heart disease and LDL
cholesterol levels below 130 mg/dL had been randomized to receive
atorvastatin at 10 mg or 80 mg per day. The primary end-point was
time to the first major cardiovascular event.

The researchers found that there was a highly significant reduction
in the risk of major cardiovascular events with descending levels of
LDL cholesterol. The lowest risk was seen in patients who had
achieved levels below 64 mg/dL.

Further analysis showed that that risk of individual events
including fatal and non-fatal myocardial infarction and stroke were
significantly reduced with lower LDL levels.

In addition, although there was no significant influence across LDL
levels on the risk of death from any cause or non-cardiovascular
causes, such deaths were lowest in patients with the lowest on-
treatment LDL levels.

Overall the researchers conclude that in "patients with established
atherosclerotic cardiovascular disease, a further risk reduction
without sacrifice of safety can be achieved by reducing LDL
cholesterol to very low levels."

Am J Cardiol 2007;100:747-752.

esidents and interns are likely to overestimate how much time
actually passes during cardiopulmonary resuscitation (CPR),
investigators reported here this week at CHEST 2007, the American
College of Chest Physicians 73rd Annual Scientific Assembly.

This could have a significant adverse effect on patient outcome,
said principal investigator Lewis A. Eisen, MD, of Beth Israel
Medical Center in New York City.

CPR is driven by a strict protocol that is highly time dependent and
is based on the onset and duration of action of various medications,
in particular epinephrine, as well as the most effective timing of
the delivery of shocks to restore a viable rhythm.

If the timing is off, successful CPR is less likely to happen, Dr.
Eisen said.

"At our institution, a new code team is assigned every month,
consisting of residents and interns who train on manikins and who
are drilled in [Advanced Cardiopulmonary Life Support; ACLS]
algorithms." Dr. Eisen and colleagues timed each new group after
they had finished their training to assess their concept of how much
time was required to run a code.

"Their perception of time was really distorted," Dr. Eisen
reported. "They overestimated how much time was involved."

Each new team participated in CPR scenarios, with a third-year
resident running the code. The scenario began with 1 intern
responding to a cardiac arrest. Thirty seconds after the start of
the scenario, the remaining interns joined in, and 30 seconds after
that, the residents entered. One of the investigators recorded the
times of each step of the algorithm.

After completing the code, Dr. Eisen's team asked the subjects
independently how much time they thought had elapsed during the
code.

The mean scenario took 383.6 seconds. "On average, subjects felt the
scenario took about 43 seconds longer than it actually had. The mean
absolute error was 163 seconds, or about 2.5 minutes," Dr. Eisen
said.

There was a huge variation in perception, from an underestimation of
286 seconds at one end of the range to an overestimation of 685
seconds at the other.

Men were more likely to overestimate and women were more likely to
underestimate scenario time. Interns were more likely to
underestimate scenario time than residents.

"On average, house staff believes that the scenario takes longer
than it actually does," Dr. Eisen noted.

"The literature shows that when people are in very stressful
situations, they feel like time is passing very slowly.... Maybe
this has some evolutionary basis, like when we were being attacked
by a tiger it gave our brains the ability to react," he commented.

This disadvantage in this situation is that the ACLS protocol
requires that drugs and other maneuvers be given in a very timed-
based order, the New York investigator pointed out.

"Most successful resuscitations occur when medications are given
systematically and in a timely fashion," echoed Steven W. Brown, MD,
medical director of the Lung Center and a clinical professor of
medicine at the University of Wisconsin in Madison.

"When we run a code, we have 1 person dedicated to a time clock,
giving us frequent feedback.... We're multitasking to the maximum.
When we're so focused on the patient, we're not focused on internal
Circadian rhythms," Dr. Brown said. He reiterated what Dr. Eisen
observed, that "when we're in situations with negative stress, we
think time is moving very slowly.

"The clinical lesson is that we need a time-keeper." Dr. Brown said,
adding that he wasn't surprised by Dr. Eisen's findings. "We can't
rely on the person running the code to keep track of the time,
too.... When we're seeing residents being off by a minute or 2 in a
6-minute code, that variation is pretty significant."

Dr. Eisen and Dr. Brown have disclosed no relevant financial
relationships.

CHEST 2007: American College of Chest Physicians 73rd Annual
Scientific Assembly. Presented October 22, 2007.

A drug widely used to lower blood lipids has been shown to cure the
symptoms of adult CPT2 deficiency, one of the most common fatty acid
oxidation (FAO) disorders, which currently has no effective therapy.
Bezafibrate, a pan-peroxisome-proliferator-activated receptor (PPAR)
agonist, accomplishes this cure by restoring the cells' capacity for
FAO.

Lead investigator Fatima Djouadi, PhD, from the Centre National de
la Recherche Scientifique, University Paris Descartes, Paris,
France, presented the results of the phase 2, open-label trial here
at the American Society of Human Genetics 57th Annual Meeting.

She described the 3 clinical expressions of deficiency of carnitine
palmitoyltransferase 2 (CPT2), an enzyme located in the inner
mitochondrial membrane: The neonatal form of the disease is rare and
lethal in the first month of life, the (severe) infantile form
involves liver failure and cardiomyopathy, and the adult (mild) form
is characterized by myalgia, muscle weakness, and rhabdomyolysis.
CPT2 deficiency is a syndrome in which muscle fibers break down,
allowing their contents to leak into the circulation. This
destruction can be precipitated by fasting, exercise, or fever.

Talking with Medscape Pathology, Dr. Djouadi discussed the size of
the experiment and the choice of dose: "We have only 6 patients,
because in France there are around 25 CPT2-deficient patients. So we
only had 6 patients who agreed to participate in the trial...it was
difficult to give different doses." Earlier studies on myoblasts
derived from CPT2-deficient patients provided a guideline for the
effective dose. "In vitro, we did a dose response, and the better
dose [in the myoblasts] corresponds to the physiological range of
600 mg/day."

The study enrolled 6 patients (2 women/4 men), aged 22 to 79 years.
All had early onset of the disease, with muscle pain, limited
physical activity, and rhabdomyolysis. Both hetero- and homozygous
genotypes were represented. Before treatment, all patients had a
medical examination, quality-of-life assessment (SF-36 health
questionnaire), and muscle biopsy. The biopsy cells were cultured to
assess their response to bezafibrate and showed increased FAO and an
increase of 20% to 100% in CPT2 mRNA.

Each patient took 200 mg of bezafibrate 3 times per day for 6
months. At the end of treatment, patients had another muscle biopsy
and quality-of-life assessment. In all 6 patients, long-chain FAO
increased in isolated muscle mitochondria. This was shown to result
from upregulation of CPT2 mRNA and increased protein levels. For the
quality-of-life assessment, significant improvement occurred in the
4 domains of physical health and in vitality. No adverse effects
were reported. In addition, all patients increased physical activity
and experienced a decrease in the duration and severity of pain.

Looking to the future, Dr. Djouadi observed, "Now there are more
potent PPAR agonists." One of these new compounds acts at a
concentration of 10 nanomoles instead of 400 micromoles. Even with
present PPAR agonists, this treatment is a great step forward. As
Dr. Djouadi and colleagues conclude in their abstract: "For the
first time, a pharmacological approach impacting the cause of the
disease and not only its consequences has proven to be efficient in
treating a mitochondrial FAO disorder."

Wylie Burke, MD, PhD, from the Department of Medical History and
Ethics, University of Washington School of Medicine, Seattle, and
comoderator of the session, also discussed the study with Medscape
Pathology. "I think there are 2 really interesting things about [Dr.
Djouadi's] work. The first is, it's a small pilot study, and clearly
they need to go on and do more work, but in fact it's very
impressive."

Dr. Burke continued, "You're looking at a turning-the-corner kind of
benefit, and you have to wonder if the lessons from this, which is
for the milder form of the disease, may ultimately be instructive
for the severe."

However, the mild form of the disease does have residual enzyme
activity 10% to 20% of normal, whereas the severe form has 0%
residual activity. "The caution here is that this drug stimulates
production, and if you have no production...I don't think the
transition's going to be easy," Dr. Burke concluded. "But knowing
that this works has got to be at least a clue that you can work on
for the much tougher problem.


"I think the other really important aspect, the more generalizable
aspect, is that this was an existing drug," he added, "and it was an
understanding of the disease pathophysiology that allowed them to
say 'OK, maybe this will work'... What's so important about that is
that I see the [genome-wide association] studies...as being the door
into finding new biologic pathways that we didn't understand were
related, and then understanding the pathophysiology."

Dr. Djouadi has disclosed no relevant financial relationships.

American Society of Human Genetics 57th Annual Meeting: Abstract 4.
Presented October 24, 2007.

A new study suggests diffusion-weighted imaging (DWI) may help to
differentiate between patients who will have a good vs a poor
outcome among those who remain comatose after a resuscitated cardiac
arrest.

Researchers led by Christine Wijman, MD, PhD, from the Stanford
Stroke Center, Stanford University, in Palo Alto, California, found
that patients who had good and poor outcomes could be differentiated
by the temporal and spatial profile of quantitative brain absolute
diffusion coefficient (ADC) values between 24 hours and 5 days after
cardiac arrest using DWI.

"It appears that [magnetic resonance imaging] MRI can certainly
identify the most severely affected patients fairly easily, but
whether it's going to be predictive in a prospective data set would
need to be validated," Dr. Wijman told Medscape Neurology &
Neurosurgery. "We would not recommend ¡X now, at least ¡X making a
decision to withdraw life support based on this, but I do think that
MRI may be a very promising additional prognostic tool in these
patients."

Their findings were presented at the 132nd Annual Meeting of the
American Neurological Association.

Accurate Prediction of Outcome

Approximately 350,000 cardiac arrests occur each year in the United
States, and as many as half of these can be resuscitated
successfully, the authors write. To date, only 10% to 30% of these
patients have good neurologic recovery, although this is expected to
improve with the use of therapeutic hypothermia, they note.

Currently available prognostic indicators identify only about one-
third of poor-outcome patients reliably. This has been further
hampered recently by the more widespread use of hypothermia as a
standard of care in the United States. Patients are sedated for the
first 24 hours, and sedation may last even longer if the liver or
kidneys are damaged, inhibiting clearance of these medications, said
Dr. Wijman, "so we've sort of lost our window for getting serial
neurologic examinations or using [electroencephalography] EEG at
least up to 36 hours."

MRI has been shown to be more sensitive for detecting hypoxic brain
injury than computerized tomography, for example, which can be
unremarkable unless the brain injury is very severe, she said. DWI,
in particular, is "exquisitely sensitive" in detecting early
ischemic changes, she noted.

Previous pathology studies had suggested that susceptibility to
hypoxic injury differs by brain region. In this study, the
researchers set out to look at spatial and temporal differences in
susceptibility to changes on DWI in comatose post¡Vcardiac arrest
patients and to see whether differences in these patterns of
quantitative brain ADC values could differentiate those with good
outcomes, defined as those who were alive at 3 months, and those
with poor outcomes. Poor outcome was defined as death, the bilateral
absence of cortical responses by somatosensory evoked potentials,
clinical evidence of brainstem dysfunction after 72 hours, or in a
vegetative state after 1 month.

Regional and Temporal Differences

This substudy is part of an ongoing pilot project funded by the
American Heart Association looking at the utility of MRI and a
variety of serum biomarkers in these patients. A total of 35
patients with 42 scans were included; 20 scans in 18 good-outcome
patients and 18 scans in 15 poor-outcome patients, all acquired
within 8 days of the arrest. Patient MRIs were then compared with
those from 14 normal controls.

The researchers found both regional and temporal differences in the
quantitative ADC patterns in patients with good vs poor outcomes.

"The differentiation between patients with good and poor outcomes by
MR imaging seems to be time dependent over the first week and to be,
to some extent, also regionally different ¡X in other words, some
areas are more affected than others," Dr. Wijman said.

"The main ones affected are the gray matter ¡X the cortical
structures and the deep gray nuclei ¡X more so than the corona
radiata and the internal capsule, which are white-matter
structures," she added. In the white-matter structures, it appeared
that there were some changes in the poor-outcome group as well, but
these seemed to be more gradual and delayed compared with changes in
gray-matter structures.

Specifically, they reported that in good-outcome patients, the mean
ADC values of the cortical structures were higher than controls at
nearly all time points starting at 24 hours after the arrest. The
opposite pattern was seen in the cortex of those with poor
outcome, "with early, marked restricted diffusion in all 4
structures between 49 and 120 hours after the arrest," the authors
write.

In the hippocampus, good-outcome patients showed increased
diffusivity starting with early scans at 24 hours that continued
through 192 hours. Poor-outcome patients showed no significant
difference in diffusivity from controls in this structure.

Deep gray-matter structures showed increased diffusivity at 49 to 96
hours among good-outcome patients that continued through 120 hours
in the putamen, they note. "In contrast, in the poor-outcome group,
the putamen showed restricted diffusion as early as 25 to 72 hours
following cardiac arrest," the authors write. "When compared with
the decrease in mean ADC values seen in the cortical structures, the
decrease in these structures was more modest."

Finally, in good-outcome patients, white-matter structures,
including the corona radiata and the internal capsule, showed
milder, facilitated diffusion occurring later than in gray-matter
structures. "Only ADC values of the corona radiata were
significantly higher, but not until 49 to 96 hours, and this was
carried out to 192 hours," they write. In the poor-outcome patients,
restricted diffusion was also less severe and more delayed in the
white-matter structures compared with the gray matter.

Others Investigating This Modality

David M. Greer, MD, from Massachusetts General Hospital, in Boston,
who was not involved with this study, said his group is also
studying the use of DWI at their institution for this purpose. They
plan soon to publish findings in their own series of patients. "It's
a very good modality to study hypoxic-ischemic brain-injured
patients, but we're still scratching the surface of what exactly it
will mean in terms of prognostication," he told Medscape Neurology &
Neurosurgery.

The authors report no conflict of interest. The study is supported
by the American Heart Association Scientist Development Award and
the Katherine McCormick Fund for Women.


132nd Annual Meeting of the American Neurological Association:
Abstract #T-124. Presented Tuesday, October 9, 2007.

The codevelopers of prasugrel (Daiichi Sankyo, Eli Lilly), the
antiplatelet agent on an investigational trajectory to compete with
clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), announced
yesterday that further patient enrollment and administration of the
drug in two small phase 2 studies is being suspended so that the
protocols can be changed [1].

"The amendments are due to preliminary results from pharmacokinetic
analyses, including patients and healthy subjects/volunteers,
indicating that a dose adjustment may be appropriate for certain
subpopulations," according to a sparsely written joint statement
from the two companies. Both studies have been comparing the
antiplatelet prowess of prasugrel and clopidogrel in patients with
coronary artery disease.

The two suspended prasugrel studies are listed on the US government
website www.clinicaltrials.gov by the identifiers NCT00385944 and
NCT00356135 [2], confirmed Eli Lilly spokesperson Joedy Isert for
heartwire. One was a crossover comparison of 10-mg prasugrel vs 150-
mg clopidogrel for 14 days as daily maintenance therapy following a
900-mg clopidogrel loading dose in patients with ACS. The other was
comparing daily maintenance with 10-mg prasugrel vs 75-mg
clopidogrel in patients who had been on 75-mg/day clopidogrel after
PCI performed for ACS. Isert said no signal of risk associated with
prasugrel had been observed in either study.

Neither of the trials was designed to test clinical efficacy. That's
the goal of the TRITON-TIMI 38, a comparison of the two
thienopyridine agents given at PCI in >13 000 patients with unstable
angina or ST-elevation or non-ST-elevation MI [3,4]. As covered by
heartwire, the trial's results have been anticipated with some
interest for several years. Clopidogrel is one of the world's best-
selling drugs and is currently the only antiplatelet agent other
than aspirin used in PCI and for the long-term management of ACS.

Analysts say TRITON-TIMI 38 will produce mixed results

The announcement of the suspension of the phase 2 studies comes less
than two weeks before the scheduled presentation of TRITON-TIMI 38
at the American Heart Association Scientific Sessions 2007 and on
the same day that Lilly's stock was downgraded by investment
analysts [5], who predicted that the trial will produce mixed
findings for prasugrel: an increase in bleeding complications paired
with superior clinical efficacy. The analysis, as it was described,
was based on educated assumptions and apparently conducted without
knowledge of the trial's primary outcomes.

Daiichi Sankyo and Elli Lily. Study protocols will be amended in two
small early-phase prasugrel studies [press release]. October 24,
2007. Available at: http://newsroom.lilly.com/ReleaseDetail.cfm?
ReleaseID=271191.
ClinicalTrials.gov
The TIMI library
Daiichi Sankyo. Enrollment phase III completed: Study comparing
prasugrel to clopidogrel. Available at: http://www.daiichi-
sankyo.eu/site_eu/?node_id=2485.
Scala S, Kaplan B, Sanderson I, et al. Study data may hurt Eli Lilly
stock. Barron's, October 22, 2007. Available at:
http://online.barrons.com/article/SB119317396317368850.html?
mod=b_hpp_9_0002_b_online_exclusives_right.

Selective use of transesophageal echocardiography (TEE) appeared to
be as effective at preventing embolic events as routine use in a
cross-Canada study looking at use of the procedure prior to left
atrial ablation for atrial fibrillation (AF) [1]. The survey-based
study was presented at the Canadian Cardiovascular Congress 2007.

The results indicate a potential cost-effectiveness issue with
routine use, noted Dr Damian Redfearn (Queen's University, Kingston,
ON) in his presentation of the data. The study was undertaken to
assess the use of TEE across Canada as well as to determine the
prevalence of left atrial clot identified by routine or selected use
and to compare the different practices across the country,
correlating them with cerebral thromboembolic events.

Cross-country checkup

A survey was emailed to 10 Canadian electrophysiology centers that
practice left atrial ablation for AF.

Retrospective analysis on data from all 10 centers revealed a total
of 2225 cases of AF, with a median of 110 per center, or roughly 55
per year. The great majority--80%--of cases were paroxysmal AF. TEE
was performed in a total of 1194 cases. Routine TEE was performed in
996 patients. A total of 16 left atrial clots were identified
(prevalence of 1.25%).

Eleven cerebroembolic events were observed, nine with previous
negative TEE. At an incidence of 0.49%, the rate of thromboembolic
complications is low, observed Redfearn. No difference was seen in
the rate of embolic complications between routine TEE (six of 996
cases) and selected TEE (five of 1190 cases), and there were no
reported complications from TEE use.

Although he feels a more comprehensive analysis is needed before
talking of clinical impact, he doesn't foresee a change in practice.
¡§The images and the subjective experience of colleagues are such
that, if they do routine TEE, they're resistant to change,¡¨ he
noted, adding that his center performs routine TEE.

Redfearn DP. Transesophageal echocardiography (TEE) prior to atrial
fibrillation: A Canada Atrial Fibrillation and Complex Ablation
Alliance (CAFCAA) study. Canadian Cardiovascular Congress 2007;
October 22, 2007; Quebec City, QC.

In a classic example of too little, too late, results of the
EUROSTAR II trial show that the now-defunct paclitaxel-eluting
CoStar stent is significantly better than its bare-metal platform
stent in terms of reducing restenosis and late loss, as well as
target lesion revascularization (TLR), target vessel
revascularization (TVR), and MACE at eight months. The CoStar,
however, after being approved in Europe, was yanked off the shelves
in May 2007 following its inferior performance vs the Taxus stent in
the US pivotal COSTAR II trial.

The COSTAR II trial was designed to prove that the next-generation
CoStar stent, which incorporated a unique bioabsorbable polymer in
little reservoirs to elute the drug, was as good as a market-
approved drug-eluting stent (DES) but may have shot itself in the
foot by failing to first prove itself in a large randomized clinical
trial against a bare-metal stent.

"COSTAR II showed the Costar was inferior to the Taxus, so they took
it off the market," primary investigator for the EUROSTAR trial, Dr
Sigmund Silber (Dr Müller Hospital, Munich, Germany),
commented. "But even though it might be inferior to Taxus, it's
still better than a bare-metal stent. And since it's a highly
flexible stent, why take it off? Leave it for the market to decide."
If he could, Silber added, "I'd have it back on my shelves."

The Costar was developed by Conor, bought out by Cordis/Johnson &
Johnson (J&J) last year, which made the decision to pull the plug on
the paclitaxel-coated version; it had been available in Europe since
February 2006. Cordis/J&J, however, is moving ahead with plans to
rejigger the device, including tweaking the stent's deliverability,
drug-elution characteristics, and radial strength, a company
spokesperson told heartwire.

"It's all a question of timing," Dr Alexandra Lansky (Columbia
University, New York, NY) commented. "If the original trial had been
like the EUROSTAR trial--a comparison with bare-metal stents--it
wouldn't have been pulled off the market. But the stent has been
resurrected and is being loaded with sirolimus, so will be entering
new trials. It may not be a lost technology."

But she also pointed out that the late loss with the CoStar is
higher than that seen with the Cordis/J&J's Cypher stent, which
likely partly explains the company's reluctance to continue
developing the stent in its current form, particularly since
paclitaxel is its competitor's drug. "The CoStar was clearly better
than bare metal but also clearly inferior to the DES they already
had on the market."

"Hope to see you back soon"

EUROSTAR II was a prospective multicenter randomized comparison of
the CoStar and its bare-metal platform stent, the UniStar, that
enrolled 303 patients at 18 European centers. As Silber showed here
at the TCT 2007 meeting, the CoStar stent was statistically superior
to the bare-metal stent in terms of eight-month binary restenosis,
as measured by angiography, the primary end point of the trial. It
was also superior in terms of the other angiographic and clinical
outcomes (TVR, TLR, and MACE) at eight months, with no differences
in cardiac death, Q-wave MI, and non-Q-wave MI.

"If someone uses something for two years, don't take it away if
there are no problems. There were no major safety issues. In our
study, we saw not a single stent thrombosis," Silber said.

Discussing the results following Silber's presentation, Dr Carlo Di
Mario (Brompton Hospital, London, UK) also expressed regrets for the
CoStar's removal, noting that it was a platform with excellent
performance. "Bye-bye, CoStar," he said, "We hope to see you back
soon."

¡§The much-needed alternative to drug-eluting stents may not be the
next-generation drug-eluting stents.¡¨ Such was the message conveyed
here yesterday at the TCT 2007 meeting by Dr Robbert de Winter
(Academic Medical Center, Amsterdam, the Netherlands).

DeWinter presented preliminary results from TRIAS HR, the first
randomized comparative study between the prohealing Genous
bioengineered R stent (OrbusNeich, Wanchai, Hong Kong) and Boston
Scientific¡¦s first-generation Taxus paclitaxel-eluting stent.

At 30-day and six-month follow-up, the prohealing Genous stent
displayed efficacy similar to Taxus in high-risk restenosis patients.

The single-center, single-blind study included 193 patients at high
risk of restenosis, defined as patients who had diabetes mellitus,
small vessels (<2.8 mm), long lesions (>20 mm), or chronic total
occlusions. Of the patients treated, 98 received a Genous
bioengineered R stent, while 95 received a Taxus paclitaxel-eluting
stent.

There were no significant differences in death or MI between the two
groups. There were more instances of non¡Vtarget-vessel
revascularization in the Taxus arm (14% of patients) than the Genous
arm (3.2%). The level of acute thrombosis was lower in the Genous
arm, and there was no evidence of subacute or late-stage thrombosis.
In the Taxus arm, the acute-thrombosis levels were slightly higher
and there was also evidence of both subacute and late-stage
thrombosis.

At six-month follow-up, 44% patients treated with a Genous stent
were on clopidogrel, compared with 73% treated with the Taxus stent.

So how does Genous differ?

The Genous stent relies on the use of naturally circulating
endothelial progenitor cells (EPCs), which are produced in the bone
marrow and are involved in the repair of blood vessels. Genous is
coated with an antibody that attracts the EPCs to the surface of the
stent and allows for a layer of endothelium to form around the
device.

In the discussion following de Winter¡¦s presentation, Dr Cindy
Grines (William Beaumont Hospital, Royal Oak, MI) said that the
trial results were promising in that the Genous stent requires a
shorter treatment of clopidogrel and seems to reduce the risk of
stent thrombosis. She did voice concerns about the size of the
patient sample, however, stating that it needed to be expanded.

According to deWinter, his team has started enrolling patients in
the multicenter, multiarm TRIAS study in Europe to address this
issue. The trial will compare bare-metal stents and drug-eluting
stents with the Genous stent across 50 centers and will include 1250
patients.

¡§Genous is a very promising, innovative device with a wide range of
applications for physicians and many benefits to patients,¡¨
deWinter said. ¡§The results of our pilot study fully support our
rationale for the large-scale TRIAS study that will compare Genous
with both drug-eluting and bare-metal stents.¡¨

Two newly identified genes, ARTS1 and IL23R, may be associated with
4 major autoimmune disorders, according to the results of a study
published online October 21 in Nature Genetics. The diseases linked
to these genes are ankylosing spondylitis (AS), autoimmune thyroid
disease (AITD), multiple sclerosis, and breast cancer.

The investigators suggest that IL23R, in particular, may be a common
susceptibility factor for the major "seronegative" diseases. Earlier
research has shown an association between IL23R and both
inflammatory bowel disease (Crohn's disease) and psoriasis.

"Clinically these diseases tend to occur together ¡X people with
inflammatory-bowel disease also tend to have a higher probability of
having ankylosing spondylitis and psoriasis," senior author Lon R.
Cardon, PhD, from the Fred Hutchinson Cancer Research Center in
Seattle, Washington, says in a news release. "The IL23R gene
provides a genetic link that sheds new light on their co-
occurrence."

This study resulted from a large-scale collaboration between the
Wellcome Trust Case Control Consortium and the Australo-Anglo-
American Spondylitis Consortium (TASC). The investigators genotyped
14,436 protein-coding variants, or nonsynonymous single nucleotide
polymorphisms (nsSNPs) and 897 major histocompatibility complex
(MHC) tag SNPs from 1000 independent cases of AS, AITD, multiple
sclerosis, and breast cancer. These data were compared against a
common control data set derived from 1500 randomly selected healthy
British subjects.

Two genetic loci were initially shown and independently replicated
in a North American sample to be related to AS. The strongest
genetic associations were observed in the MHC region shown to be
strongly associated with autoimmunity. These genes, ARTS1 and IL23R,
in addition to the previously recognized gene HLA-B27, are now all
known to be involved in the pathogenesis of AS. An individual with
all 3 of these genetic variants would have a 25% probability of
developing AS.

"These findings, enabled in part by increased statistical power
resulting from the expansion of the control reference group to
include individuals from the other disease groups, highlight notable
new possibilities for autoimmune regulation and suggest that IL23R
may be a common susceptibility factor for the major 'seronegative'
diseases," the authors write. "The challenge now is to design
functional studies that will reveal how variation in these genes
translates into physiological processes that influence disease risk."

On the basis of a comprehensive analysis of the human genome using
genotyping technology, the investigators also confirmed the
previously documented association of 2 genes involved in Graves'
disease, or autoimmune thyroid disease, namely, TSHR and FCRL3.

By determining the specific effects of the implicated genes in model
organisms on pathways known to influence the pathogenesis of the
associated disease, the investigators are targeting improved
diagnostics and drug discovery. Because genetic variation in IL23R
increases risk for both Crohn's disease and AS, for example, drugs
thought to be effective in one of these diseases also may benefit
patients with the other.

"We already knew that IL23R is involved in inflammation, but no one
had ever thought it was involved in [AS]," said coauthor Matthew
Brown, MD, from the Wellcome Trust Centre for Human Genetics at the
University of Oxford, United Kingdom.

The Wellcome Trust supported this study. TASC is funded by the
National Institute of Arthritis and Musculoskeletal and Skin
Diseases; the University of Texas at Houston; Cedars-Sinai, Los
Angeles, California; the Rosalind Russell Center for Arthritis
Research at the University of California, San Francisco; and the
Intramural Research Program, National Institute of Arthritis and
Musculoskeletal and Skin Diseases, National Institutes of Health,
Bethesda, Maryland.

Nature Genetics. Published online October 21 2007.

Pregnancy-related deaths are usually the result of peripartum
cardiomyopathy, preeclampsia, HELLP syndrome, fatty liver of
pregnancy, and amniotic fluid emboli, according to a retrospective
autopsy case analysis.

HELLP is a group of symptoms that occur in pregnant women who have
hemolysis (H), elevated liver enzymes (EL) and low platelet count
(LP). HELLP syndrome occurs in pregnant women with preeclampsia or
eclampsia. If severe, it causes elevated blood pressure and protein
in the urine and can progress to life-threatening seizures
(eclampsia).

"Maternal death is rare, in that only 58% of cases were caused by or
strongly associated with pregnancy; 42% of cases had fatal
complications that might have occurred in other, nonpregnancy
settings," Amanda Crowe, MD, pathology resident, University of
Alabama at Birmingham, reported here during a poster session at the
American Society for Clinical Pathology (ASCP) 2007 Annual Meeting.

In a retrospective case series from the University of Alabama at
Birmingham Hospital, which serves a high-risk clinic and treats high-
risk transfers, the number and causes of maternal deaths were
determined at autopsy by searching 4307 reports from between January
1, 1991, and March 9, 2007. This search identified 36 cases of
maternal death (0.8% of all cases). The age range was 14 to 46 years
(mean age, 26.2 years).

Deaths were categorized as conditions seen only in pregnancy,
conditions where pregnancy is a risk factor, surgical complications,
and underlying conditions not related to pregnancy. Twelve deaths
(33%) were caused directly by pregnancy, 9 deaths (25%) were
pregnancy associated, 4 deaths (11%) were caused by surgical
complications, and 11 deaths (31%) were from underlying medical
conditions.

Pregnancy-related deaths were caused by peripartum cardiomyopathy,
preeclampsia, HELLP syndrome, fatty liver of pregnancy, and amniotic
fluid emboli, whereas deaths in the pregnancy-associated category
included pulmonary thromboemboli, infection, drug reaction, and
aortic dissection.

Surgical complications included hemorrhage, intraoperative death,
and esophageal perforation.

Deaths attributed to underlying conditions were cases in which there
were preexisting, potentially fatal medical problems that were not
pregnancy related, Dr. Crowe said.

"Advances in the field of obstetrics and gynecology have now made
the peripartum period much safer for both mother and child," she
added.

Elizabeth Wagar, MD, from the University of California, Los Angeles,
and program chair of the ASCP annual meeting committee, who was not
associated with the study, noted in an interview with Medscape
Pathology that maternal death occurred in only 0.8% of all autopsies
(more than 4300 autopsies were reviewed).

"Modern healthcare has clearly reduced the percentages of deaths
that are associated with pregnancy. In the 19th century, as many as
700 deaths occurred per 10,000 births. Many of these deaths were
related to delivery complications and infection," Dr. Wagar
noted. "The present study indicates most maternal deaths were caused
by or strongly associated with pregnancy and were due to preexisting
medical problems that were not pregnancy related. Notably, mortality
was not related to infectious disease complications, a common cause
of maternal mortality 100 years ago."

Dr. Crowe has disclosed no relevant financial relationships.

American Society for Clinical Pathology 2007 Annual Meeting:
Abstract 2. Presented October 18, 2007.

Kidney impairment raises levels of N-terminal pro¡VB-type
natriuretic peptide (NT-proBNP), a finding that may mean that the
tests for this neurohormone lose their specificity for congestive
heart failure (CHF), which is common in elderly patients, according
to a multicenter study.

However, a new formula presented here at the American Society for
Clinical Pathology (ASCP) 2007 Annual Meeting may provide a way
to "fine tune" the test, improving its accuracy in the future.

NT-proBNP, as measured by tests made by Roche Diagnostics and
Response Biomedical are commonly evaluated through blood tests given
in hospital emergency departments to predict the risk for myocardial
infarction in patients with coronary heart disease; they also have
served more recently as a diagnostic tool for CHF risk
stratification.

"Older individuals develop a [reduction in the] number of nephron
units that progresses until there is no functional reserve, which
means that the test may not be as predictive for patients over 50,
due to a failing renal condition," Larry Bernstein, MD, chief of
clinical pathology, New York Methodist Hospital, Brooklyn, said
during his poster presentation.

In the Renal Insufficiency in Predicting NT-ProBNP Level Elevation
(RIPPLE) study, Dr. Bernstein and colleagues examined the effects of
risk factors, such as renal insufficiency, on the predictive value
of NT-proBNP in a large group of patients from 3 major metropolitan
areas.

"Impaired renal function elevates NT-proBNP independently of
congestive heart failure or anemia. Our study found that the effect
of renal disease was substantial, and it may have an even greater
effect than [CHF] on NT-proBNP test results," Dr. Bernstein told
Medscape Pathology.

In the study, 1184 patients from 3 sites who presented to the
emergency departments with shortness of breath or symptoms
suggestive of CHF. The patients underwent testing for NT-proBNP
levels and were examined for the size of the effect of renal
insufficiency on NT-proBNP concentration. All patients were
evaluated for end-stage renal disease or chronic renal insufficiency.

Patients with elevated troponin T exceeding 0.07 ng/mL and atrial
fibrillation were excluded, leaving 834 patients in the study.

The diagnostic studies evaluated included an electrocardiogram, a
hemoglobin concentration, a white blood cell count, troponin T,
creatinine, and a transthoracic echocardiogram for left ventricular
and valvular dysfunction. These are either tests that had to be
applied or comorbidities that had to be accounted for to isolate the
effects of kidney function.

To isolate the effect of the patients' renal function, the NT-proBNP
levels were normalized to remove the effect of the estimated
glomerular filtration rate (eGFR) by dividing 1000*log(NT-proBNP) by
eGFR. Data were further normalized to age younger than 50 years by
means ratios.

Thirty-nine patients with renal impairment had a mean NT-proBNP
level of 8753 pg/mL compared with 2558 pg/mL in 320 patients without
renal impairment (P = .0001), after removing confounders.

The receiver operating characteristic curve of the NormKLog(NT-
proBNP/eGFR) by eGFR gives an area under the curve of 0.865;
sensitivity and specificity were invariant.

"The report provides an opportunity to eliminate the multiple
reference ranges and have one basic reference range that removes the
large effect of the kidney. This algorithm that was used to study
the effects of the kidney...will have potential for clinicians' use
as well ¡X and eventually could be incorporated into a simple
laboratory report," Dr. Bernstein said.

ASCP President Lee Hilborne, MD, professor of pathology and
laboratory medicine at the David Geffen School of Medicine at the
University of California, Los Angeles, told Medscape
Pathology, "It's important to understand the overall condition of
the patient, and the test may not provide the whole picture."

The study was did not receive commercial support. Dr. Bernstein and
Dr. Hilborne have disclosed no relevant financial relationships.

American Society for Clinical Pathology 2007 Annual Meeting:
Abstract 6. Presented October 18, 2007.

Measuring waist circumference (WC) and triglyceride levels may
identify patients at risk for CV disease who would otherwise be
misclassified, says Dr Jean-Pierre Després (Université Laval, Quebec
City, QC) [1]. Speaking at the Canadian Cardiovascular Congress
2007, he presented highlights of results from the European
Prospective Investigation of Cancer (EPIC)-Norfolk study that
suggest the hypertriglyceridemic waist (HTGW) significantly predicts
CHD beyond the Framingham risk score.

Although awareness of the issues surrounding the obesity epidemic
has grown, Després, who is director of research at the Hôpital Laval
Research Centre and scientific director of the International Chair
on Cardiometabolic Risk at University Laval, notes that mixed
results from epidemiological studies cause confusion. While some
clearly label obesity as a culprit in CV disease, others fail to
show obesity as an independent risk factor for CVD after controlling
for hypertension, dyslipidemia, diabetes, and smoking.

The problem, he states, lies in a continued reliance on body-mass
index (BMI) as a measure of obesity, despite recent data that show
it is abdominal--particularly visceral--fat that is associated with
the group of risk factors that characterize metabolic syndrome:
insulin resistance, elevated triglycerides, low HDL cholesterol,
hypertension, and WC. The complexity of the algorithm--any three of
the five risk factors indicate the presence of the syndrome--and the
ensuing disagreement over the clinical usefulness of the term
metabolic syndrome in the past few years have added to the confusion.

Determining the specific relationship between obesity and heart
disease may be not be so complicated. "There is a continuous
relationship between waist line and prevalence of CVD and type 2
diabetes," Després says. Despite recent data demonstrating the
effectiveness of WC measurement as a predictor of risk, some
patients who are obese but whose fat is predominantly subcutaneous
don't share the same risk as those with visceral fat distribution.
An analysis of the International Day for the Evaluation of Abdominal
Obesity (IDEA) study, published in the October 23, 2007 issue of
Circulation, compares patients with visceral vs subcutaneous fat who
have similar WCs [2]. He notes that there is no cutoff that defines
a patient as clinically obese, citing the example of a very obese
woman with a BMI of 55 kg/m2 with high HDL cholesterol and low
triglycerides whose fat was distributed subcutaneously.

Després suggested a potential explanation: "Visceral fat
accumulation is a marker of the relative inability of subcutaneous
fat to act as a protective metabolic sink, leading to ectopic fat
deposition." He notes that a simple way to detect this phenomenon is
to measure both WC and fasting plasma triglycerides. Study data from
2000 show that men with a WC >90 cm and triglycerides >2.0 mmoL/L
have an 80% chance of having the metabolic syndrome (WC >85 cm and
triglycerides >1.5 mmoL/L in women) [3].

What does measuring cardiometabolic risk add to current definitions?
Despite data showing the relationship between WC measurement and
risk, 75% of physicians still don't reach for the measuring tape.
Després notes that the NCEP ATP III guidelines are effective for a
first screening, but measuring WC and plasma triglycerides can
identify residual risk. In his upcoming article from the EPIC-
Norfolk study, the HTGW measurement revealed major discrepancies in
CHD event rates compared with groups assessed by the Framingham risk
score. The data suggested up to two-thirds of women were
misclassified by the Framingham data.

"Risk is further increased when a given Framingham score is
accompanied by a HTGW measurement, and the risk is markedly reduced
with the standard risk score alone," Després remarked. "This will
lead to the development of a brand-new CV risk assessment algorithm.
Is it going to change the way we assess risk? The answer is a clear
yes," he told heartwire.

The science of lifestyle modification

Determining the risk accurately is one obstacle to overcome, but the
biggest challenge by far is to change the "obesogenic" environment
that pervades developed and developing cultures alike. On this
subject, Després had some pointed criticisms of society, beginning
with the education system. He called for daily physical education
classes to be reinstated in schools, noting the opportunity to
establish healthy lifestyle practices early on. "It's totally
unethical to make our kids prisoners of a sedentary lifestyle in
schools," he asserted.

SYNERGIE, an ongoing lifestyle-modification study at Laval,
demonstrated impressive results in education and lifestyle change.
Over half of the 200 abdominally obese men who volunteered were
found to have impaired glucose tolerance or type 2 diabetes. After
diabetes patients were excluded, the remaining were assigned to a
lifestyle-modification program or usual clinical care. After a year
of once-monthly visits with a dietician and kinesiologist--for an
average cost of Can$1000 per patient per year--average waist
circumference dropped by 9 cm, although weight did not change for
many, as muscle mass replaced adipose. Retention rates were 82% at
one year and 75% at two years. Patients also saw decreased
triglycerides and apolipoprotein B, an increase in LDL-particle
size, and a nearly 50% decrease in C-reactive protein. Visceral fat
dropped by 30%, more so than subcutaneous fat.

In light of this data, he emphasized the importance in focusing on
waist, not weight, stating that campaigns to reduce weight are
confusing: "We are misleading the population when we talk
about 'healthy weight.' "

Deprés JP. Canadian Cardiovascular Congress 2007; October 21, 2007;
Quebec City, QC.
Balkau B, Deanfield JE, Després JP, et al. International Day for the
Evaluation of Abdominal Obesity (IDEA): A study of waist
circumference, cardiovascular disease, and diabetes mellitus in 168
000 primary care patients. Circulation 2007; DOI:
10.1161/CIRCULATIONAHA.106.676379. Available at:
http://circ.ahajournals.org.
Lemieux I, Pascot A, Couillard C, et al. Hypertriglyceridemic waist:
A marker of the atherogenic metabolic triad (hyperinsulinemia;
hyperapolipoprotein B; small, dense LDL) in men? Circulation. 2000;
102:179-84. Abstract

More than one mutation can cause the mitochondrial disease that
results in deafness and diabetes, according to a British research
team reporting in the September issue of Diabetes Care.

Dr. Roger G. Whittaker and his associates note that patients with
inherited deafness and diabetes are routinely screened for the
m.3243A>G mutation in mitochondrial DNA. Based on their findings,
however, they advise that patients should be referred to a
specialist for further testing if m.3243A>G results are negative.

"The association between the m.3243A>G mutation and
diabetes/deafness is well known," Dr. Whittaker told Reuters
Health. "However, in our cohort of patients, there are several who
present in this way but who carry different mutations. We were a bit
surprised by how many there were like this."

To assess whether screening for only the m.3243A>G mutation is
a "sensible" strategy for these patients, Dr. Whittaker and his
associates at Newcastle University reviewed the records of 242
patients treated at a special mitochondrial clinic during the
previous 25 years.

Twenty-nine of the patients diagnosed with mitochondrial disease had
presented with deafness and diabetes. However, only 21 screened
positive for the single m.3243A>G mutation.

In the other eight patients, other mitochondrial point mutations
were identified in three, single large-scale mtDNA deletions in
four, and multiple mtDNA deletions in one.

Three had "clear evidence of mitochondrial disease with ptosis,
marked external ophthalmoplegia and clear dysarthria," the
investigators report; three others had less severe manifestations.
The remaining two had no other symptoms than mild fatigue.

The mechanism whereby mitochondrial genome mutations cause these
clinical features remains a puzzle. Dr. Whittaker speculated
that, "in a simplistic sense, mutations of mitochondrial DNA affect
the cell's ability to produce ATP, but why the pancreas and auditory
nerves are preferentially affected is unknown."

He stressed the need for correct diagnosis "to avoid potentially
dangerous complications that can arise in mitochondrial disease,"
such as heart disease, neuropathy, and epilepsy.

Diabetes Care 2007;30:2238-2239.

The FDA has approved a test that can help predict a person's likelihood
of developing ischemic stroke. The assay, called the F5/F2/MTHFR
Nucleic Acid Test (Nanosphere, Northbrook, IL), looks for mutations in
three specific genes linked with disorders in blood coagulation and
vitamin B12 (folate) metabolism.

The same company makes a test for warfarin sensitivity that was granted
FDA approval last month. This newly approved F5/F2/MTHFR Nucleic Acid
Test runs on same Verigene System as the warfarin sensitivity test.

An individual with all three genetic mutations screened in the test has
an increased risk of thrombus formation and ischemic stroke, a company
press release states.

Canadian surgeons have performed the first prospective, double-
blind, randomized controlled trial comparing use of a novel cell-
saver device with cardiotomy suction in coronary artery bypass
surgery and have found that the cell saver improved neurological
outcomes [1]. Dr George Djaiani (Toronto General Hospital, ON) and
colleagues report their study online October 8, 2007 in Circulation.

Second author Dr Ludwik Fedorko (Toronto General Hospital, ON)
explained to heartwire that cell savers clean and process shed blood
during surgery, making it suitable for retransfusion into the
patient. The logic is that by removing fat particles from the blood,
the devices reduce cerebral lipid microembolization, which is
thought to be one of the causes of postoperative cognitive
dysfunction. However, this hypothesis is based primarily on animal
experiments and postmortem data, and the present study is the first
human study to investigate a direct link between fat emboli and
cognitive dysfunction after cardiac surgery, Fedorko noted.

Anesthesiologist and expert on neurocognitive dysfunction Dr Mark F
Newman (Duke University Medial Center, Durham, NC) told
heartwire: "This is a very interesting study showing the potential
for continuous flow cell savers to reduce perioperative cognitive
decline. The authors have performed a well-controlled study
demonstrating cognitive benefit."

There is one possible drawback, however, in that the cell saver
might result in the loss of coagulation factors and increase
bleeding. This needs to be further investigated, say both Newman and
the Canadian researchers.

Cell savers reduced cognitive dysfunction by more than 50%

In their paper, Djaiani and colleagues explain that cardiotomy
suction has been used in cardiopulmonary bypass for the 50 years
that this surgery has been around. But the blood collected in
cardiotomy suction, which is passed through a filter that traps only
large particles, contains high levels of cellular debris and lipid
microparticulates. When this blood is put back into the patient, it
is thought that the fat microemboli lodge in the capillaries,
contributing to cognitive decline after surgery.

The Canadian surgeons used a continuous-flow cell saver with a novel
spinning design (Fresenius Corp, Bad Homburg, Germany), which
Fedorko says removes 100% of the fat particles from blood compared
with around 70% for the other cell savers on the market, which are
all of a similar ball design. Use of cell savers varies widely
across North America, he explained, depending upon the institution
and the surgeon.

They randomly allocated 226 elderly patients to either cell-saver or
control groups (cardiotomy suction) during conventional on-pump
bypass surgery. Standardized neuropsychological testing was
conducted one week before and six weeks after surgery. Cognitive
dysfunction was present in 6% of patients in the cell-saver group
and 15% in the control group six weeks after surgery (p=0.038). The
group chose six weeks as an end point because this is a good time to
assess neurocognitive function, after the acute effects of surgery
have worn off, says Fedorko. Any neurocognitive decline present at
six weeks after surgery is usually still present six months
postoperatively, he noted.

"The present study demonstrates that 'cleansing' of the unprocessed
shed blood reduces cognitive decline in elderly patients after CABG
surgery," say the researchers.

"The question now," says Fedorko, "is should people abandon using
cardiotomy suction altogether and replace it with red cells or
should a cell saver of the Fresenius type be introduced? Cell savers
are not mandated, and some surgeons won't do anything until they are
forced to. But other surgeons are using cell savers. In certain
places in the US, some surgeons have already abandoned cardiotomy
suction. Period," he notes.

But do cell savers lead to loss of clotting factors and bleeding?

There is one possible downside to using the cell saver, however, in
that it may have an adverse impact on coagulation parameters and/or
result in increased blood transfusion rates.

A total of 28 patients (25%) in the cell-saver group and 14 (12%) in
the control group received fresh frozen plasma (FFP) transfusion at
any time during the postoperative period (p=0.018). A post hoc
analysis of the cell-saver group showed that patients that received
an FFP transfusion received significantly more cell-saver blood than
patients that did not get a transfusion (632 mL vs 379 mL;
p<0.0001).

Newman told heartwire that caution needs to be exercised. "The
concern with any intervention is the risk/benefit. The results
appear to indicate an increase in FFP transfusion associated with
the use of the continuous-flow cell saver."

Djaiani et al note that a recent small randomized study has shown no
difference in postoperative blood loss, hemoglobin concentration,
platelet count, and blood product transfused between patients
managed with either a cell saver or cardiotomy suction. Two other
studies have shown that use of a cell saver was not associated with
any adverse impact on coagulation parameters or increased blood-
product transfusion rates. Nevertheless, most of these studies were
too heterogeneous and underpowered to draw firm conclusions, they
admit.

"The extensive use of cell-salvage systems to process cardiotomy
blood may lead to a critical loss of coagulation factors and
platelets, resulting in a bleeding diathesis," they note, adding
that a large prospective randomized controlled trial concentrating
on transfusion outcomes as the primary objective is needed to
further explore this issue.

Newman concludes: "Hopefully, the benefit of continuous flow cell
saver to cognitive function will be confirmed and any negative
effects on coagulation and transfusion can be minimized."

Doctor, what would you do? Off-pump or on-pump with cell saver

Fedorko explained to heartwire that the problem with neurocognitive
dysfunction following CABG is that "it is not immediately obvious to
surgeons, patients, or their caregivers." Patients feel physically
better as a result of the surgery, and "it's only later on that the
patient starts to notice, but then often they put the symptoms down
to fatigue, aging, and so on."

Asked by heartwire whether he would prefer to have on-pump bypass
surgery using a cell-saver device or off-pump CABG, he said, "This
is a difficult question." He says that studies regarding cognitive
dysfunction and off-pump surgery have been conflicting, but it now
appears there is no difference in this parameter between on- and off-
pump surgery. There does, however, seem to be a lower stroke rate
associated with off-pump CABG, he noted.

"I would say, the decision depends on the morphology," he adds. "If
I were having a simple, one- or two-vessel procedure on the front of
my heart, I would prefer off-pump surgery. But if it were a distal
right coronary artery, and I know that every time they lift my heart
my blood pressure plummets and my brain doesn't get much blood flow
for that period of time, then I would opt for on-pump with a cell
saver."

Fedorko says he and his colleagues are also investigating other ways
of reducing neurocognitive decline following surgery. "It's not
confirmed that it's the emboli per se that cause the injury; it
could be an inflammatory reaction in the brain in response to the
embolization. The thrust of our current research is looking at
neuroprotective or inflammatory agents that can modify this
response, but we are two to three years from any answers."

Djaiani G, Fedorko L, Borger MA et al. Continuous-flow cell saver
reduces cognitive decline in elderly patients after coronary bypass
surgery. Circulation 2007: DOI: 10.1161/CIRCULATIONAHA.107.698001.
Available at: http://circ.ahajournals.org. Abstract

Dutch researchers are hoping to publish a new risk calculator for
pregnancy in women with congenital heart disease, listing already
known and newly identified predictors of maternal and fetal
complications.

Last month, Dr William Drenthen (University Medical Center,
Groningen, the Netherlands) presented results from the largest-ever
series of pregnancies in women with congenital heart disease at the
European Society of Cardiology Congress 2007 [1], in which he and
his colleagues identified several new predictors of maternal cardiac
and fetal complications. Drenthen told heartwire that a risk index
developed by Siu et al in 2001 [2] is already widely used, and his
team plans to add in the new predictors: "We are doing a modified
Siu risk score, and then we will attempt to convert that risk model
into a kind of calculator."

He says this kind of information is vital to doctors caring for
patients with congenital heart disease who wish to become pregnant
or who are already pregnant. Such women have an increased risk of
cardiac and obstetric complications, and their offspring have a
greater risk of premature delivery, intrauterine growth restriction,
and recurrence of congenital heart disease. The number of women
falling into this category is increasing, as people with congenital
heart disease survive longer, often well into adulthood, he noted.

Valve regurgitation and mechanical valves predict maternal cardiac
risk

Drenthen's team--the ZAHARA investigators--used data from CONCOR, a
nationwide registry and DNA bank for patients with congenital heart
disease in the Netherlands as well as data from a tertiary center in
Belgium. They retrospectively assessed 1696 pregnancies, with 1302
completed (>20-week gestation), 336 miscarriages (19.8%), and 58
elective abortions (3.4%).

Using multivariable logistic regression analysis, they identified
independent predictors of three composite end points: cardiac
complications--clinically significant episodes of heart
failure/arrhythmias, endocarditis, cardiovascular events (MI,
cerebrovascular accidents, dissection), and thromboembolic
complications (pulmonary emboli and deep venous thrombosis);
obstetric complications--pregnancy-induced hypertension, (pre-)
eclampsia, HELLP syndrome, premature labor, and postpartum
hemorrhage; and neonatal complications--premature delivery, small
for gestational age, and mortality.

The newly identified predictors of maternal cardiac complications
were valvular regurgitation, mechanical valve prosthesis, and
cyanotic heart disease. Valvular regurgitation has previously been
regarded as fairly harmless for the mother, "so it was somewhat
surprising that atrioventricular valve regurgitation predicted
maternal cardiac complications with a predictive power comparable to
NYHA class," Drenthen said.

With regard to the presence of a mechanical valve, Drenthen told
heartwire that Siu et al had expected to find that this was a poor
predictor of maternal outcome in their analysis, but they had only a
small number of patients with mechanical valves in their study.

"We now know from our database that those with mechanical valves are
more at risk," he said, adding that this is thought to be due to the
hypercoagulable state of pregnancy.

The Dutch team found no new predictors of obstetric complications.

New neonatal risk predictors include

With regard to neonatal complications, they identified cyanotic
heart disease, mechanical valve prosthesis, and cardiac medication
before pregnancy as new predictors of neonatal complications.

The identification of cardiac medication as a predictor of poor
neonatal outcome probably reflects a worse prepregnancy condition of
the mother rather than a direct negative effect of the medication,
Drenthen told heartwire.

He concluded that prospective studies are still needed to improve
risk stratification in these women and to elucidate the mechanisms
responsible for the complications.

Drenthen W, Roos-Hesselink JW, Van Der Tuuk K, et al. Predictors of
pregnancy-related cardiac, obstetric and neonatal complications in
women with congenital heart disease. European Society of Cardiology
Congress 2007; September 1-5, 2007; Vienna, Austria.
Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of
pregnancy outcomes in women with heart disease. Circulation 2001;
104:515-21. Abstract

A high level of crowding in the emergency department (ED) was
predictive of a higher rate of later cardiovascular complications in
patients with potential ACS, a new study has shown [1].

The study was presented by Dr Jesse Pines (University of
Pennsylvania, Philadelphia) at the American College of Emergency
Physicians (ACEP) 2007 Scientific Assembly, held here on October 8-
11, 2007. Pines concluded: "Public policy initiatives to improve
emergency-department crowding may improve the care of patients with
ACS and potential ACS (and maybe everyone else)."

Pines explained that ED crowding has been associated with poorer
quality of care and outcomes among several patient groups (such as
antibiotic delays for patients with pneumonia and delays to lysis
for patients with MI). One Australian study even suggested that an
increased death rate was linked to overcrowded emergency
departments, but few studies have examined ACS patients in this
regard.

He thus conducted a prospective cohort study of patients aged 30
years or older who presented at the ED of the University of
Pennsylvania Hospital with chest pain and potential ACS between
September 1999 and March 2006. The primary outcome was adverse
cardiovascular events between six hours and 30 days after presenting
at the ED. Adverse cardiovascular events were defined as death,
cardiac arrest, or the development of heart failure, late MI,
ventricular tachycardia or fibrillation, supraventricular
dysrhythmias, symptomatic bradycardia, stroke, or hypotension. The
study included 6869 patients. Of these, 33% received an ECG within
10 minutes of arrival at the ED, 57% were given aspirin in the ED,
and 8% were given beta blockers in the ED. A total of 33% of
patients were treated in the ED and discharged; the remaining 67%
were admitted to the hospital.

Of the 6646 patients available for follow-up, 831 actually had an
ACS--273 had an MI and 558 had unstable angina. Of these, 301 (4%)
patients developed a cardiovascular complication that met primary
outcome criteria. Patients were more likely to have a cardiovascular
complication if the ED was crowded (defined as more than 12 patients
in the waiting room, patient care hours >142, or occupancy over
72.5%).

Pines commented to heartwire: "We found that at times when the
emergency department was crowded, patients with potential ACS were
more likely to experience cardiovascular complications within the
next 30 days." He noted that the results were not due to longer
waiting times to ECG or time to treatment with aspirin or beta
blockers; these variables were the same regardless of how busy the
ED was because chest-pain patients always get priority.

Instead, Pines believes that ED crowding is a measure of
hospitalwide dysfunction--that is, patients are not getting
appropriate inpatient testing, and other interventions and
treatments are being delayed. "A crowded emergency department is
like a canary in a coal mine for the whole hospital. When the
emergency department is crowded, the waiting times for tests and
procedures in the whole hospital are longer. The overall culture of
the whole hospital changes. Inpatient floors feel the pressure to
admit more patients, so they discharge patients before they would
have done so otherwise. If the hospital is full, ACS patients may be
cared for by the inpatient team while still in the ED. If a patient
is in the ED for a long time, they get worse care. This may be just
because they are not geographically in the best place," he said.

What do we do about it?

Pines noted that the solution to this problem is to try to improve
ED crowding. "Across the US, emergency-department crowding is a
major issue. Care of ACS patients will continue to suffer as
emergency departments continue to be overcrowded. There are 114
million emergency-department visits each year in the US--that is one
for every three people. As long as hospitals have to operate at high
occupancy to remain competitive, patients admitted through the
emergency department will often not get an inpatient bed. They will
therefore have to stay in the emergency department, so they are in
the wrong place to get the best treatment. We need more funding and
better policies to reduce this problem," he added.

Pines JM, Hollander JE. Association between cardiovascular
complications and ED crowding. American College of Emergency
Physicians 2007 Scientific Assembly; October 8-11, 2007; Seattle,
WA.

People with serious mental illness lose 25 years of life expectancy
as compared with the general population, and this loss is due
primarily to an increased risk of cardiovascular disease (CVD), Drs
John W Newcomer (Washington University, St Louis, MO) and Charles H
Hennekens (Florida Atlantic University, Boca Raton) write in the
October 17, 2007 issue of the Journal of the American Medical
Association [1]. The numbers cry out for better communication
between mental-health specialists and cardiologists, the authors
argue.

"Most psychiatrists tend to not be surprised that there's a
shortened lifespan, but they also tend to assume that this is
suicide--a leading cause of death in this population--when in fact
it's really premature cardiovascular disease," Newcomer told
heartwire. "It's also very important that we get this message out
beyond the psychiatric community to those primary-care physicians
and specialists who would see patients with diabetes mellitus or CVD
who also happen to have a mental-health condition. Because
historically what we're seeing is that those patients are not
getting appropriate access to either primary or secondary CVD
prevention."

Recent research has illuminated the relationship between depression
and cardiovascular disease, but the impact of other mental illnesses
on cardiovascular health is poorly understood. As the authors note
in their paper, 50% to 80% of patients with diagnosable mental
illness are smokers, as compared with approximately 25% of the US
population as a whole. People with severe mental illness are also up
to two times more likely to have diabetes, dyslipidemia,
hypertension, obesity, and/or metabolic syndrome, yet they are
significantly less likely to receive CVD risk-lowering drugs,
including aspirin, beta blockers, and ACE inhibitors. The mentally
ill are less likely to undergo revascularization procedures, and
they are more likely to die following an MI.

Part of the problem is the way mental-health patients are handled in
the US medical system, Newcomer explains. Historically, people with
serious psychological disorders such as schizophrenia, bipolar
disorder, and depression have been treated through outpatient mental-
health centers, which are kept geographically remote from hospitals
or more generalized medical facilities. While this may have worked
well for targeting mental-health issues, it has allowed CVD risk
factors to go largely unchecked.

"Just the simple act of referring a patient to one of your
colleagues in another specialty often, for the patient, involves
driving across town. And this is a patient group where the act of
organizing one's life to schedule the appointment, drive across
town, arrange follow-up, and get to the lab has much less success."

Possible solutions

In their paper, Newcomer and Hennekens describe possible solutions,
including physical colocalization of medical facilities or having a
primary-care physician or cardiologist on staff at the mental-health
centers to perform the risk-factor screening that would improve
primary and secondary CVD prevention efforts. But there are also
professional barriers to overcome, Newcomer acknowledged. In some
cases, there may be the misconception that psychiatric issues need
to be "resolved" before other health problems can be addressed.

"Clinicians may think, well, I can't really engage this patient in a
discussion of risk-reduction approaches because they have
schizophrenia, and I can tell that they have some active symptoms.
But, in fact, if the clinician talks to the patient's psychiatrist,
the psychiatrist might say that this patient is actually as stable
as he or she is going to get. And although the patient may speak of
some delusional material at some point in the conversation, in fact
they're very good at listening to and understanding instructions
about diet or smoking."

On the flip side, psychiatrists may feel that the CVD prevention
agenda is not part of their scope of practice. "So everyone is
thinking it's someone else's job," Newcomer said.

While systemwide changes to how serious mental illnesses are handled
in the medical system will take time, Newcomer stressed that
cardiologists can take steps now to improve outcomes in this
vulnerable population. "I think it's important that the
cardiovascular physician understand that this is very much an at-
risk patient population, that they often have not been receiving
appropriate screening in primary prevention, and that they have a
high prevalence of smoking and poor dietary habits," he said. "And
there are psychiatrists who are potential partners in trying to work
to lower risk in these patients."

Even after prescribing medications, a cardiologist or general
practitioner should know that a psychiatrist or case manager is
likely available to help make sure the patient follows through on
cardiovascular tests or medication.

A second area for collaboration or consultation is in choice of
drugs targeting the particular mental illness, says Newcomer. "Many
times psychiatrists struggle with decisions regarding prescription
of certain psychotropic medications, and across the range of drugs
that are available, there are some agents or some combinations of
agents that would make weight reduction for a given patient very
difficult. So we want to encourage communication between the
psychiatry provider and the cardiologist so that both are pulling in
the same direction. If the cardiologist thinks that it's very
important that a patient be on a medication that treats their
psychiatric disorder but does not create an undue burden in terms of
weight loss, then they should say that."

According to disclosure information in the paper, Newcomer receives
grant support from and/or consults for Janssen, Pfizer, Bristol-
Myers Squibb, Wyeth, AstraZeneca, GlaxoSmithKline, and Solvay.

Newcomer JW, Hennekens CH. Severe mental illness and risk of
cardiovascular disease. JAMA 2007; 298:1794-1796.

A syndrome that included exercise intolerance and a kind of
hypertrophic cardiomyopathy was identified in several children in a
family of Syrian descent, many of whom were ultimately found to
carry a mutation in the gene encoded for muscle glycogen synthase,
describes a report in the October 11, 2007 New England Journal of
Medicine [1].

The authors, led by Dr Gittan Kollberg (Sahlgrenska University
Hospital, Gothenburg, Sweden), propose that the disorder be
called "muscle glycogen storage disease 0," in parallel with the
name of an analogous genetic disorder of liver glycogen storage.

Skeletal- and heart-muscle biopsies from affected children in the
family revealed cardiomyocyte hypertrophy without fibrosis and
a "profound deficiency of glycogen in all muscle fibers," whereas
liver glycogen stores appeared normal. The biopsy specimens also
displayed a predominance of oxidative fibers and proliferation of
mitochondria, the authors write.

One of the children with the muscle disorder, who died suddenly at
age 10, also had an EEG-documented history of epilepsy that may or
may not have been connected with the mutation, according to Kollberg
et al.

The muscle glycogen synthase gene mutation, they observe, was
identified throughout the siblings' extended family in a pattern
consistent with a recessively inherited disorder.

One carrier of the mutation was identified among 100 control
subjects of the same ethnicity, suggesting that "the disorder might
occur at a frequency of the same magnitude as other rare metabolic
disorders in this ethnic group. The findings in our patients
indicate that such cases might be found by a wider use of exercise
tests and screening for muscle disease in children and adolescents
not only with obvious muscle symptoms but also with myocardial
disease or epilepsy."

Kollberg G, Tulinius M, Gilljam T, et al. Cardiomyopathy and
exercise intolerance in muscle glycogen storage disease 0. N Engl J
Med 2007; 357:1507-1514.

Physicians in Belgium are warning colleagues about a misdiagnosis
they say may be relatively common, particularly among young
patients, but easily prevented with electrophysiological studies.
Writing in the October 2007 issue of Heart Rhythm, Dr Tom
Rossenbacker (University of Leuven, Belgium) and colleagues describe
the case of a 15-year-old girl, misdiagnosed with epilepsy at age 11
and treated fruitlessly with antiepileptic drugs for four years
before her true condition--long-QT syndrome--was discovered [1].

"Although we now describe a single case report, we have the feeling
that many young patients who are referred to our Center for
Hereditary Heart Diseases have been treated inappropriately in the
past for 'epilepsy,' " Rossenbacker told heartwire. "Seemingly, many
physicians have the reflex to assign fainting or syncope to a
neurological disorder. First, they focus on the brain and the
nervous system while assessing a young patient with syncope, and
sometimes a trial therapy with antiepileptics is started. . . . With
this case report, we hope to help educate all physicians involved in
the care of patients with fainting [that] although not always that
straightforward, the long-QT syndrome or other cardiac arrhythmias
can sometimes be easily diagnosed with a few simple investigations."

In the case Rossenbacker et al describe, physicians diagnosed the 11-
year-old as having epilepsy on the basis of her symptoms--weekly
seizures--and clinical presentation. Long-QT syndrome was diagnosed
only when the antiepileptic drugs failed to curb the seizures, and
the patient underwent 24-hour electrocardiographic,
electroencephalographic, and video recording; she fortuitously
developed a convulsive seizure during the 24-hour period. A
polymorphic ventricular tachycardia recorded at the onset of
symptoms prompted further cardiac examination, ultimately leading to
the diagnosis of long-QT syndrome.

According to the authors, the diagnosis of long-QT syndrome could
have been made much earlier had an ECG been used in the initial
diagnostic workup of the patient presenting with syncope.

In the case of the 15-year-old girl, her antiepileptic drugs were
stopped and she was started on a course of beta blockers and
potassium supplements, Rossenbacker told heartwire. She has also
received an implantable defibrillator.

"She is doing very well and has not had another seizure attack for
more than two years," he said.

Rossenbacker T, Nuyens D, Van Paesschen W, Heidbuchel H. Epilepsy?
Video monitoring of long QT syndrome-related aborted sudden death.
Heart Rhythm 2007; 4:1366-1367. Abstract

New research has come up with a possible answer (and a potential
solution) as to why blood transfusions are often not associated with
the benefit expected and may actually be harmful [1,2].

In two papers published online October 11, 2007 in the Proceedings
of the National Academy of Sciences, researchers report that stored
red blood cells are depleted of nitric oxide (NO), and, as a result,
their ability to deliver oxygen to ischemic tissues is impaired. But
when the stored red blood cells were reconstituted with NO, this
problem appeared to be fixed.

Senior author of one of the papers, Dr Jonathan Stamler (Duke
University Medical Center, Durham, NC), commented to
heartwire: "Many studies have suggested that transfusions are
associated with an increase in MI, heart failure, stroke, and death,
which hasn¡¦t really made sense, but nevertheless doctors are now
very cautious about giving transfusions. While it has been suspected
that banked blood is different in some way from blood in the body,
the reasons behind the worse outcomes with blood transfusions have
not been well understood. We are providing a solid rationale for the
first time as to why transfusions are associated with harm, and we
are offering a potential solution to the problem. Just soaking the
red blood cells in NO solution for a few seconds before infusion
could be all that is needed to make transfusions work better."

In his study, whose lead author was Dr James Reynolds (Duke
University Medical Center), Stamler et al found that NO levels in
red blood cells rapidly dropped when blood was stored and that this
was directly correlated with reduced ability to cause vasodilation
both in laboratory models and in an animal model of ischemia.
However, when the stored red blood cells were reconstituted with NO,
their vasodilatory activity was restored. In the second study, led
by Dr Elliott Bennett-Guerrero (Duke University Medical Center), the
researchers analyzed the NO content of red blood cells and how well
they dilated blood vessels as a function of how long they had been
stored. They found that NO levels were already depleted by three
hours and had dropped by 70% in just one day, and at every point the
decline in NO correlated with the inability of red blood cells to
dilate blood vessels.

Stamler commented to heartwire: "We have shown that stored blood is
impaired in its ability to deliver oxygen. That is because stored
red blood cells are depleted of nitric oxide, which is needed to
dilate blood vessels, targeting the red blood cells to the ischemic
region."

He continued: "There has been a crucial disconnect about blood
transfusions. Everyone has focused on how much oxygen is carried by
the red blood cells, but we should instead be concentrating on how
much oxygen they can deliver to the ischemic tissue. Delivery of
oxygen requires vasodilation, which is brought about by NO. Fresh
red blood cells will release NO, which will dilate blood vessels,
allowing the red blood cells to get to their target area--the site
of ischemia. If stored red blood cells are used, which are depleted
of NO, then the vessels cannot dilate and the cells cannot get to
the ischemic area. So they build up in the larger blood vessels,
causing further blockages and further ischemia, which could explain
the worse outcomes in ischemic patients given blood transfusions. In
addition, red blood cells are like sponges when it comes to NO, they
will absorb it very easily. So a red blood cell depleted of NO will
suck up NO from surrounding tissues, which could cause
vasoconstriction in that area, which could also contribute to bad
outcomes."

Possible therapeutic implications too

Stamler suggests that as well as making blood transfusions more
effective, NO-reconstituted red blood cells may have potential as
therapeutics for ischemic conditions. "We showed that in a dog model
of coronary ischemia, these NO-reconstituted red blood cells brought
about a marked improvement in coronary blood flow. This raises the
possibility of using blood therapeutics in patients with MI or
stroke or in those undergoing cardiac surgery. Surgeons performing
CABG at present are uncertain when to transfuse. We are struggling
to know whether we are doing good by giving a transfusion. The
relatively simple procedure of NO reconstitution may change all
that."

He added: "In principle, we now have a solution to the nitric-oxide
problem--we can put it back--but this needs to be proven in a
clinical trial."

One of these studies was supported by the National Institutes of
Health and Duke Anesthesiology Fund and the other by the American
Heart Association and N30 Pharma, a company that has a license
agreement with Duke to develop nitric-oxide-based therapies.

Reynolds JD, Ahearn GS, Angelo M, et al. S-nitrosohemoglobin
deficiency: A mechanism for loss of physiological activity in banked
blood. Proc Natl Acad Sci 2007; DOI: 10.1073/pnas.0707958104.
Available at: http://www.pnas.org
Bennett-Guerrero E, Veldman TH, Doctor A, et al. Evolution of
adverse changes in stored RBCs Proc Natl Acad Sci 2007; DOI:
10.1073/pnas.0708160104. Available at:
http://www.pnas.org/cgi/reprint/0708160104v1.

A new report published this week hints at another possible
therapeutic use for statins [1]. Investigators showed that the
cholesterol-lowering drugs reduced the decline of lung function in
older adults and that this benefit was modified by smoking status.

"To our knowledge, this is the first study to report a beneficial
effect of statins on the rate of lung-function decline," write lead
investigator Dr Stacey Alexeef (Harvard School of Public Health,
Boston, MA) and colleagues in the October 15, 2007 issue of the
American Journal of Respiratory and Critical Care
Medicine. "Although several promising medications are under
investigation, no treatment for patients with [chronic obstructive
pulmonary disease] COPD other than smoking cessation has been
consistently shown to improve the long-term rate of lung-function
decline."

The findings, suggest the authors, point to a possible treatment
that could potentially benefit those with COPD.

Anti-inflammatory and antioxidant properties of statins

COPD, characterized by airway restrictions, inflammation, and long-
term lung-function decline, is one of the leading causes of
mortality in the US, report the authors. Statins are known to have
numerous pleiotropic effects, such as antioxidant and anti-
inflammatory properties, and because inflammation and oxidative
stress are associated with decreased lung function, the group sought
to determine whether the pleiotropic effects could attenuate the
decline in lung function.

The study population consisted of 803 elderly men participating in
the Veterans Administration Normative Aging Study. Subjects had lung
function--as assessed by forced expiratory volume (FEV1) and forced
vital capacity (FVC)--measured two to four times between 1995 and
2005, and all subjects were assessed for statin use and smoking
status.

Subjects taking statins experienced, on average, a significantly
slower annual decline in lung function, with those on statin therapy
experiencing a 10.9-mL decline in FEV1. Those not taking statins, on
the other hand, lost 23.9 mL annually. In terms of FVC, statin users
lost, on average, 14 mL annually, while nonusers lost 36 mL.

Investigators also wanted to determine whether smoking, known to
cause rapid lung-function decline, modified the estimated effect of
the statins. The cohort was divided into four groups: never-smokers;
longtime quitters (>10 years); recent quitters (<10 years); and
current smokers.

Within each of these four groups, those not taking statins
experienced faster declines in FEV1 and FVC than those who were
taking the drugs. Longtime quitters and recent quitters experienced
the largest beneficial effect from statins compared with never-
smokers and current smokers, but further research into these
subgroups, especially among smokers and recent quitters, is needed
to confirm the findings, write the authors.

Dr Dan Hackam (University of Western Ontario, London), who commented
on the findings for heartwire, said the results were "interesting."
Like the investigators did, Hackam, a frequent contributor to
theheart.org forum, said that the main limitations of the analysis
are that it was a nonrandomized, observational study and that no
data were available on women or younger patients. Equally important,
he said, relatively few patients had pulmonary disease at baseline.

"However, the association reported by the authors does seem to be in
keeping with recent clinical trials of statins in rheumatoid
arthritis and multiple sclerosis (both published in the Lancet), in
which a fairly robust anti-inflammatory effect of statins was seen,"
Hackam wrote in an email to heartwire. "Trials are really needed to
confirm these findings. If the association is confirmed, statins
might represent a very attractive intervention for treating patients
with COPD, a condition that has relatively few disease-modifying
therapies (other than oxygen and pulmonary rehabilitation in
selected patients)."

The authors and Hackam have no conflicts of interest to report.

Alexeef SE, Litonjua AA, Sparrow D, et al. Statin use reduces
decline in lung function. Am J Respir Crit Care Med 2007; 176:742-
747. Abstract

The National Institutes of Health (NIH) is making available a
database of genetic and clinical data from large population-based
studies, starting with the landmark Framingham Heart Study, which
should help in understanding the genetic basis of heart disease and
other conditions.

Called SHARe (SNP Health Association Resource), the web-based data
set is funded by the NIH's National Heart, Lung, and Blood Institute
(NHLBI) [1].

Framingham SHARe includes data on more than 9300 participants
spanning three generations, including more than 900 families, who
had their DNA tested for 550 000 genetic variations (single
nucleotide polymorphisms [SNPs]). In addition, the participants'
clinical data gathered during the study, such as test results or
weight, are included. SHARe will enable researchers to relate study
participants' genetic variations with their clinical and laboratory
test results.

Data from ongoing Framingham Heart Study research as well as from
other large studies will continue to be added to the database.

"The widespread availability of Framingham Heart Study data provides
unprecedented opportunities to investigate the connections between
genes and disease," said Health and Human Services (HHS) secretary
Mike Leavitt. "SHARe represents a major milestone in moving toward
an era of personalized health care--a future in which the ways we
prevent, diagnose, and treat health problems are tailored to an
individual's genetic makeup."

NHLBI director Dr Elizabeth Nabel said, "As one of the most
comprehensive studies ever undertaken, the Framingham Heart Study
will play a vital role in laying the foundation for this vast data
set to help researchers link genes and disease."

Dr Christopher O'Donnell, associate director of the Framingham Heart
Study and scientific director of Framingham SHARe, says: "Analyzing
individual-level data with computer programs, researchers will be
able to search for new connections between genetic variations and
phenotypes such as high cholesterol. The thousands of Framingham
participants--some of whom have been monitored for almost 60 years--
have already contributed greatly to our understanding of the role of
risk factors for heart disease and other conditions, and now they
will contribute a wealth of new and detailed information about the
inherited basis of these conditions."

Dr Eric Topol (Scripps Translational Science Institute, San Diego,
CA) commented to heartwire: "This is certainly going to be a
valuable resource for the cardiovascular genomics community. Having
a large, exceptionally well-characterized cohort followed for
decades with genomewide SNP/variant coverage is far better than
waiting for years for prospective studies to accrue. It¡¦s terrific
that the NHLBI made this possible."

SHARe is accessed through the database of Genotypes and Phenotypes
(dbGaP), a web-based collection of data from studies that explore
the associations between genes and observable traits, such as
weight, cholesterol levels, or the presence or absence of a disease.
Launched in December 2006, dbGaP was developed and is operated by
the National Center for Biotechnology Information (NCBI), also part
of the NIH [2]. Researchers interested in applying for access to
individual-level Framingham SHARe data should follow the directions
on the website.

Framingham SNP Health Association Resource (SHARe)

A new prospective cohort study shows that negative aspects of a
close relationship--such as not confiding and not getting emotional
support--can increase the risk of coronary events [1]. Dr Roberto De
Vogli (University College, London, UK) and colleagues report their
findings in the October 8, 2007 issue of the Archives of Internal
Medicine.

"We think the quality of social relationships can be a very
important factor for health and well-being," epidemiologist De Vogli
told heartwire. "There is a growing body of literature that shows
that being exposed to negative relationships that increase worry,
anxiety, and feelings of low self-esteem can in the long term
produce emotional effects that may trigger biological changes in the
body."

De Vogli said poor marital quality has previously been reported as
an important prognostic factor for MI, heart failure, and metabolic
syndrome and that women seem to be more affected by the negative
aspects of a close relationship than men. "Our findings expand and
corroborate previous research . . . by showing that negative
interactions in close relationships are determinants of coronary
events."

Negative aspects of relationship up CHD risk by 34%

De Vogli and colleagues prospectively studied 9011 British civil
servants (6114 men and 2897 women) and assessed negative aspects of
close relationships and other social-support measures with a
questionnaire. Of the respondents, 80% cited marriage or a
partnership as their closest relationship.

Associations between negative aspects of relationships and coronary
events were determined during an average of 12.2 years of follow-up.
The researchers set out with the preconception that the association
would be stronger among women and among people of lower social
position, based on previous work in this field.

Of the 8499 individuals who did not have coronary heart disease
(CHD) at the beginning of the study and who provided sufficient
information for analysis, 589 reported a CHD event.

After adjustment for a number of factors, including
sociodemographic, biological (obesity, hypertension, diabetes, and
cholesterol levels), and health behaviors (smoking, alcohol intake,
exercise, and fruit and vegetable consumption), they found that
people who experienced negative aspects of a close relationship had
a 34% higher risk of incident coronary events (hazard ratio 1.34;
95% CI 1.10-1.63) than those who did not.

The association was attenuated but remained significant after
additional adjustment for negative affectivity and depression (HR
1.25).

Contrary to their prior hypothesis, they found that although women
and people in a lower employment grade were more likely to be
exposed to negative aspects of a close relationship, sex and social
position had no significant interaction effects.

This shows that negative interactions in close
relationships "produce similar effects on heart disease regardless
of sex and social position," the researchers say.

"Be nicer to each other"

De Vogli et al go on to suggest that negative close relationships
may be more powerful predictors of health than other aspects of
social support because previous research indicates that "individuals
tend to mentally replay negative encounters more than they replay
positive ones."

De Vogli told heartwire that he believes emotional effects could
trigger changes in the neuroendocrine, inflammatory, and
immunomodulatory systems. And although pharmacological
approaches "may cure the symptoms, they are just responding to the
crisis and not tackling the root causes," he said. Increasing
pressures in society, evidenced by the stresses seen in children
these days, also contribute to negative aspects of relationships.

"People just need to be nicer to each other," he says. "It seems so
simple, but it's basically a truism."

De Vogli R, Chandola T, and Marmot MG. Negative aspects of close
relationships and heart disease. Arch Intern Med 2007; 167:1951-1957.

Pre-emptive isolation appears to be an effective means of preventing
(MRSA) cross-transmission in patients hospitalized with diabetic
foot ulcers, according to French researchers.

In the September issue of Diabetes Care, Dr. Agnes Hartemann-
methicillin-resistant Staphylococcus aureus Heurtier of Hopital
Pitie-Salpetriere and colleagues note that as many as 30% of
infected diabetic foot ulcers show evidence of MRSA, which puts
other patients with open wounds at risk of cross infection.

To help prevent cross-transmission, the researchers placed MRSA
carriers in a single room and staff underwent a variety of contact
isolation measures, including use of disposable gowns and gloves and
antiseptic hand wash on leaving patients' rooms. In addition MRSA
screening was performed on admission and weekly until patient
discharge.

The precautions were employed after MRSA isolation, which generally
took about 72 hours. The team then switched to pre-emptive
isolation, in which contact isolation was employed until wound
samples were confirmed to be negative.

The researchers compared the results for approximately 15 months
using the earlier approach with those during about 4.5 years of the
pre-emptive isolation protocol.

Overall, 527 patients had 581 admissions over the course of the
study. A total of 179 patients (31%) were MRSA carriers on admission.

The team found that the pre-emptive intervention resulted in a
significant drop in infection (p = 0.04). This amounted to 7
acquisitions per 10,154 MRSA-free patient days (0.07%), compared
with 6 per 2,854 MRSA-free patient days (0.21%) using the
intervention.

Overall, the researchers estimate that the relative risk of
acquiring MRSA during the second period was one third of that seen
before pre-emptive isolation was employed.

"Our results show that with simple contact isolation clinical
measures, the rate of MRSA cross-transmission in diabetic patients
with foot ulcers is very low," Dr. H

"This rate can further be reduced by systematic pre-emptive contact
isolation implemented on patients' admission, before getting the
results of MRSA screening," Dr. Hartemann-Heurtier concluded.

Diabetes Care 2007;30:2341-2342.