Serum levels of complement factors C3 and C4 were predictors of
stroke risk over two years in a cohort of men referred for coronary
angiography, with C4 emerging as predictive independent of other
inflammation markers, in a prospective study appearing in the July
15, 2007 issue of the American Journal of Cardiology [1].

The findings, though limited by their observational nature, add to
the evidence that inflammation and the complement system are involved
in the pathogenesis of stroke and suggest "that baseline levels of
serum complement C4 may represent an important gauge for future risk
of stroke," according to the authors, led by Dr Erdal Cavusoglu (SUNY
Downstate Medical Center, Brooklyn, and the Bronx VA Medical Center,
Bronx, NY).

Cavusoglu told heartwire that adding measurements of C4 to the assay
for C-reactive protein (CRP), which appears to work in parallel with
complement and has previously been linked to stroke risk, could
potentially be more prognostic for stroke than CRP alone.

Levels of the two complement factors and other markers were measured
in a Veterans Affairs cohort of 389 men referred for angiography
because of known or suspected coronary disease. Among the 97% with
available data at 24 months, 23 (5.9%) had strokes that were
confirmed by MRI or CT; they were classified as ischemic in the vast
majority, but hemorrhagic in one case and "undetermined" or of
multiple etiology in five cases.

A one-standard-deviation increase in levels of C4, but not C3, was
associated with a 1.57 hazard ratio for stroke (95% CI, 1.03-2.39, p=
0.0358) after controlling for baseline parameters that had been
significantly predictive in univariate analysis. They include age,
heart failure at presentation, both complement factors, CRP,
erythrocyte sedimentation rate, fibrinogen, and tissue inhibitor of
metalloproteinase-1 (TIMP-1). Age and CRP also emerged as
independently significant predictors.

When C4 was excluded from the multivariate analysis, C3 became an
independent predictor of stroke at 1.79 (1.22-2.63), p=0.003.

A stroke occurred in 9.9% of the cohort in which baseline C4 levels
were above the median of 26.4 mg/dL, compared with 3.9% of those with
levels <26.4 mg/dL (p=0.0127).

Cavusoglu said that "a substantial minority" of the strokes had
occurred during diagnostic catheterization, PCI, or CABG during the
first weeks of follow-up, so C4 "may identify patients at risk not
only during the short term but also in the long term." He cited
supporting evidence that CRP elevation is also a risk factor for
periprocedural stroke.

In fact, he said, most of the established stroke risk factors
evaluated in the analysis correlated with two-year stroke risk,
supporting C3 and C4 also as risk factors. "There's no reason to
believe that the C3 and C4 findings were spurious. I think the other
findings validate the data set."

Complement-Mediated CV Risk in the Community

Malmö, Sweden - In some ways consistent with the report from
Cavusoglu and associates, a prospective analysis of a community-based
population of 5850 "initially healthy" men followed for more than 18
years showed that baseline levels of both C3 and C4 correlated with
cardiovascular events [2]. People with a history of MI, stroke, or
cancer had been excluded.

The complement proteins were not predictors of ischemic stroke as a
solo end point, however, and their significance for cardiovascular
events (a composite of MI, ischemic stroke, or cardiovascular death)
went away after controlling for smoking, body mass index (BMI),
cholesterol, diabetes and systolic blood pressure, reported Dr Gunnar
Engström (Lund University, Malmö, Sweden) and associates. Their paper
appears in the June 2007 issue of European Journal of Cardiovascular
Prevention and Rehabilitation.

A significant relationship was observed for C4, but not for C3, in an
analysis that considered only men with initial concentrations in the
top 10%, that is, >0.34 g/L, compared with <0.34 g/L. The high C4
levels corresponded to a hazard ratio of 1.34 (95% CI 1.09-1.6) after
adjustment for the same covariates. The significant risk increase
was "largely unchanged after further adjustments for occupation,
alcohol consumption, physical inactivity, log triglycerides, recent
respiratory infections, and angina," according to the group.

"C3 and C4 show substantial correlations with cardiovascular risk
factors, including blood pressure, BMI, and lipids. This relationship
accounts for the increased incidence of cardiovascular disease in men
with high C3 levels," Engström and colleagues write. "However, very
high C4 levels may be associated with increased cardiovascular risk
independent of traditional cardiovascular risk factors."

Cavusoglu E, Eng C, Chopra V, et al. Usefulness of the serum
complement component c4 as a predictor of stroke in patients with
known or suspected coronary artery disease referred for coronary
angiography. Am J Cardiol 2007; 100:164-168.
Engström G, Hedblad B, Janzon L, Lindgärde F. Complement C3 and C4 in
plasma and incidence of myocardial infarction and stroke: a
population-based cohort study. Eur J Cardiovasc Prev Rehabil 2007;
14:392-397.

This is so much better than the abstract.

http://circ.ahajournals.org/cgi/content/full/116/5/526

I am a surgeon as well as a professor in a prestigious school for the global
advancement of medicine and healthcare. I dedicated my life in this field to
improve the global healthcare practices

I recently read an article about medical tourism and healthcare crisis in
http://medicalstreamline.blogspot.com/ which actually states that the healthcare
in the United States is in crisis. I need your help. I would like to know your
opinion on this behalf.

Thanks,
Philip Allen, MD. Ph.D


---------------------------------
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[Non-text portions of this message have been removed]

Patients with bipolar disorder and schizophrenia face a similarly
elevated risk of cardiovascular disease (CVD), according to a report
in the June issue of the Journal of Clinical Psychiatry.

"Although there has been much less research on physical health
issues in bipolar disorder than in schizophrenia, several recent
studies have indicated that the prevalence of CVD risk factors, such
as obesity, hypertension, and diabetes, as well as the clustering of
risk factors generally known as metabolic syndrome, is alarmingly
high also in patients with bipolar disorder," Dr. Astrid Brate
Birkenaes told Reuters Health.

Dr. Birkenaes, from Ulleval University Hospital, Oslo, Norway, and
colleagues compared CVD risk factors among 273 patients diagnosed
with schizophrenia and bipolar disorder with reference data from the
general population of the same geographic and sociocultural area
gathered through the 2000/2001 Oslo Health Study.

CVD risk factors were generally similar for patients with
schizophrenia and patients with bipolar disorder, the authors
report, though women with schizophrenia had lower levels of HDL
cholesterol than did women with bipolar disorder, and bipolar
disorder patients had higher systolic blood pressure than did
patients with schizophrenia.

Both groups of patients had a higher prevalence of overweight,
obesity, central obesity, and hypertension than the general
population, the investigators found, and daily smoking was
significantly more frequent in the two patient groups than in the
general population.

Low HDL cholesterol was more prevalent in schizophrenia patients and
diabetes more prevalent in bipolar patients than in the general
population, the report indicates.

"The reason for the seemingly increased risk of CVD in bipolar
disorder is largely unknown," Dr. Birkenaes said. "Poor lifestyle
and side effects of medication may be part of the explanation.
However, factors intrinsic to the disorder itself may also play a
role."

Monitoring physical health "should be an important item in the
treatment of bipolar disorder from day one," Dr. Birkenaes
concluded. "It is very important to help these patients not to gain
weight, because overweight, as soon as established, is extremely
difficult to conquer."

J Clin Psychiatry 2007;68:917-923.

Poor dietary carbohydrate quality as defined by the dietary glycemic
index -- a modifiable risk factor -- may increase the risk of age-
related macular degeneration (AMD), according to study results
published in the July issue of the American Journal of Clinical
Nutrition.

"AMD appears to share several carbohydrate-related mechanisms and
risk factors with diabetes-related diseases, including retinopathy
and cardiovascular disease (CVD)," write Dr. Allen Taylor, of Tufts
University, Boston, Massachusetts, and colleagues. "However, to
date, only one small study has addressed this issue."

To investigate further, the researchers conducted a cross-sectional
study of 4099 participants, aged 55 to 80 years, in the Age-Related
Eye Disease Study (AREDS).

The team classified a total of 8125 eyes at baseline into one of
five AMD groups based on the size and extent of drusen, the presence
of geographic atrophy, and neovascular changes.

The dietary glycemic index (dGI) for each subject was calculated
from the weighted average of the glycemic index scores for each item
on a food questionnaire. The glycemic index values for the
foods "were either derived from published values based on white
bread as the reference food or were imputed from glycemic index
values of comparable foods."

The investigators report that eyes in the fourth and fifth quintiles
of dGI had a significantly "or suggestively" higher risk of large
drusen, geographic atrophy, and neovascularization compared to eyes
in the first quintile. There was a significant positive association
between dGI and severity of AMD (p for trend <0.001).

"There was a 49% increase in the risk of advanced AMD (geographic
atrophy plus neovascularization) for persons with a dGI higher than
the sex median," Dr. Taylor's team found. They calculate that 20% of
prevalent cases of AMD would have been prevented if subjects had
consumed diets with a dGI below the median.

Am J Clin Nutr 2007;86:180-188.

Treatment with a regimen aimed at reducing inflammation and inducing
immunologic tolerance can permanently restore normoglycemia in mice
with new-onset type 1 diabetes, US researchers report.

The therapy, described as a combination of "rapamycin plus agonist
IL-2-related and antagonist-type mutant IL-15-related Ig cytolytic
fusion proteins," works by addressing two problems: autoimmune
destruction of beta cells and the widespread inflammatory state,
according to the report in July 30th Early Edition of the
Proceedings of the National Academy of Sciences.

In the study, Dr. Terry B. Strom, from Beth Israel Deaconess Medical
Center in Boston, and colleagues assessed the outcomes of non-obese
diabetic mice treated or not treated with the combination for a few
weeks.

Untreated animals remained hyperglycemic and usually died several
weeks later despite insulin therapy. Treated animals, by contrast,
showed normalization of blood sugar levels and immune tolerance to
beta cells.

The researchers found that it was not the enhanced beta cell
tolerance that led to euglycemia, but rather a reduction in the
inflammatory state, resulting in enhanced insulin sensitivity.

"This triple-therapy regimen, possessing both tolerance-inducing and
select antiinflammatory properties, may represent a prototype for
therapies able to restore euglycemia and self-tolerance in type 1
diabetes mellitus," Dr. Strom and colleagues conclude.

Proc Natl Acad Sci USA 2007

Oral anticoagulants are superior to antiplatelet therapy for primary
stroke prevention in patients with nonvalvular atrial fibrillation
(AF), according to a new report published in the Cochrane Database
of Systematic Reviews July 18.

The meta-analysis, which included 8 randomized controlled trials and
almost 10,000 patients, found warfarin and other anticoagulants
reduced primary stroke risk in patients with AF by about 33%
compared with antiplatelet therapies. Patients who received
antiplatelet therapy had a 20% reduction in primary stroke risk
compared with their counterparts who received no preventive
treatment.

"When it comes to secondary stroke prevention, it's well-known
warfarin is superior to aspirin or other antiplatelet therapy, but
we wanted to compare the efficacy of these agents in primary
prevention. We found warfarin or other anticoagulant therapy reduced
the risk of stroke and other ischemic vascular events in patients
with nonvalvular AF and that this effect was superior to the effect
of antiplatelet therapy in this patient population," study
investigator Maria Aguilar, MD, from the Mayo Clinic in Scottsdale,
Arizona, told Medscape.

"Anticoagulants reduced [stroke] risk 10% to 20% more than
antiplatelet therapy, including aspirin, clopidogrel, and other
antiplatelet agents. Based on these results, we think warfarin is
probably the best option for primary stroke prevention in patients
who can take it safely," she added.

For the review, the investigators included all unconfounded,
randomized trials in which long-term (more than 4 weeks), adjusted-
dose oral anticoagulant treatment was compared with antiplatelet
therapy in patients with chronic nonvalvular AF.

Management Challenges

The 8 trials included 9598 patients without prior stroke or
transient ischemic attack (TIA) and looked at warfarin vs adjusted-
dose aspirin (in doses ranging from 75 to 325 mg/day). The mean
overall follow-up was 1.9 years per study participant.

Oral anticoagulants were associated with lower risk of all stroke,
ischemic stroke, and systemic emboli. In addition, the authors
report that all disabling or fatal strokes and myocardial infarction
(MI) were substantially, but not significantly, reduced by oral
anticoagulants.

Vascular death and all-cause mortality outcomes were similar between
the 2 treatments; intracranial hemorrhage was increased by
anticoagulant therapy.

While the study's results are not unexpected, said Dr. Aguilar, she
hopes that the findings will help strengthen physicians' confidence
in the benefits of anticoagulant therapy in this patient group.

Admittedly, said Dr. Aguilar, warfarin is not a benign agent and can
cause devastating complications, including death. In addition, there
are significant challenges associated with its management.

"Treating patients with warfarin requires an anticoagulation clinic,
access to a lab, and a significant commitment from the patient and
the patient's family. As a result, most general practitioners favor
antiplatelet therapy," she said.

Only Available Option

Nevertheless, she added, at this point it is the only available
option for stroke prevention in this patient group and, when
administered correctly, is safe and effective.

"I hope these results will help clinicians who are still reluctant
to use anticoagulation therapy take a more open-minded approach
toward it," she said.

What is needed ultimately, she said, is an agent that combines the
efficacy of warfarin with the safety of aspirin. The best recent
hope for this was ximelagatran.

The one-size-fits-all drug promised to overcome the monitoring, drug
interaction, and dietary issues associated with warfarin therapy.
Unfortunately, said Dr. Aguilar, the agent turned out to be
hepatotoxic and never made it to market.

"At this point, there are no new therapies in the pipeline to
prevent stroke in this growing population of older patients with
nonvalvular atrial fibrillation. We will have to learn to live with
what we have and do our best to prevent stroke using existing
antithrombotic therapy," she said.

Cochrane Database Syst Rev. 2007;3:CD006186

The American Medical Association (AMA) has now published the
scientific report behind last year's recommendations calling for a
reduction in the amount of sodium in processed and restaurant foods.
Combined with education and improved labeling, individuals should be
able to enjoy a lower-sodium diet without inconvenience or a loss of
food choices, say the authors, but they note that in the continued
absence of voluntary measures from the food and restaurant industry,
new regulations will be required to achieve lower sodium
concentrations.

"In the past, what people weren't fully cognizant of was the fact
that most of the salt was coming from restaurant and packaged
foods," author Dr Stephen Havas (American Medical Association,
Chicago, IL) told heartwire. "The message we had been giving to the
public, as well as the message the doctors had been giving to their
patients--don't use salt at the table, don't use salt when you're
cooking--was advice of very limited value, especially since 80% of
people's salt was coming from restaurants and processed foods.
Unless we pay attention to that, we are never going to reduce sodium
intake."

The new report, from the Council on Science and Public Health, is
published in the July 23, 2007 issue of the Archives of Internal
Medicine [1].

A few dissenting voices still out there

In June 2006, as part of a campaign to reduce the burden of
cardiovascular disease, the AMA published new recommendations to
help reduce the amount of sodium in processed and restaurant food.
The new guidelines were designed to the help change the way
Americans thought about salt, as well as emphasize the importance of
paying attention to the various sources of sodium in their daily
lives.

The new recommendations urged the Food and Drug Administration to
revoke the "generally-recognized-as-safe" status of salt and to
develop regulatory measures to limit sodium in processed and
restaurant foods. Over the next decade, the AMA called for a minimum
50% reduction in sodium in processed foods, fast-food products, and
restaurant meals. The AMA also called for ways of improving labeling
to assist consumers in understanding the amount of sodium in
processed food and develop a marking system to warn of foods high in
sodium.

Havas told heartwire that there has been some "reluctance" on the
part of the food industry to adopt these recommendations, and as
such, voluntary measures have been slow to arrive. The link between
sodium consumption, high blood pressure, and cardiovascular disease
is solidly established, said Havas, but some scientists, as well
industry, have argued the evidence isn't fully there.

"The problem is that the case hasn't really been brought to the
physician community in a good way, or to the public," he
said. "Until the time we published the report last June, and it got
out to the public by the media, people still thought there was a
controversy, because these few scientists and the Salt Institute
have kept trying to make it appear that the issue is not settled."

In the new report, the AMA points out that substantial public-health
benefits can be gained from small reductions in sodium intake. A 1.3-
g/day reduction in sodium, for example, translates into a 5-mm-Hg
smaller rise in systolic blood pressure. Between the ages of 25 and
55 years, this small reduction would translate into an estimated 150
000 lives saved. The paper also notes that populations with an
average sodium ingestion of less than 1400 mg/day have virtually no
hypertension and show no progressive increase in blood pressure with
age. In the US, average sodium consumption has been estimated to be
4000 mg/day per 2000 kcal, substantially higher than the 2300 mg/day
recommended by the American Heart Association.

One of the more disturbing trends figures in the literature, said
Havas, is the 55% increase in sodium intake in the US from the early
1970s to 2000, a trend he attributes to more and more people eating
out, as well as larger portion sizes.

"We don't know if sodium intake is still increasing, but it's a huge
concern," said Havas. "Until that figure was published, the
knowledge of this was not out there in any big way. We assumed,
because we were putting out these messages from the High Blood
Pressure Education coordinating committee about sodium and the need
to reduce sodium intake, that the public would be consuming less.
However, we didn't recognize that we weren't giving quite the right
message, because we didn't concentrate on processed and restaurant
foods."

Dickinson BD, Havas S for the Council on Science and Public Health.
Reducing the population burden of cardiovascular disease by reducing
sodium intake. Arch Intern Med 2007; 167:1460-1468.

A new prospective study shows that high levels of adiponectin, a
hormone secreted by the adipose tissue, is associated with increased
all-cause and CVD mortality in older men [1]. Dr S Goya Wannamethee
(Royal Free and University College Medical School, London, UK) and
colleagues report their findings in the July 23, 2007 issue of the
Archives of Internal Medicine.

Although some prior studies have found a favorable CVD risk profile
associated with high adiponectin levels, others have not, and these
conflicting findings raise the possibility that "adiponectin may
have different prognostic implications in older subjects or in
populations at high risk of vascular disease," Wannamethee et al
note.

The new findings suggest that more studies are needed to evaluate
the relationship between adiponectin concentrations and vascular
morbidity and mortality. Such studies may help establish whether
there is any clinical role for adiponectin, they say.

Conflicting prior research means more work needed

Adiponectin levels are known to increase with age, the authors
state, with some recent suggestions that this may be due to age-
related decline in renal function, resulting in a reduction in renal
adiponectin clearance.

Some prior research has shown that high levels of adiponectin are
associated with reduced risks of CVD, while others show no
association, and more recent prospective studies have demonstrated
that high levels of the hormone were a predictor of mortality in
patients with coronary artery disease and chronic kidney disease
and, most recently, in older community-dwelling men and women, they
explain.

Wannamethee et al examined the relationship between adiponectin
levels and mortality in elderly men (aged 60-79 years) drawn from
general practices in 24 British towns and followed up for a mean of
six years, during which 734 deaths occurred. They divided the men
into those with and without CVD and those with and without HF
(including those with and without CVD).

"Our aim was to determine whether adiponectin levels were associated
with increased CVD mortality in only those with existing vascular
disease or HF or whether this extended to all [older] individuals,"
they note.

After adjustment for a wide range of baseline characteristics,
adiponectin levels were positively associated with significantly
increased all-cause and CVD mortality in men with no diagnosed CVD
or HF, as well as men with diagnosed HF. No association was seen,
however, in those with diagnosed CVD but without HF.

"Despite the favorable CVD risk profile associated with high
adiponectin levels, high adiponectin levels were associated with
increased cardiovascular and all-cause mortality in this population
of older men. The association was particularly strong in those with
HF but, critically, was present also in those with no diagnosed HF
or CVD," they observe.

"These data further stress the need to reevaluate the direction of
the relationship between adiponectin concentrations and vascular
morbidity and mortality in older men and suggest the need for
further studies to disentangle relationships, which may help better
determine any clinical role for adiponectin," they conclude.

Wannamethee SG, Whincup PH, Lennon L, et al. Circulating adiponectin
levels and mortality in elderly men with and without cardiovascular
disease and heart failure. Arch Intern Med 2007; 167:1510-1517.

Oral anticoagulants are superior to antiplatelet therapy for primary
stroke prevention in patients with nonvalvular atrial fibrillation
(AF), according to a new report published in the Cochrane Database
of Systematic Reviews July 18.

The meta-analysis, which included 8 randomized controlled trials and
almost 10,000 patients, found warfarin and other anticoagulants
reduced primary stroke risk in patients with AF by about 33%
compared with antiplatelet therapies. Patients who received
antiplatelet therapy had a 20% reduction in primary stroke risk
compared with their counterparts who received no preventive
treatment.

"When it comes to secondary stroke prevention, it's well-known
warfarin is superior to aspirin or other antiplatelet therapy, but
we wanted to compare the efficacy of these agents in primary
prevention. We found warfarin or other anticoagulant therapy reduced
the risk of stroke and other ischemic vascular events in patients
with nonvalvular AF and that this effect was superior to the effect
of antiplatelet therapy in this patient population," study
investigator Maria Aguilar, MD, from the Mayo Clinic in Scottsdale,
Arizona, told Medscape.

"Anticoagulants reduced [stroke] risk 10% to 20% more than
antiplatelet therapy, including aspirin, clopidogrel, and other
antiplatelet agents. Based on these results, we think warfarin is
probably the best option for primary stroke prevention in patients
who can take it safely," she added.

For the review, the investigators included all unconfounded,
randomized trials in which long-term (more than 4 weeks), adjusted-
dose oral anticoagulant treatment was compared with antiplatelet
therapy in patients with chronic nonvalvular AF.

Management Challenges

The 8 trials included 9598 patients without prior stroke or
transient ischemic attack (TIA) and looked at warfarin vs adjusted-
dose aspirin (in doses ranging from 75 to 325 mg/day). The mean
overall follow-up was 1.9 years per study participant.

Oral anticoagulants were associated with lower risk of all stroke,
ischemic stroke, and systemic emboli. In addition, the authors
report that all disabling or fatal strokes and myocardial infarction
(MI) were substantially, but not significantly, reduced by oral
anticoagulants.

Vascular death and all-cause mortality outcomes were similar between
the 2 treatments; intracranial hemorrhage was increased by
anticoagulant therapy.

While the study's results are not unexpected, said Dr. Aguilar, she
hopes that the findings will help strengthen physicians' confidence
in the benefits of anticoagulant therapy in this patient group.

Admittedly, said Dr. Aguilar, warfarin is not a benign agent and can
cause devastating complications, including death. In addition, there
are significant challenges associated with its management.

"Treating patients with warfarin requires an anticoagulation clinic,
access to a lab, and a significant commitment from the patient and
the patient's family. As a result, most general practitioners favor
antiplatelet therapy," she said.

Only Available Option

Nevertheless, she added, at this point it is the only available
option for stroke prevention in this patient group and, when
administered correctly, is safe and effective.

"I hope these results will help clinicians who are still reluctant
to use anticoagulation therapy take a more open-minded approach
toward it," she said.

What is needed ultimately, she said, is an agent that combines the
efficacy of warfarin with the safety of aspirin. The best recent
hope for this was ximelagatran.

The one-size-fits-all drug promised to overcome the monitoring, drug
interaction, and dietary issues associated with warfarin therapy.
Unfortunately, said Dr. Aguilar, the agent turned out to be
hepatotoxic and never made it to market.

"At this point, there are no new therapies in the pipeline to
prevent stroke in this growing population of older patients with
nonvalvular atrial fibrillation. We will have to learn to live with
what we have and do our best to prevent stroke using existing
antithrombotic therapy," she said.

Cochrane Database Syst Rev. 2007;3:CD006186

UK researchers have found that the decline in coronary heart disease
mortality rates over the last 20 years appears to be leveling off
among younger adults aged 35 to 44 years. This disturbing trend is
likely due to increases in obesity and diabetes, a "stubborn"
smoking prevalence in this age group, and the role of deprivation,
say Dr Martin O'Flaherty and colleagues in a paper published online
July 19, 2007 in Heart [1].

"The flattening trends in CHD mortality among younger adults suggest
that the cardiovascular disease epidemic is not being controlled.
The party is over, and complacency runs a high risk," say O'Flaherty
et al. "Clinicians should be aware of the stable mortality rate for
CHD among younger adults in recent years and vigorously counsel
their patients about appropriate lifestyle behaviors using recent
guidelines," they add.

But they note that younger people and those in a less advantaged
socioeconomic position have less success in changing behaviors,
so "a vigorous public-health response is needed, particularly
increased efforts to improve diet [and] initiatives to accelerate
past declines in smoking."

Good news masks bad

O'Flaherty et al note that the rate of decline in mortality from CHD
slowed in the US during the 1990s compared with earlier decades, and
they wanted to find out whether the UK is following American trends.
Although previous reports out of the UK have emphasized the
continuing declines in age-adjusted CHD mortality among
adults, "trends in age-specific rates have received little
attention," they note.

Limiting their analyses to adults aged 35 and over, they examined
mortality data from 1984 to 2004 and used joinpoint regression to
assess changes in trends. Overall, the age-adjusted mortality rate
decreased by 54.7% in men and by 48.3% in women; among older adults,
the mortality rates continued to decline steadily.

But this good news masked an unfavorable trend in younger people. In
men aged 35 to 44 years, CHD mortality rates in 2002 "increased for
the first time in over two decades," the researchers note, and the
recent declines in CHD mortality rates seem to be slowing in both
men and women aged 45 to 54, they add.

"The flattening mortality rates for CHD among younger adults may
represent a sentinel event. Deteriorations in medical management of
CHD appear implausible," they note. "Thus, unfavorable trends in
risk factors for CHD, specifically obesity and diabetes, provide the
most likely explanation for the observed trends."

"Policy changes nationally and internationally potentially offer the
most effective and cost-effective interventions," they
add. "Messages about caloric restriction and increased physical
activity will need to be amplified. . . . Timely interventions could
counteract the adverse risk-factor trends before they kill more
young adults," they conclude.

O'Flaherty M, Ford E, Allender S, et al. Coronary heart disease
trends in England and Wales from 1984 to 2004: concealed leveling of
mortality rates among young adults. Heart 2007;
DOI:10.1136/hrt.2007.118323. Available at: http://heart.bmj.com.

A new study shows that use of the pulmonary artery catheter (PAC)
decreased by 65% in the US between 1993 and 2004 [1]. This is likely
the result of growing evidence that this invasive procedure does not
reduce mortality for hospitalized patients, say Drs Renda Soylemez
Wiener and H Gilbert Welch (Department of Veterans Affairs Medical
Center, White River Junction, VT) in their paper published in the
July 25, 2007 issue of the Journal of the American Medical
Association (JAMA).


In one editorial accompanying the study [2], critical-care doctor
and contributing JAMA editor Dr Derek C Angus (University of
Pittsburgh School of Medicine, PA) says that while the many PAC
trials do not settle the controversy surrounding it, they do
illustrate that "its benefits, if any, are not easily harnessed."
Wiener concurs. She told heartwire: "Most of the studies that have
been done show that physicians have trouble interpreting the
information provided by PAC."


In another editorial [3], Dr Gordon D Rubenfeld (University of
Toronto, ON) and colleagues say: "The 40-year story of the PAC is
nearing its end. It is a cautionary tale of rapid adoption and slow
evaluation of a monitoring device that, when used correctly,
provides exquisitely detailed physiologic data that, regrettably,
does not appear to benefit patients."


Use of PAC declined by 81% in MI and by 65% in HF


Wiener and Welch explain that the PAC first became available as a
practical diagnostic tool in 1970 and was rapidly embraced by
critical-care physicians, making measurements such as cardiac output
and pressure within the small vessels in the lungs accessible to
physicians at the bedside. "Many physicians assumed that these
numbers could guide treatment and ultimately reduce mortality in
critically ill patients. Within several years, PAC was widely used
throughout the US. In the 1980s, 20% to 43% of seriously ill
patients who were hospitalized were reported to undergo the
procedure," the authors say.


But Wiener explained to heartwire that PAC is an invasive procedure,
which carries a number of risks, such as cardiac arrhythmias,
bleeding, and infection, and by the mid and late 1980s, there were
challenges to the benefits of this procedure. "And a number of newer
technologies were introduced that can offer some of the same
information in a less invasive way," she noted.


In addition, during the past five years multiple randomized trials
and a meta-analysis have demonstrated that PAC has no impact on the
risk of death in diverse populations of critically ill patients.


But until now, it is has not been known how this information has
changed the use of this procedure, Wiener explained.


Thus, she and Welch examined trends in the use of PAC from 1993 to
2004 using data from all US states contributing to the Nationwide
Inpatient Sample. They found that use of PAC from 1993 to 2004
decreased by 65%, from 5.66 to 1.99 per 1000 medical admissions.
Among common diagnoses associated with PAC, the decline was most
prominent for MI, where use decreased by 81%; its use in heart
failure also fell by 65%.


In particular, the decline appears to have begun after the reporting
of one specific trial, a multicenter observational study by Connors
et al that suggested an increased risk of death with PAC, the
researchers note. This was first presented at the 1994 American
Thoracic Society conference and published in 1996, along with an
accompanying editorial that was "strongly worded," and called for a
moratorium on PAC use until a randomized controlled trial could be
conducted.


"It is possible that [as a result of the Connor et al study] certain
prominent critical-care physicians acted as early adopters and not
only discontinued PAC placement but also influenced the local
culture in their hospitals through their role as opinion leaders,"
they say.


"Most doctors have responded appropriately to the evidence that PAC
does not reduce mortality, which is reflected in the national
decrease in PAC use that we have observed," Wiener said.


Several options for those still using PAC

Wiener acknowledges, however, that some doctors remain proponents of
PAC and that it is still used in some institutions. In their
editorial, Rubenfeld et al give advice on the use of
the "increasingly rare procedure of PAC," explaining that hospitals
continuing to use it should think about several options.


"First, centers performing only a few PAC procedures should consider
not doing any. Second, if PAC use is continued, the procedure should
be limited to a small number of skilled clinicians.


"Third, consider alternate hemodynamic monitoring tools, but
consider them skeptically until convincing outcome data are
available. . . . Fourth, continued use of PAC demands intensive
evaluation and education," the editorialists write.


"In the waning years of PAC, when the risks of infrequent use may
outweigh any unproven benefit, it is more important than ever to
remain vigilant for common errors in PAC placement and data
interpretation," they conclude.

Wiener RS and Welch HG. Trends in the use of pulmonary artery
catheter in the United States, 1993-2004. JAMA 2007; 298: 423-429.
Angus DC. Caring for the critically ill patient. Challenges and
Opportunities. JAMA 2007; 298: 456-457.
Rubenfeld GD, McNamara-Aslin E, Rubinson L. The pulmonary artery
catheter, 1967-2007 Rest in peace? JAMA 2007; 298: 458-461.

Isreali Researcher Discovers Cinnamon Anti-Viral Extract From Bible!

For most of his professional life, Tel Aviv University professor
Michael Ovadia focused on snakes and the medicinal properties of their
venom. But seven years ago, after meditating on a biblical passage,
Ovadia's career focus began to take a twist... a cinnamon twist to be
exact.

Today the spiritual scientist from TAU's Department of Zoology is
commercializing a unique cinnamon extract that is touted to quell
viral infections from HIV to the Avian flu.

A research and license deal on his patent-pending cinnamon extract was
signed last week between TAU's technology transfer company Ramot and
Frutarom, a multinational nutraceutical company based in Israel.
Frutarom is expected to use the extract in a whole host of
applications from disinfecting the air as a spray against Avian flu in
airports; to a daily supplement that protects people against the
common flu.

Those researching in the field of natural medicine know that snake
venom, especially the notorious poisonous kind, has unique anti-viral
and analgesic properties that can help fight human illness and
disease. For the past 40 years, Ovadia had been working with natural
antidotes and found that certain kinds of venom can deactivate
Parainfluenza (Sendai) virus - a virus similar to the human flu.

Work was going well. Papers were published, patents had been
developed, and his reputation in the field was established. But Ovadia
was still waiting for the breakthrough that every scientist dreams about.

That breakthrough would come to him one morning in the synagogue while
listening to a reading from the Old Testament.

"There is a passage that explains how the High Priests - the Kohens -
would prepare a holy oil used on their bodies before they made a
ritual animal sacrifice," recalls Ovadia. "I had a hunch that this
oil, which was prepared with cinnamon and other spices, played a role
in preventing the spread of infectious agents to people."

Taking his hunch to the laboratory bench, Ovadia's initial experiments
proved to be true - his savory cinnamon extract was able to quickly
and effectively immunize chicken embryos from the Newcastle disease
virus - one which costs the poultry industry in the US millions of
dollars a year.

Further studies on Avian Flu H9, Sendai virus, the HIV virus, and
Herpes Simplex 1 also achieved positive results. Not only was the
extract able to neutralize the viruses, it also showed for selected
viruses that it has the potential to immunize against them as well.

Now before people start dropping cinnamon sticks in their hot
chocolate and sprinkling it all over their lattes - take note that the
cinnamon extract developed by Ovadia has special properties that won't
be found at coffee shops or in the kitchen cupboard. First of all, it
comes from a special variety of cinnamon; coumarin and cinnamon
aldehyde, which are by-products of cinnamon 'juice'. These are
actually damaging to the liver in high quantities, and must be removed.

"You cannot take high doses from the natural form of cinnamon," Ovadia
told ISRAEL21c. "If you used it several times a day to protect you
from the flu, it would be toxic."

During seasonal epidemics, around 10-20% of the world is infected with
the influenza virus and the elderly and young are particularly at
risk. In America alone, the U.S. Centers for Disease Control and
Prevention estimates that 35-50 million Americans are infected with
the flu every season. Despite the use of vaccines, the influenza virus
is still associated with significant mortality worldwide - especially
now that people travel regularly and work together in offices and
closed spaces.

Moreover, the global circulation of the deadly Bird Flu H5 (with more
than 50% mortality in infected humans) may cause a sudden worldwide
pandemic within two to three months. Until a vaccine is invented,
antivirals will be the only medical intervention for use in such a
pandemic, says Ovadia.

"What we know is that this technology is capable of neutralizing
viruses very fast and that it is applicable to various applications,"
said Dr. Nissim Chen, the business development manager of Ramot who
managed the commercialization process which ending up with the
licensing to Frutarom. "For example, it can be used in air
conditioning systems in hospitals and prevent infections spreading
from one person to the other in closed spaces."

There is a growing tendency for researchers and clinicians to explore
natural compounds against disease, agrees Chen, adding that Ovadia is
well-known for his work in natural inhibitors of snake venom.

"This work with cinnamon is really an extension of his research. And
at Tel Aviv University in general, there are several groups working on
biological and chemicals structure of natural inhibitors," he said.

Besides the human application, Ovadia sees that cinnamon fills an
important niche in the agriculture industry where chicks need to be
immunized by hand against the deadly Newcastle disease virus.

"If someone needs to immunize 1,000 chicks through drops in the
chick's eye, then we know they are not doing this accurately - it is
also an issue of animal welfare," says Ovadia.

Instead, he believes, "we will be able to administer this cinnamon
extract through a tiny pin prick in the shell before the chick
hatches." Such an immunization gives the chickens protection against
the Newcastle virus, Ovadia assures.

Applying this research to the global scale could only be done with the
help of a large company - which is where Frutarom comes in. The
Israeli-based flavor and food additive company has grown in the last
10-15 years from $10 million a year to a projected $350 million by the
end of 2007.

"We're going to take this know how from a food supplement to protect
people from illness to neutraceuticals in drugs; it can also be used
in agriculture against Bird flu - certainly it represents a very
diversified product line," said Frutarom's CEO Ori Yehudai.

According to the company, Ovadia will continue to lead research into
the development of the extract, and Frutarom estimates that the new
cinnamon product will be launched in about a year. Hopefully just
before flu season.

This information appeared in the Israeli21C Newsletter

Researchers have identified the first gene variant associated with
susceptibility to periodic limb movements in sleep, involuntary
movements that are present in most patients with restless legs
syndrome (RLS). An inverse correlation of the variant with iron
stores is consistent with the suspected role of iron depletion in the
pathogenesis of RLS, they write.

The report was published online July 18 and will appear in the August
16 issue of the New England Journal of Medicine.

The work was a collaboration between an international group of
researchers at deCODE Genetics and the Landspitalinn University
Hospital and Clinical Research Center, in Rekjavik, Iceland; Emory
University, in Atlanta, Georgia; the Hospital Clinic de Barcelona, in
Spain; and King's College, in London, United Kingdom.

"We now have concrete evidence that RLS is an authentic disorder with
recognizable features and underlying biological basis," said David
Rye, MD, PhD, professor of neurology at Emory University School of
Medicine, director of the Emory Healthcare Program in Sleep, and 1 of
the study's lead authors, in a statement from Emory. "This is the
most definitive link between genetics and RLS that has been reported
to date. We have known for quite some time that the majority of RLS
patients have a close family member with the disorder, and now we
have found a gene that is clearly linked to RLS," he said.

The population-attributable risk for RLS with periodic movements in
sleep with this variant is approximately 50%, the researchers note.
First author on the paper is Hreinn Stefansson, PhD, chief executive
officer of deCODE Genetics.

A second study, led by Juliane Winkelmann from the Institute of Human
Genetics in Munich, Germany and also published online July 18, in
Nature Genetics, confirms the involvement of this variant and adds 2
other possible variants to the mix, all of which were associated with
a more than 50% increased risk for RLS.

Major Cause of Sleep Disruption

Restless legs syndrome is a common neurologic disorder with both
sensory and motor symptoms. A distressing urge to move the legs
during rest or inactivity at night or in the evening is often
accompanied by involuntary, highly stereotypical limb movements
during sleep called period limb movements in sleep, the authors
write.

A substantial genetic contribution to RLS has been well documented,
they note. However, "identification of the genetic underpinnings has
been challenging because of age-dependent expressivity; the
influences of anemia, uremia, diabetes, and peripheral neuropathy;
and possibly the modulation of phenotype by body iron stores."

Periodic limb movements in sleep are detectable in most patients with
RLS, the authors note. To minimize phenotypic heterogeneity in this
study, Dr. Stefansson and colleagues limited their investigation to
RLS patients who had objectively documented periodic limb movements
in sleep. They carried out a genomewide association study and 2
replication studies, looking for sequence variants contributing to
RLS. They also measured serum ferritin, because iron depletion has
previously been linked with the pathogenesis of RLS.

In the initial sample of 306 RLS patients with periodic limb
movements in sleep from Iceland, the researchers found a genomewide
significant association with a common variant in an intron of BTBD9
on chromosome 6p21.2, with an odds ratio of 1.8 (P = 2x10-9).

They then tried to replicate that finding in a second Icelandic
sample of similar patients and found a similar significant
association, with an odds ratio again of 1.8 (P = 4x10-4). The
association was then replicated in a US sample of 188 patients, with
an odds ratio this time of 1.5 (P = 4x10-4).

With this variant, namely the A allele of marker rs3923809, they
estimated the population-attributable risk for RLS with periodic limb
movements in sleep to be approximately 50%.

Interestingly, serum ferritin levels were decreased by 13% per allele
of the at-risk variant, they write (95% CI, 5 ¡V 20%; P = .002)

"The association between a sequence variant and subjects who have
periodic limb movements without RLS ¡X and the absence of such an
association in subjects with RLS without periodic limb movements ¡X
suggest that we have identified a genetic determinant of periodic
limb movements in sleep," they write. "Further study is required to
determine whether the A allele of marker rs3923809 is associated with
periodic limb movements outside the context of RLS," they
conclude. "It also remains to be determined whether a sequence
variant for RLS without periodic limb movements can be found."

In an interview with Medscape, Dr. Rye said that the fact that this
genetic variant is related to periodic limb movements in sleep and to
low iron "speaks to the fact that this gene has something intimate to
do with this disorder."

This variant is common in the population, found in about 65% of
Northern Europeans, Dr. Rye pointed out. However, about 35% of
Japanese have the variant, where, perhaps not coincidentally, the
prevalence of RLS is about half that of Western populations, he
noted. "I think with this, we can explain a lot of what's been
described on the epidemiologic side of restless legs concerning
frequency in the population, the effects of iron, and that if you
have 2 copies of this gene you're twice as likely to kick as someone
with 1 copy ¡X and the kicking you do is twice as frequent, so
there's a dose-effect on symptoms."

In the "bigger picture," he added, it may also provide insight into
more general sleep biology and other sleep disorders, as well as
potentially circadian rhythms, given that RLS typically manifests
sensory symptoms between 10 PM and 2 AM.

Supportive Findings

Their finding was supported by a second paper that was published
simultaneously July 18 by Juliane Winkelmann, MD, from the Institute
of Human Genetics in Munich, Germany and colleagues in Nature
Genetics. Using German and Canadian cohorts, Dr. Winkelmann and
colleagues identified significant associations between RLS and
intronic variants in the homeobox gene MEIS1, the BTBD9 gene variant
also described by Stefansson and colleagues, and a third locus
containing genes encoding mitogen-activated protein kinase MAP2K5 and
the transcription factor LBXCOR1 on chromosomes 2p, 6p, and 15q,
respectively, the authors write.

"Each genetic variant was associated with a more than 50% increase in
risk for RLS, with the combined allelic variants conferring more than
half of the risk," the authors write. "MEIS1 has been implicated in
limb development, raising the possibility that RLS has components of
a developmental disorder."

A "Bona Fide Disorder"

In an editorial accompanying the New England Journal of Medicine
paper, John W. Winkelman, MD, PhD, from Brigham and Women's Hospital,
in Boston, Massachusetts, points out that some of the earliest
descriptions of RLS recognized the strong familial nature, and
although recent linkage studies have shown a number of susceptibility
loci for RLS, no gene has been identified until now. "For this
reason, the report by Stefansson et al in this issue of the Journal
showing an association between a sequence variant in chromosome 6p
and periodic limb movements in sleep in distinct Icelandic and
American cohorts of subjects with RLS and their families, as well as
controls, is exciting and important."

He adds, though, that "inspection of the data provided by Stefansson
et al, however, shows that this sequence variant does not appear to
be a gene for RLS but, rather, for periodic limb movements in sleep."

The highest odds ratios were seen in those with periodic limb
movements in sleep without RLS, and the association became less and
less apparent as more patients with RLS were added, he notes. The
association was not seen at all in those with RLS without periodic
limb movements in sleep.

However, there may still be value in knowing the genetic basis for
these movements, as it is possible that periodic limb movements in
sleep may be used as a heritable biologic marker, or "endophenotype,"
for RLS, he writes. For example, it may aid in linkage to other
relevant susceptibility genes to illuminate polygenic interactions,
he notes.

Dr. Winkelman asserts, though, that the demonstration of a strong
association between a sequence variant and periodic limb movements in
sleep, and to a lesser extent, RLS, is not what validates RLS as a
genuine disorder.

"The legitimacy of RLS as a bona fide disorder is provided by the
clinically apparent and well-documented sleep disturbance and
distress of the roughly 3% of the adult population with frequent and
bothersome RLS symptoms," he concludes. "The genetic finding reported
by Stefansson et al offers hope to patients with periodic limb
movements in sleep and RLS that the syndrome's pathophysiology will
be understood and that such knowledge will lead to additional
effective and durable treatments."

In response to Dr. Winkelman's comments about the phenotypes of RLS
and how they relate to genetic underpinnings, Dr. Rye largely agreed
that a potential by-product of these new genetic techniques is that,
rather than a group of experts coming to some clinical consensus on
what makes up a disorder, these high-throughput techniques are going
to provide a genetic definition. "In other words, what is the gene
frequency that's discovered with a disorder going to tell us about
what the real disorder is?"

The study was supported in part by the Restless Leg Syndrome and
Arthur L. Williams Jr. Foundations and the Robert W. Woodruff Health
Sciences Fund. Dr. Rye reports receiving consulting fees from or
serving on paid advisory boards for GlaxoSmithKline, Boehringer
Ingelheim, Ortho-McNeill, and Sepracor and lecture fees from
GlaxoSmithKline and Boehringer Ingelheim. Dr. Stefansson is chief
executive officer of deCODE Genetics and has equity in the company.
The company has a financial interest in the results of the study,
including diagnostic products and patents. Disclosures for other
coauthors appear in the paper. Dr. Winkelman reports receiving
research support and consulting fees from Boehringer Ingelheim,
GlaxoSmithKline, and Schwarz Pharma and lecture fees from Boehringer
Ingelheim and GlaxoSmithKline; no other potential conflicts were
reported.

N Engl J Med. 2007. Published online July 18, 2007

Elevated urine albumin excretion is more strongly associated with
intra-abdominal fat (IAF) than with abdominal subcutaneous fat (SQF)
in men with type 1 diabetes, suggest the results of a study published
in the July issue of Diabetes Care.

"We previously examined obesity-related factors and albumin excretion
within the total Diabetes Control and Complications
Trial/Epidemiology of Diabetes Intervention and Complications
(DCCT/EDIC) cohort," Dr. Shalamar D. Sibley, of the University of
Minnesota, Minneapolis, and colleagues write. "In our cross-sectional
analysis 4 years after the end of the DCCT, waist-to-hip ratio -- a
visceral fat surrogate -- was associated with elevated albumin
excretion."

In the current study, the researchers examined whether IAF relates
more strongly to elevated albumin excretion than SQF. They assessed
IAF and other obesity measures in relation to urine albumin excretion
in a cohort of 64 clinical trial participants.

Trained technicians blinded to the status of the participants read
single-slice umbilical abdominal computed tomography scans for IAF
and SQF. Urine was collected from second-morning voids, and urinary
creatinine and microalbumin were measured. The team defined elevated
urine albumin-creatinine ratio (ACR) as at least 30 mg/g creatinine.

Of the 64 subjects, nine had elevated urine ACR. Six of those cases
had microalbuminuria (ACR 30 to 300 mg/g) and three had clinical
albuminuria. Men with elevated ACR were more likely than those with
normal ACR to smoke, use ACE inhibitors, and to have received
conventional insulin therapy during the clinical trial. Men with
elevated ACR were also more likely to have higher blood pressures,
higher levels of glycosylated hemoglobin, and dyslipidemia.

The researchers report that IAF, but not SQF, was greater in men with
elevated ACR compared to those with normal ACR (p = 0.048). Waist
circumference (p = 0.048) and waist-to-hip ratio (p = 0.006) were
greater in men with elevated ACR.

There was an association between elevated ACR and greater levels of
each obesity measure, except SQF.

"Futures studies are needed to elucidate mechanisms underlying the
IAF-albumin excretion link," the authors conclude.

Diabetes Care 2007;30:1898-1900

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A new analysis of two genomewide association studies has identified
several genetic loci that seem to substantially affect the risk of
development of coronary artery disease (CAD) [1]. One of these--
9p21, a region on chromosome 9--was linked to a higher risk of MI by
two research groups in Canada and Iceland in May, but the other two
are novel markers associated with CAD.

Dr Nilesh J Samani (University of Leicester, UK) and colleagues
report their findings from two relatively large cohorts--the UK
Wellcome Trust Case Control Consortium (WTCCC) study and the German
MI Family Study--online July 18, 2007 in the New England Journal of
Medicine.

Dr Eric J Topol (Scripps Translational Science Institute, San Diego,
CA), who was not involved with the research, told heartwire: "This
study advances the field by identifying at least two other gene
markers associated with CAD. It is an incremental advance beyond the
landmark findings of chromosome 9p21, which is remarkably prevalent
and has a large effect size. We are seeing the chipping away at the
genomic underpinnings of CAD and MI, and it is happening very fast."

In a special editorial accompanying the paper [2], journal editor-in-
chief Dr Jeffrey M Drazen and deputy editor Dr Elizabeth G Phimester
say that it represents "an important advance in medicine,"
conveying "novel, unbiased information about the heritable basis of
disease at a level of detail that has not been possible previously."
However, they note, "because the links between such studies and
disease biology are likely to be obscure at this time, as we publish
these articles we will provide commentary to help you understand how
the new data enhance our understanding. . . . We invite you to watch
as the fruits of this major advance in genetics begin to have an
impact on medicine."

Alleles could contribute substantially to overall disease burden

Samani et al performed their genomewide association study in the two
populations, which were selected for early presentation and a strong
family history of coronary disease to increase the chances of
finding genetic contributions.

They analyzed more than 350 000 single nucleotide polymorphisms
(SNPs) in the 5000 case subjects and controls of the WTCCC cohort.
Replication of the SNPs most strongly associated with CAD was then
sought in the German MI Family Study. Of almost 400 SNPs
significantly associated with coronary disease in the WTCCC study
(p<0.001), only three (located on chromosomes 9p21.3, 6q25.1, and
2q36.3) were replicated.

Samani et al also conducted a few more analyses that yielded loci on
different chromosomes that may have some association with CAD, but
these findings require replication and therefore should be
interpreted with caution, they note.

In an accompanying editorial [3], Dr Anthony Rosenzweig (Harvard
Stem Cell Institute, Boston, MA) says that although the individual
risk attributed to the disease-associated allele for each of these
three SNPs on chromosomes 9, 6, and 2 "is relatively modest
(unadjusted odd ratios 1.20-1.37), the alleles are common (minor
allele frequencies 0.25-0.55) and thus could contribute
substantially to overall disease burden."

Samani agrees. "We are not talking about rare genetic variants here,
but rather variants that are very common in our population. Many of
these genetic variants are carried by between a quarter and three-
quarters of white Europeans. They are clearly very important and
explain a significant proportion of the heart attacks that occur,"
he comments in a Wellcome Trust press release.

The strongest association was for the locus 9p21.3, which,
Rosenzweig notes, is a "strikingly similar" result to that published
by the Canadian and Icelandic groups in May, as reported by
heartwire. This provides "further support for the robustness of this
association in particular," he adds.

However, while the work published in May found that the 9p21.3
allele was present in both whites and blacks, all subjects in the
new paper by Samani et al were of white European ancestry,
Rosenzweig points out.

"Extending this work to other racial and ethnic groups, as well as
to other phenotypes, will be important," he notes, concluding, "The
technology and our understanding of how to apply it will continue to
improve."

Quantum leap in information about inherited component of disease

In a perspective accompanying the paper and editorials [4], Harvard
School of Public Health epidemiologists Dr David J Hunter and Dr
Peter Kraft discuss some of the statistical problems likely to be
encountered by studies of this nature. "The avalanche of recent data
provided by genomewide association studies represents a quantum leap
in information about the inherited component of certain diseases,"
they say. "However, a few caveats should be noted."

"Although SNP chips provide a vast quantity of information on common
genetic variation, there is a substantial proportion of the known
common variation that they do not capture." Also, non-SNP gene
variants are not formally represented on the SNP chips, they add.
But manufacturers are producing newer chips with probes for as many
as one million SNPs that will increase coverage, particularly for
persons of African ancestry, they point out.

"This first wave of genomewide association studies is producing an
impressive list of unexpected associations between genes or
chromosomal regions and a broad range of diseases. There have been
few, if any, similar bursts of discovery in the history of medical
research."

But the statisticians warn that newer methods will ultimately be
needed to properly analyze future studies. "Relatively conventional
statistical techniques are adequate for the analysis and
interpretation of these initial studies. But as we delve further
into the genome in the search for networks of interacting gene
variants and interactions between these networks and environmental
factors, much more sophisticated methods of statistical analysis are
likely to be required," they conclude.

Samani NJ, Erdmann J, Hall AS et al. Genomewide association of
coronary artery disease. New Engl J Med 2007; 357:443-453.
Drazen JM and Phimester EG. Publishing genomewide association
studies. New Engl J Med 2007; DOI:10.1056/NEJMe078130. Available at:
http://www.nejm.org.
Rosenzweig R. Scanning the genome for coronary risk. New Engl J Med
2007; 357:497-499.
Hunter DJ and Kraft P. Drinking from the firehose--statistical
issues in genomewide association studies. New Engl J Med 2007;
357:436-438.

According to the authors of the current study, BNP and NT-proBNP
levels have been shown to be strongly predictive of short-term and
long-term survival in patients with acute coronary syndromes and
have been used as diagnostic tools for heart failure, but it is
uncertain if they are useful for low-risk patients with stable
coronary disease and if they can be used to predict response to ACE
inhibitors in such patients.

This is a subanalysis of patients with normal systolic function and
stable coronary disease, within a randomized control trial of
trandolapril (the PEACE study), who had BNP and NT-proBNP levels
measured at baseline. The study determines the predictive value of
BNP and NT-proBNP levels for cardiovascular events.

Highlights

In the PEACE study, 8290 patients were randomized to receive
trandolapril or placebo and followed up for median of 4.8 years.
3761 patients who received baseline BNP and NT-proBNP measurements
who met entry criteria were included.
Inclusion criteria were age 50 years or older, documented coronary
disease, and left ventricular function greater than 40%.
Exclusion criteria were serum creatinine level greater than 2 mg/dL,
valvular heart disease requiring surgery, and coronary
revascularization plans.
BNP concentrations were measured using a 2-step microparticle enzyme
immunoassay.
NT-proBNP levels were determined with electrochemiluminescence
immunoassay on a modular platform.
US Food and Drug Administration¡Vapproved cutoff value for BNP
decision threshold for heart failure is 100 pg/mL; for NT-proBNP,
cutoff value is 125 pg/mL for those aged younger than 75 years and
450 pg/mL for those aged 75 years or older.
Primary outcomes were coronary events, stroke, and death from
cardiovascular causes.
BNP and NT-proBNP performance was assessed using univariate and
multivariate models of cardiovascular risk prediction.
Mean age was 63 years, 19% were women, 93% were white, mean body
mass index was 28 kg/m2, 54% had a documented history of myocardial
infarction, 40% had hypertension, 15% had diabetes, and 15% were
current smokers.
Mean blood pressure was 132 mm Hg systolic and 78 mm Hg diastolic.
Half were allocated to trandolapril, 35% were taking a calcium
channel blocker, and 55% were taking a £]-blocker.
During 4.8 years of follow-up, there were 127 cardiovascular deaths,
104 fatal or first nonfatal congestive heart failure, 241 fatal or
first nonfatal myocardial infarction and 86 fatal or first nonfatal
stroke events.
By univariate analysis, both BNP and NT-proBNP levels significantly
predicted cardiovascular mortality, fatal and nonfatal stroke, and
fatal and nonfatal congestive heart failure but not fatal or
nonfatal myocardial infarction.
By multivariate analysis, after adjustment for cardiovascular risk
factors, NT-proBNP level remained a significant independent
predictor of cardiovascular mortality, fatal or nonfatal congestive
heart failure, and fatal or nonfatal stroke.
Both BNP and NT-proBNP levels remained significant predictors of
congestive heart failure, but only NT-proBNP remained a significant
predictor of cardiovascular death and stroke.
For cardiovascular mortality, NT-proBNP but not BNP level improved
prognostic accuracy significantly.
Neither BNP nor NT-proBNP level predicted fatal or nonfatal
myocardial infarction.
Adjusting for interim congestive heart failure did not substantially
modify association between NT-proBNP level and risk for
cardiovascular death.
For example, hazard ratio for cardiovascular death was reduced from
4.9 to 4.5 for the fourth vs first quintile of NT-proBNP level after
adjustment for interim congestive heart failure.
NT-proBNP level performed significantly better than BNP level as
predictor of cardiovascular mortality, fatal or nonfatal stroke, and
fatal or nonfatal congestive heart failure.
Adding either BNP or NT-proBNP level to the traditional cardiac risk
model improved the prognostic accuracy significantly.
Association between treatment group and each outcome did not vary
according to BNP or NT-proBNP level.
Authors concluded that adding NT-proBNP level to conventional risk
factors improves prognostic accuracy for endpoints of cardiovascular
mortality and congestive heart failure, whereas adding BNP level
improves prognostic accuracy for heart failure.
BNP and NT-proBNP levels did not help identify subset of patients
likely to benefit from an ACE inhibitor.

Pearls

Adding BNP level to risk assessment in low-risk patients with stable
coronary artery disease after adjusting for cardiovascular risk
factors improves prognostic accuracy for heart failure, but not
fatal or nonfatal myocardial infarction.
In low-risk patients with stable coronary artery disease, adding NT-
proBNP levels to conventional risk factors after adjusting for
cardiovascular risk factors improves prognostic accuracy for
cardiovascular mortality and congestive heart failure, but not fatal
or nonfatal myocardial infarction.

In low-risk patients with stable coronary artery disease, B-type
natriuretic peptides (BNPs) provided good prognostic information in
addition to traditional risk factors, according to the results of a
study published in the July 11 issue of the Journal of the American
College of Cardiology.

"The prognostic value of BNPs in low-risk patients with stable
coronary artery disease remains unclear," write Torbjørn Omland, MD,
PhD, MPH, from Akershus University Hospital in Lorenskog, Norway,
and colleagues from the Prevention of Events With Angiotensin-
Converting Enzyme Inhibition (PEACE) Investigators. "The purpose of
this study was to assess the association between B-type natriuretic
peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-
proBNP) and the incidence of specific cardiovascular events in low-
risk patients with stable coronary disease, the incremental
prognostic information obtained from these two biomarkers compared
with traditional risk factors, and their ability to identify
patients who may benefit from angiotensin-converting enzyme (ACE)
inhibition."

The investigators measured baseline plasma BNP and NT-proBNP
concentrations in 3761 patients with stable coronary artery disease
and preserved left ventricular function who were enrolled in the
PEACE study, a placebo-controlled trial of trandolapril. Using
multivariable Cox regression, the investigators determined the
association between natriuretic peptide concentrations and the
incidence of cardiovascular mortality, fatal or nonfatal myocardial
infarction, heart failure, and stroke.

The BNP and NT-proBNP levels were strongly correlated with the
incidence of cardiovascular mortality, heart failure, and stroke but
not to myocardial infarction. Multivariable models revealed that
after adjustment BNP remained independently associated with
increased risk for heart failure, whereas NT-proBNP remained
independently associated with increased risk for cardiovascular
mortality, heart failure, and stroke.

Using BNP and NT-proBNP levels significantly improved the predictive
accuracy of the best available model for incident heart failure, and
NT-proBNP also improved the model for cardiovascular death, based on
C-statistic calculations. Regardless of either BNP or NT-proBNP
baseline concentrations, the magnitude of effect of ACE inhibition
on the likelihood of having cardiovascular endpoints was similar.

"In low-risk patients with stable coronary artery disease and
preserved ventricular function, BNPs provide strong and incremental
prognostic information to traditional risk factors," the authors
write. "Current data support measurement of BNPs in low-risk
populations for prognostic assessment but do not provide a mandate
for the use of these peptides for tailoring therapy in individual
patients."

Study limitations include the selection of patients participating in
clinical trials who may not be representative of all patients with
stable coronary artery disease and the use of biobank specimens
obtained at multiple sites and shipped for peptide analysis.

"Lack of prediction of myocardial infarction suggests that
determination of BNPs may not be useful for selection of anti-
ischemic therapies in low-risk patients," the authors
conclude. "Contrary to our expectations, BNP and NT-proBNP failed to
identify stable coronary artery disease patients who benefit from
ACE inhibition."

The National Heart, Lung, and Blood Institute (NHLBI); Knoll
Pharmaceuticals; Abbott Laboratories; and Roche Diagnostics
supported this study and/or provided kits and financial support for
NT-proBNP analysis. Some of the authors have disclosed various
financial relationships with National Institutes of Health/NHLBI,
Knoll Pharmaceuticals, Abbott Laboratories, Bayer Diagnostics,
and/or Roche Diagnostics and/or being inventors of relevant patent
(s).

J Am Coll Cardiol. 2007;50;205-214.

The addition of oral anticoagulation to antiplatelet therapy for
peripheral artery disease (PAD) doesn't further reduce the
likelihood of cardiovascular events, but it does raise the risk of
serious bleeding complications, including hemorrhagic stroke,
according to a randomized study appearing in the July 19, 2007 New
England Journal of Medicine [1].

The Warfarin Antiplatelet Vascular Evaluation (WAVE) study also
cautions against extrapolating therapies that have passed clinical-
trial muster in one arterial bed to the treatment of disease in
another, its investigators say.

In this case, for example, combined antiplatelet and oral
anticoagulant therapy has been found effective and safe for MI
secondary prevention, but in WAVE it raised the risk of life-
threatening complications, observed the trial's principal
investigator, Dr Sonia S Anand (McMaster University, Hamilton, ON).
The trial, she told heartwire, "points to the need for doing
carefully conducted trials within each vascular subgroup rather than
assuming the risk/benefit ratio is the same when you go from
coronary to peripheral to cerebrovascular disease."

But the trial's primary message, she said, is that "in patients with
PAD who don't have a clear indication for oral anticoagulants, such
as a mechanical heart valve or atrial fibrillation, using an oral
anticoagulant on top of antiplatelets as a prevention method is not
indicated at this point."

In an accompanying editorial, Dr Emile R Mohler (University of
Pennsylvania, Philadelphia) agrees [2]. WAVE, in combination with
other, smaller studies, "shows clearly that the addition of an
anticoagulant to an antiplatelet drug results in increased rates of
bleeding complications" and that outcomes are superior with
antiplatelet therapy alone in the long-term management of PAD.

As previously reported by heartwire, Anand presented WAVE in
preliminary form at the World Congress of Cardiology 2006.

The seven-country trial had randomized 2161 patients with PAD to
receive antiplatelet therapy (primarily aspirin) either with or
without an oral vitamin-K antagonist (primarily warfarin). The PAD
could be in the lower extremities, the carotids, or the subclavian
arteries.

An attempt had been made to exclude patients with a propensity for
bleeding or who were unlikely to tolerate combined therapy,
according to the authors. To that end, eligibility required that
patients first receive both agents without untoward side effects for
two to four weeks and achieve a stable INR of 2.0 to 3.0. Randomized
patients also could not have a specific indication for
anticoagulation, active or recent bleeding, recent stroke, renal
failure, or chronic NSAID use.

Even with those entry criteria plus INR monitoring that was probably
more careful than what is generally done in clinical practice, Anand
said, "We observed this excess risk of bleeding. In the real world,
it's likely to be much higher."

No significant difference was seen in the primary end point of MI,
stroke, or CV death over a follow-up averaging 35 months, nor in a
second primary composite end point that consisted of the first one
or severe ischemia in the coronary or peripheral arterial beds. Nor
were there significant differences for the primary end points'
individual components; a closer look, however, showed a significant
increase in hemorrhagic strokes with combination therapy. In
addition, rates of minor, moderate, and "life-threatening" bleeding
complications were significantly higher with double antithrombotic
therapy.

Although WAVE doesn't address why its combination therapy caused
more serious bleeding complications than have been observed in
secondary-prevention MI and stroke trials, Anand speculated that the
PAD patients were older and sicker. "They had more comorbid
conditions, such as diabetes or other vascular disease, and were
more likely to be smokers," she said. "All of those comorbid
conditions increase both the vascular-event risk and bleeding risk."

WAVE "was sponsored by the Canadian Institutes of Health Research,
the Heart and Stroke Foundation of Ontario, and the Population
Health Research Institute. Donations were also provided by Roche
Diagnostics (in kind) and DuPont Pharma. In Hungary, acenocoumarol
was provided by ICN Pharma." Mohler reports receiving lecture fees
from Bristol-Myers Squibb, Sanofi, and Astra-Zeneca and grant
support from Bristol-Myers Squibb and Sanofi.

Warfarin Antiplatelet Vascular Evaluation Trial investigators. Oral
anticoagulant and antiplatelet therapy and peripheral arterial
disease. N Engl J Med 2007; 357:217-227. Mohler III ER.
Atherothrombosis--wave goodbye to combined anticoagulation and
antiplatelet therapy? New Engl J Med 2007; 357:293 -296.

In men with type 2 diabetes, testosterone levels are inversely
related to body fat mass and correlate with some measures of bone
density, according to findings published in the July issue of
Diabetes Care.

"Hypogonadism is associated with an adverse body composition
(increased subcutaneous fat) in type 2 diabetic men," Dr. Sandeep
Dhindsa from the Diabetes Center of the Southwest in Midland, Texas,
told Reuters Health. "This may predispose them to more
cardiovascular disorders."

Dr. Dhindsa and associates investigated the body composition of 138
hypogonadal and eugonadal men with type 2 diabetes.

Free testosterone levels were inversely related to body-mass index
(BMI) and to arm, trunk, and total subcutaneous fat, the authors
report.

Arm lean mass (but not leg or total lean mass) was positively
related to free and total testosterone, the report indicates.

Free and total testosterone were not related to leg, hip, spine, or
total bone mineral density (BMD), the researchers note, but free
testosterone was positively related to arm and rib BMD and total
testosterone was positively related to rib BMD.

"Testosterone concentrations appear to be related strongly with BMD
in non-weight bearing bones such as arms and ribs but not with hip
and spine in type 2 diabetic men," Dr. Dhindsa commented. "Many DEXA
machines nowadays have the capability of measuring arm BMD.
Physicians may want to include arm bone density scanning (in
addition to hip and spine) when evaluating the bones of hypogonadal
type 2 diabetic men."

"We are currently investigating the effects of testosterone
replacement on visceral, hepatic and subcutaneous fat in hypogonadal
men with type 2 diabetes," Dr. Dhindsa added.

Diabetes Care 2007;30:1860-1861.

Patients with diabetes, especially women, who take
thiazolidinediones (TZDs) may have an increased risk of developing
cancer, according to a report in the June 21st publication of BMC
Medicine.

"There is more to these drugs than first meets the eye," Dr. Maria
E. Ramos-Nino from the University of Vermont, Burlington, told
Reuters Health. "The long-term consequences and benefits are not
understood."

Dr. Ramos-Nino and colleagues investigated the association of TZDs
and cancer prevalence among nearly 9000 diabetic patients
participating in the Vermont Diabetes Information System. A randomly
selected sample of 1003 of these participants were interviewed about
personal and clinical parameters, including any history of
malignancy.

The investigators found that the use of any TZD was associated with
a 59% increased risk of cancer in a logistic regression model
corrected for use of sulfonylureas and biguanides, age, HbA1c, BMI,
smoking, comorbidity, and other medications.

There was a significant association with rosiglitazone use with an
odds ratio of 1.89 (p = 0.02) for malignancy, but not with
pioglitazone use (OR = 1.09, p = 0.76).

"We are not aware of a convincing explanation or previous results to
support the finding in this study of an association with cancer for
rosiglitazone, but not for pioglitazone," the researchers write. "As
both are thought to activate PPAR-gamma with similar potency, this
finding suggests another mechanism for the association."

Women taking TZDs were more than twice as likely to have cancer as
women not taking TZDs (OR = 2.07, p = 0.01), the researchers note,
but the association was not significant in men (OR = 1.20, p= 0.63).

The use of sulfonylurea by women was associated with a 51% lower
risk of cancer, the report indicates.

"The gender-dependent observation is difficult to explain," the team
notes. "We do not know which specific tumors are increased in the
TZD users in this population."

The authors acknowledge that the study has several limitations,
including its cross-sectional design, lack of confirmation of cancer
and absence of information on the temporal relation between TZD use
and cancer.

"Our data do not provide strong evidence to change practice at this
time," Dr. Ramos-Nino said. "They are disturbing, to be sure, but
require further investigation before clinical decisions should be
changed."

BMC Medicine 2007;5.

Cardiologists and emergency department (ED) physicians faced with a
young woman complaining of chest pain may want to choose a
diagnostic test other than cardiac CT angiography (CTA), despite
promising results for this modality in ruling out CAD in people with
a low to intermediate pretest probability of disease [1]. A new
study modeling the life-adjusted risk (LAR) of cancer associated
with radiation exposure during 64-slice CTA suggests that the
lifetime risk is particularly high in women and in younger patients
generally, especially if they are undergoing combined cardiac and
aortic scans.

Lead author on the study, Dr Andrew J Einstein (Columbia University,
New York, NY), pointed to a growing number of studies examining
radiation dose associated with CTA, but little data on how this
might be linked to cancer risk.

"I think there's a general perception among cardiologists that the
radiation associated with CT coronary angiograms is relatively high,
but what 'high' means hasn't really been clear to people," Einstein
told heartwire. "Our study shows that for many patients it should be
reassuring that despite a relatively high dose, the estimated risk
of cancer is not especially high, although conversely, for some
patients, particularly young women, there's a relatively high
estimated LAR of cancer. As clinicians, we're faced with a growing
array of diagnostic tests for a variety of patient populations, and
I think this may steer us toward CTA for many patients, and away
from CTA in others."

Their study appears in the July 18, 2007 issue of the Journal of the
American Medical Association.

CTA and cancer risk

Einstein et al's study used the Biological Effects of Ionizing
Radiation (BEIR) VII Phase 2 report to estimate the age- and sex-
specific LARs of different cancers that were then combined to
estimate whole-body LARs. Doses received by different organs during
a given scan were estimated using Monte Carlo simulation methods
based on standard spiral CT protocols. Different estimates were
calculated for standard cardiac scans as well as for heart and aorta
scans, with and without tube-current modulation (TCM)--an
electrocardiographically guided protocol that minimizes radiation
dose during part of the cardiac cycle.

According to their calculations, the estimated LAR of cancer from a
standard cardiac scan, without TCM, ranges from one case for every
143 women for a 20-year-old woman to one out of 3261 for an 80-year-
old man. Risk in both men and women lessened with age, a reflection
of reduced tissue radiosensitivity in older adults as well as the
long lag time between radiation exposure and development of
malignancies, meaning that older adults exposed may die of other
causes before developing cancer.

But at any age, women face a higher LAR of cancer than men, due to
the risk of breast cancer, the authors note. As Einstein explained
to heartwire, "One issue with CTA is that radiation is delivered to
the thorax and the heart sits right behind the breast, so women's
breasts are irradiated throughout the cardiac CT scan, and the risk
of female breast cancer attributed to CT coronary angiography
accounts largely for the difference in the risk profiles between
women and men, putting women at particularly high risk in this
study, and particularly younger women."

The authors also calculated LARs from radiation exposure during CTA
when TCM protocols were used, simulated by reducing tube current by
35%, the degree of reduction typically seen when these protocols are
applied. In this setting, cancer risk was similarly reduced by 35%,
the authors report. By contrast, cancer risk was highest when
combined heart/aorta scans were performed--a common "triple-rule-
out" test for CAD, aortic dissection, and pulmonary embolism,
requiring the baseline scan to be extended by 10 cm, cranially, to
include the aortic arch.

"I think CT coronary angiography is a great test, and I think all of
us who take care of patients can see the value of CTA in the ED,"
Einstein said. "However, for young women, with all the virtues of
the test, it still may not be the test of choice, simply because the
estimated attributable risk of cancer is just a little bit too high
for comfort."

Hypothetical risk

Commenting on the study for heartwire, Dr Sam Wann (Wisconsin Heart
Hospital, Wauwatosa), called concerns over radiation
dose "legitimate" but pointed out that the BEIR VII report is not
universally accepted or evidence-based, a point also acknowledged by
the study authors.

"When we talk about radiation, there really isn't any hard evidence
that low-dose radiation causes any harmful effects," Wann
said. "This is all based on the nonlinear threshold hypothesis that
if a lot of radiation is bad for you, a little bit is bad for you
too, all the way down to zero. It's a reasonable safety measure to
take, and I certainly abide by that, but I just need to point
out . . . that the proof that radiation at very low doses increases
cancer risk is really hypothetical, it's not based on direct
experimental evidence."

But Einstein, in response, points out that only a small minority of
organizations do not support the linear-no-threshold model for
estimating cancer risk at doses less than <100 mSv; a majority,
including the US Environmental Protection Agency and numerous
government departments, were involved in the BEIR VII report, and
other reputable national and international organizations have come
to similar conclusions about estimating radiation risk.

"The majority of serious organizations that have considered this
question really believe that there is no lower threshold," Einstein
stated. "You can certainly find people who will criticize this, most
notably the French National Academy of Sciences, and who are
skeptical of the approach that was ultimately taken by the United
States, but the mainstream opinion is that BEIR VII is a reasonable
approach and a reasonable approximation. It's not the final word on
it, but it's the best we can do now, because these tests haven't
been around long enough for enough patients to have developed
attributable cancers."

CT manufacturers sensitive to radiation concerns

Both Einstein and Wann also point to technological upgrades being
developed by the different CT manufacturers to limit radiation dose,
including prospectively gated step-and-shoot protocols, single-
gantry-rotation whole-heart imaging, dual-source scanning, and
improved TCM algorithms. All of the commercially available 64-slice
scanners come with TCM capability, Einstein noted.

"Particularly for cardiologists who do CT coronary angiograms, this
study should remind them to use TCM when they can. I think probably
most people are doing that, but there needs to be more attention to
technique and performance of CTA, so that we can minimize dose to
patients and consequently minimize cancer risk," Einstein said.

At Columbia, he added, CT is not used in young women except
in "extenuating circumstances--for example, if we're really
concerned that a patient has anomalous coronaries. . . . Radiation
risk or not, the risk of missing an anomaly that could lead to
sudden cardiac death outweighs the radiation risk. But in general,
it's not going to be our first choice."

Most of the time, however, alternative diagnostic tests "should be
considered" in young patients, the authors say, including stress
electrocardiography, echocardiography, or MRI.

Einstein A, Henzlova MJ, Rajagopalan S. Estimating risk of cancer
associated with radiation exposure from 64-slice computed tomography
coronary angiography. JAMA 2007; 298:317-323.

A new Cochrane review of rosiglitazone (Avandia, GlaxoSmithKline
[GSK]) has found no evidence of any benefits of the drug over other
diabetes medications and, because of side effects such as edema,
fractures, and possible increased risk of MI, the review advises a
"very cautious approach to rosiglitazone use" and recommends that
if possible, other antidiabetic medications should be employed [1].

The review, which is published online on July 18, 2007, in the
Cochrane Database of Systematic Reviews, was led by Dr Bernd Richter
(Heinrich-Heine University, Düsseldorf, Germany). It examined only
published studies of at least 24 weeks in duration of rosiglitazone
in type 2 diabetics.

Richter commented to heartwire: "We are not adding any more
information on cardiovascular risk. The recent New England Journal
of Medicine meta-analysis by Nissen et al [2] has more information
on cardiovascular risk than our study, as we included only published
studies in diabetic patients, and the only one large enough to look
at cardiovascular risk was the ADOPT trial. Our review is looking
more at the bigger picture for rosiglitazone. We wanted to look at
the whole risk/benefit ratio. We didn't find any benefits of
rosiglitazone over other drugs for type 2 diabetes, but the drug is
clearly associated with increased risks of edema, fractures, and
weight gain. These adverse effects, together with the suggestion of
an increased cardiovascular risk, lead us to conclude that doctors
should think twice about using rosiglitazone, as we have good
alternatives."

The review included 18 trials, which randomized 3888 patients with
type 2 diabetes to rosiglitazone treatment. The median duration of
treatment was 26 weeks. The longest duration was four years (the
ADOPT trial). Richer et al report that in these studies
rosiglitazone did not positively influence patient-oriented outcomes
such as mortality, morbidity, adverse effects, costs, and health-
related quality of life. Metabolic control as measured by
glycosylated hemoglobin A1c (HbA1c) did not demonstrate clinically
relevant differences from other oral antidiabetic drugs. Occurrence
of edema was more than doubled; the single large randomized trial
(ADOPT) indicated increased cardiovascular risk, and new data on
raised fracture rates in women reveal extensive action of
rosiglitazone in various body tissues, they add.

More details of adverse effects

While the percentage of overall adverse events was comparable
between rosiglitazone and control groups in the studies reviewed,
serious adverse events appeared more often after rosiglitazone
treatment (median of 6% vs 4% in the control groups).
Discontinuation rate following rosiglitazone administration was also
higher than after control therapy (median of 7% vs 4%). Three
studies evaluated and reported a more pronounced (apparently dose-
related) decrease of hemoglobin after rosiglitazone intake in
comparison with other active compounds or placebo, with hemoglobin
reductions ranging between 0.5 and 1.0 g/dL. There were 11 studies
that evaluated body weight and observed an increase of as much as
5.0 kg after rosiglitazone treatment; four studies described changes
in body-mass index as increasing as much as 1.5 kg/m2.

Seven of the 18 included studies showed data on hypoglycemic
episodes: compared with active monotherapy control, rosiglitazone
treatment resulted in somewhat lower rates of hypoglycemia,
especially when compared with sulfonylureas. Severe hypoglycemic
events were rarely reported.

Data on edema were available in nine of 18 studies. Overall, 4739
participants provided information on the occurrence of edema. The
total number of events was 287 in the rosiglitazone and 134 in the
control groups, giving an odds ratio of 2.27 (95% CI 1.83-2.81).

The review also notes that the ADOPT trial showed higher fracture
rates in women with rosiglitazone than with metformin or glyburide.
"If you are a woman--and especially if you are thin--you probably
should avoid this medication due to the risk of bone fractures,"
Richter said.

Cardiovascular risk

Noting that the Nissen meta-analysis included more studies than they
did (Nissen included unpublished studies and studies in nondiabetes
patients in addition to the studies in the Cochrane review) and
found a significant increase in the risk of MI (OR 1.43, p=0.03) and
a borderline significant increase in cardiovascular death (OR 1.64,
p=0.06) with rosiglitazone, the Cochrane authors performed another
meta-analysis using Nissen's data for the MI rates for type 2
diabetes patients only. They report that this analysis could not
confirm significant differences in odds ratios for rosiglitazone vs
controls, but all odds ratios (with the exception of the comparator
glyburide--three studies only) indicated trends toward increased
risk with rosiglitazone treatment.

They describe the meta-analysis performed by GlaxoSmithKline of 42
studies suggesting a 30% increased risk of cardiovascular events
with rosiglitazone as "disturbing," adding: "Questions of timing
of this information . . . arise. Ongoing trials using rosiglitazone
(eg, RECORD) may provide additional data, but for a drug that was
approved in 1999, the delay in obtaining information about the
benefit/risk ratio is considerable."

Changes needed in drug-approval requirements

The Cochrane authors say they agree with the views expressed by
others that current drug-approval requirements for antidiabetic
medications and possibly all new drugs need to be changed. "The use
of proxy indicators like metabolic control is not sufficient to
approve drugs that many patients have to take for the rest of their
lives," they write.

They conclude that the benefit/risk ratio of rosiglitazone therapy
in type 2 diabetes mellitus needs urgent clarification and that
patient-oriented end-point studies are urgently needed for the
management of type 2 diabetes mellitus. But they add that it appears
questionable whether new studies with rosiglitazone would be
ethical, given the fact that less dangerous therapeutic alternatives
exist.

GSK's statement in response

In a statement issued in response to the Cochrane report,
GlaxoSmithKline says the review is another analysis of existing data
that have previously been reported. GSK believes that the limited
number of studies evaluated generate misleading conclusions and
provide no new evidence about the use of rosiglitazone in clinical
practice and research. The company points out that the studies
included in the review primarily measured differences in blood
glucose control over the short term, not mortality or morbidity
outcomes, and it is therefore not surprising that positive
conclusions were not drawn on this outcome.

It further notes that clinical guidelines have highlighted the
importance of maintaining long-term glycemic control and that the
ADOPT study did show a benefit in this regard of rosiglitazone over
metformin and glyburide. The company also strongly disagrees with
the Cochrane authors' questioning of the ethics of starting new
studies with rosiglitazone. "We are committed to patient safety and
carry out our clinical trials with the highest level of ethical
conduct. The totality of the data--including long-term studies such
as ADOPT and RECORD and an epidemiological analysis of more than 33
000 patients in a US managed care database--show that rosiglitazone
has a comparable ischemic cardiovascular profile to other oral
antidiabetic medicines. GSK stands firmly behind the safety profile
of rosiglitazone when used appropriately," it states.

The Cochrane review in part contributes to the ongoing critical
appraisal of randomized trials investigating the risk/benefit ratio
of thiazolidinedione use by the German Institute for Quality and
Efficiency in Health Care. Richer said he had no conflict of
interest or association with any drug company.

Richter B, Bandeira-Echtler E, Bergerhoff K et al. Rosiglitazone for
type 2 diabetes mellitus. Cochrane Database Syst Rev 2007; Issue 3.
Art No: CD006063. DOI: 10.1002/14651858.CD006063.pub2. Available at:
http://www.cochrane.org.
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes. N Engl J
Med 2007; 356:2457-2471.

Patients with metabolic syndrome and pre-existing atherosclerosis are
at a higher risk of cardiovascular events compared to those without
metabolic syndrome, according to study results published in the June
15th issue of the American Journal of Cardiology.

Dr. Christine Espinola-Klein, of Johannes Gutenberg-University,
Mainz, Germany, and colleagues determined atherosclerosis burden by
sonographic examination of carotid and leg arteries in 811 patients
with coronary heart disease (CHD).

The authors compared the 428 (52.8%) patients with low
atherosclerotic burden (CHD only) with the 383 (47.2%) patients with
high atherosclerotic burden (CHD and peripheral atherosclerosis).

A total of 349 (43.0%) of the patients had metabolic syndrome, based
on the presence of at least three of the following criteria:
triglycerides at least 150 mg/dL, high-density lipoprotein
cholesterol less than 40 mg/dL (men) and less than 50 mg/dL (women),
body mass index greater than 30, blood pressure at least 130/85 mm
Hg, and fasting blood glucose at least 100 mg/dL.

Median follow-up was 6.7 years, with data available for 807 patients.
Overall, 175 patients (21.7%) experienced cardiovascular events
(myocardial infarction, stroke, or cardiovascular death). Ninety-
eight patients (12.1%) died from cardiovascular causes, and 38 (4.7%)
died from causes unrelated to heart disease.

"The prognosis of patients with low atherosclerotic burden was worse
in patients with metabolic syndrome compared with those without
metabolic syndrome," Dr. Espinola-Klein and colleagues report. The
event rate was 21.2% in those with metabolic syndrome versus 12.9% in
those without. Corresponding mortality rates were 10.0% versus 5.1%,
respectively.

"In patients with high atherosclerotic burden, dramatically more
patients with metabolic syndrome experienced events compared with
patients without metabolic syndrome." The event rates in this setting
were 34.3% versus 26.5% for those with and without metabolic
syndrome, respectively, and mortality rates were 26.4% versus 10.3%.

Patients with high atherosclerotic burden and metabolic
syndrome "should be considered a high-risk population and treated
accordingly," the team concludes.

Am J Cardiol 2007;99:1623-1628.

A prediction model invented to stratify patients with heart failure
according to all-cause mortality risk also seems to predict their
mode of death, whether from sudden cardiac death (SCD) or from
progressive pump failure, suggests an analysis [1]. The Seattle Heart
Failure Model (SHFM) [2], which showed signs of being more
discriminating for HF mortality outcomes than the traditional New
York Heart Association functional class, could potentially be used to
guide treatment decisions, according to the authors.

In any group with the same level of SHFM-defined risk, there may be
patients at any level of NYHA class, "but conversely, within each
NYHA class, there are dramatically different risks according to the
Seattle HF model score," lead author Dr Dariush Mozaffarian (Harvard
School of Public Health, Boston, MA) told heartwire. One of the
study's messages for clinicians, he said, is that "if they want to
figure out a patient's risk, they should probably consider this model
in addition to just looking at NYHA class."

The analysis encompassed 10 538 patients with NYHA class 2-
4 "predominantly systolic" heart failure enrolled in six prospective
trials and registries, for whom all the necessary data were on record
and who had not received an implantable cardioverter-defibrillator
(ICD). Over a follow-up averaging 1.6 years, the annual rate of death
from any cause was 12%, which included 6.1% for SCD and 4.1% for pump
failure. The patients had been enrolled in the PRAISE, ELITE-2, Val-
HeFT, or RENAISSANCE trials or the IN-CHF registry or were members of
a University of Washington prospective heart-failure cohort.

The effect of SHFM score on mode of death was attenuated somewhat
among the 30% of the patients on beta blockers compared with the
rest. Still, Mozaffarian observed, the score's predictive power
remained strongly significant for either mode of death regardless of
beta-blocker use.

Importantly, according to the researcher, knowing a patient's SHFM-
based risks for both SCD and pump failure could perhaps one day
sharpen management decisions. The scores, Mozaffarian said, "might
help identify treatments that are good for a specific cause of death
but where there's not a high competing risk from another cause of
death."

As an example, ICDs clearly wouldn't be very cost effective for
patients with a low projected risk of sudden death. On the other
hand, Mozaffarian observed, a patient could have SHFM scores
suggesting a high risk for SCD but an even higher risk for pump
failure, such that an ICD would still not be very cost-effective
strategy. "You want a high enough absolute risk to justify the
treatment, but [also] low enough competing risks to justify the
treatment."

But this application of the SHFM, he cautioned, would have to be
validated in prospective studies before it could be put into use.

"Data on mortality and risk factors for calculation of the SHFM
score" were provided by Pfizer for PRAISE, by Novartis for Val-HeFT,
by Merck Research Laboratories for ELITE-2, and by Amgen for
RENAISSANCE. Disclosures for individual authors are provided in the
report; they include, in one case, ownership interest and licensing
income associated with the SHFM.

Mozaffarian D, Anker SD, Anand I, et al. Prediction of mode of death
in heart failure. The Seattle heart failure model. Circulation;
DOI10.1161/CIRCULATIONAHA.106.687103. Available at:
http://circ.ahajournals.org.
Seattle Heart Failure Model

Almost a third of the >38 million adult patients hospitalized in the
US in 2003 were at increased risk of developing venous
thromboembolism (VTE) and therefore were candidates for prophylactic
anticoagulant therapy, according to estimates based on data collected
by the Agency for Healthcare Research and Quality [1].

"If use of in-hospital VTE prophylaxis continues to be as poor as
reports to date suggest, a large proportion of these patients will be
at risk of either sudden death or long-term morbidity due to [deep
vein thrombosis] DVT and pulmonary embolism," according to report
authors Dr Frederick A Anderson Jr (University of Massachusetts
Medical Center, Worcester) and associates.

Their analysis, which used criteria for "substantial" VTE risk
devised by the American College of Chest Physicians (ACCP) [2], was
published online July 11, 2007, in the American Journal of Hematology.

In his accompanying editorial [3], Dr Samuel Z Goldhaber (Brigham and
Women's Hospital, Boston, MA), writes that estimates of the number of
hospitalized patients at risk of VTE have been lacking and that,
according to Anderson et al, "the magnitude of the problem is
staggering." However, he writes, "the true scope of the problem
includes outpatients, so that the fundamental problem is even more
profound and goes beyond the millions of hospitalized patients
annually that they have identified."

Goldhaber goes on to assert that distinctions between inpatient and
outpatient risk of VTE are "artificial." The enormous magnitude of
VTE risk in hospitalized patients tends to persist after hospital
discharge, he writes.

The estimates from Anderson et al were based on patients hospitalized
for at least three days at a sample of US community hospitals, the
time frame chosen in part to exclude patients less likely to have VTE
risk factors, according to the authors.

Of the approximately 38 221 000 patients discharged from the
country's acute-care hospitals in 2003, the report estimates, about
12 091 000 were at substantial risk of VTE according to ACCP
criteria. Of those, about 4 349 000 were surgical patients and about
7 742 000 had medical conditions.

"This large number of inpatients at risk for VTE provides support for
developing and monitoring compliance with hospital protocols and
national guidelines for VTE prevention," write Anderson et al.

Anderson Jr FA, Zayaruzny M, Heit JA, et al. Estimated annual numbers
of US acute-care hospital patients at risk for venous
thromboembolism. Am J Hematol; DOI: 10.1002/ajh.20983. Available at:
http://www3.interscience.wiley.com/cgi-bin/jhome/35105.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous
thromboembolism: The seventh ACCP conference on antithrombotic and
thrombolytic therapy. Chest 2004; 126:338S¡V400S.
Goldhaber SZ. Venous thromboembolism risk among hospitalized
patients: Magnitude of the risk is staggering. Am J Hematol; DOI:
10.1002/ajh.20997. Available at:
http://www3.interscience.wiley.com/cgi-bin/jhome/35105.

A new German study has shown, for the first time, that living near
very busy roads is associated with coronary atherosclerosis [1]. Dr
Barbara Hoffman (University of Duisberg-Essen, Germany) and
colleagues report their findings online July 16, 2007 in Circulation.

"What we found is that living close to heavy traffic is associated
with higher calcification in the coronary arteries," Hoffman told
heartwire.

"What has been studied previously is particulate matter and proximity
to roads in relation to cardiovascular events, but with that, you
never know whether it's a short-term effect or not. We are showing it
not only triggers short-term effects but influences underlying
pathology."

Fine particulate matter associated with CAC in those at home

The study of 4494 adults, age 45 to 74 years, is part of the Heinz
Nixdorf Recall Study that is being conducted in three large, adjacent
cities in the industrialized Ruhr area of Germany. Home address was
used to estimate each person's exposure to urban air pollution.
Participants were interviewed about risk factors such as diabetes and
smoking, underwent extensive clinical examinations, and had their
coronary artery calcification (CAC) measured by electron-beam
computed tomography (EBCT).

Hoffman told heartwire that the participants were informed of their
cardiology workup at baseline, but they were not told their CAC
scores, as the idea was to look at how predictive these are for
future events. "If we had told them their CAC scores, that could
influence the future events," she noted, adding that Germany does not
measure CAC scores routinely.

The researchers found that the closer the participant lived to heavy
traffic, the higher the CAC. "People who live near a German freeway
or federal highway, which can be traveled by 10 000 to 130 000 cars
daily, have more atherosclerosis the closer they live to the road,"
Hoffmann says. "If you live at a distance of, for example, 100 meters
from the freeway, then on average you have 7% more calcification in
your coronary arteries than a person with the same cardiovascular
risk profile who lives 200 meters away."

The fact that they showed a positive exposure-response relationship
for increasing traffic exposure that persisted even after
multivariable adjustment "strengthens our findings," the researchers
say.

In addition, they found evidence of an association between fine
particulate matter (particulate matter to 2.5 µg in diameter [PM2.5])
and CAC, but only in individuals who had not been working full-time
for at least five years. Hoffman told heartwire that they had not
specifically questioned people about how many hours they spent in the
home, but they were making the assumption that those who had not
worked for some time would generally be at home more than those who
still went to work.

Five-year follow-up in 2008

Hoffman and colleagues say their results concur with those from a
recent study conducted in Los Angeles, which showed an increase in
carotid intima-media thickness of 5.9% for an exposure contrast of 10
µg/m3 PM2.5.

"We examined small-scale differences in traffic exposure and used a
different outcome, making quantitative comparisons of associations
difficult," they note. "Both studies, however, show an association
between long-term air pollution and well-established quantitative
measures of atherosclerosis."

Nevertheless, the findings require corroboration in prospective
studies, they state.

Hoffman told heartwire that her team is looking at other surrogate
markers within the same German population, such as carotid intima-
media thickness and ankle-brachial index. Also, next year they will
have five-year follow-up data on the cohort, and they will be looking
at progression of coronary atherosclerosis.

"Until then," she says, "politicians, regulators, and physicians need
to be aware that living close to heavy traffic may pose an increased
risk of harm to the heart.

"Potential harm due to proximity to heavy traffic should be
considered when planning new buildings and roads. And clinicians and
cardiologists need to be aware that a patient's proximity to heavy
traffic may be a factor that should be considered when assessing
patients with coronary artery disease."

Hoffman B, Moebus S, Mohlenkamp S, et al. Residential exposure to
traffic is associated with coronary atherosclerosis. Circulation
2007; DOI: 10.1161/circulationaha.107.693622. Available at:
http://circ.ahajournals.org.

A patient with amyotrophic lateral sclerosis (ALS) ¡X himself a
neurologist and prominent ALS specialist ¡V becomes the focus of a
new article looking at the broader principles of palliative care in
this devastating disease.

The article, by Hiroshi Mitsumoto, MD, DSc, from the Eleanor and Lou
Gehrig ALS/MDA Center at the College of Physicians and Surgeons,
Columbia University Neurological Institute, in New York, and Judith
G. Rabkin, PhD, from the department of psychiatry at the College of
Physicians and Surgeons at Columbia, is published in the July 12,
2007 issue of the New England Journal of Medicine, part of a series
called Perspectives on Care at the Close of Life.

Given its predictable terminal course, the authors write, palliative
care should begin soon after diagnosis, and the goals of care be
assessed on an ongoing basis.

"Each day focus on what you can do," writes the neurologist-patient,
identified as Dr. SP. "I've always tried to prepare for the worst
and hope for the best."

Extraordinary Burdens, Extraordinary Opportunities

Chronic neurodegenerative disorders such as ALS are "among the most
difficult diseases with which clinicians must deal," Drs. Mitsumoto
and Rabkin write. The only medication approved for the treatment of
ALS in the United States, riluzole (Rilutek, Sanofi-Aventis),
prolongs life by about 2 months, but the ultimate outcome is certain
in most cases, they note.

"Virtually all skeletal muscles eventually are affected, they
write. "Multiple problems require a multidisciplinary approach,
including aggressive symptomatic management, rehabilitation to
maintain motor function, nutritional and respiratory support,
augmentative communication devices, and psychological support for
both patients and families because family members so often play a
central role in management and care."

In this article, the authors look at a variety of issues related to
management and palliative care in ALS, interspersed with
perspectives from Dr. SP and his family. For example, they discuss
not only how to diagnose the disease but also advise on specific
ways to disclose this devastating diagnosis, as well as how to
outline the prognosis.

"To deliver the diagnosis of this well-publicized disease requires
great sensitivity and care," they write. "Sooner rather than later,
the clinician must discuss the nature of the disease and the
importance of advance directives, always striving to maintain
realistic hopes."

Drs. Mitsumoto and Rabkin provide a broad discussion, describing the
symptoms to expect and how to manage them, projected costs of
various devices and services required to care for the patient, and
the emotional burden that can be expected both for the family and
the professional staff who care for them.

"Thus, the physician caring for patients with ALS experiences both
the extraordinary burdens and extraordinary opportunities in
providing expert care throughout this tragic illness," the authors
conclude.

Many of these concepts are applicable not only to ALS, they add, but
to other fatal progressive neurologic diseases such as Huntington's
chorea and late-stage Parkinson's disease.

Inhaled human insulin (Exubera) provides glycemic control comparable
to that with subcutaneous insulin with only minor, reversible
effects on pulmonary function, according to findings published in
the June issue of The Journal of Clinical Endocrinology & Metabolism.

"Diabetic control in the USA is poor, and one reason is that insulin
is started so late and usually as a last resort," Dr. Paul Norwood
from University of California at San Francisco, Valley Research,
Fresno, told Reuters Health. "Inhaled insulin will allow insulin to
be started earlier and probably decrease the average glucose level
and lower the complication rate."

Dr. Norwood and associates characterized the impact of short term
Exubera on glycemic control and pulmonary function in a 24-week
study of 226 nonsmoking patients with type 1 diabetes and normal
lung function.

At weeks 6, 12, and 24, mean hemoglobin A1c (HbA1c) levels declined
to a similar extent in patients treated with Exubera and patients
treated with subcutaneous insulin, the authors report.

At the end of the 12-week comparative phase, 46% of Exubera-treated
patients and 57% of subcutaneous insulin-treated patients had HbA1c
levels of 7% or less.

The overall risk of hypoglycemic events was about 50% lower for
patients treated with Exubera than for patients treated with
subcutaneous insulin, the report indicates.

Declines in FEV1 and carbon monoxide diffusion capacity among
Exubera-treated patients were small, nonprogressive over 12 weeks,
and reversible after discontinuation of Exubera, the researchers
note.

"I have over 225 patients who have been on inhaled Exubera, Novo
Nordisk and Mannkind insulin, and my clinical experience is that
inhaled and injectable insulin can be interchanged without problem,"
Dr. Norwood said. "I have had patients personally on inhaled insulin
for 5.5 years. There have been no significant differences in glucose
control and pulmonary function tests."

"People have a deep-seated fear of needles, spiders, and snakes,"
Dr. Norwood added. "Inhaled insulin circumvents the needle fear. It
is extremely easy to begin; I just have them take a puff."

J Clin Endocrinol Metab 2007;92:2211-2214.