The concept of the metabolic syndrome has, by now, been widely
accepted by many clinicians as a useful and strong indicator of
increased risk for diabetes and cardiovascular disease (CVD).
However, some clinicians maintain that a diagnosis of metabolic
syndrome is unnecessary, because better, more robust predictors of
CVD, such as the Framingham Risk Assessment Score, exist, and a
diagnosis of metabolic syndrome has no appreciable effect on either
prognosis or treatment. This issue was discussed here at the 2007
annual meeting of the American College of Preventive Medicine in a
heated debate by 2 prominent representatives of the opposing sides.

First, Gregory Pokrywka, MD, director of the Baltimore Lipid Center
in Maryland, outlined his position, according to which metabolic
syndrome is a very useful concept, which can be used to predict long-
term risk for CVD, particularly in men older than 45 years and ¡X
especially ¡X in women older than 55 years.

"Most of the CVD in women in this country comes from women who have
the dysmetabolic syndrome," Dr. Pokrywka said. "I believe that's the
driving force in CVD in women in this country. Low-density
lipoprotein cholesterol (LDL-C) abnormalities are not driving
cardiovascular abnormalities; it's triglyceridemia and high-density
lipoprotein cholesterol (HDL-C) abnormalities. Multiple studies have
suggested that metabolic syndrome may be more predictive of coronary
heart disease (CHD) in women than in men."

Metabolic syndrome can also help predict diabetes mellitus, Dr.
Pokrywka went on to say. "There is a significant increase in risk if
you have 4 of the 5 criteria [that are used to diagnose metabolic
syndrome]. You can almost call it a 'super metabolic syndrome,' " he
told meeting attendees. "In the West of Scotland study, diabetes
went up over 20-fold in patients who had 4 of those 5 criteria.

"We've been taught to look at cholesterol concentrations as a way to
predict risk, but cholesterol concentrations are only proxies to
what's really going on: lipoprotein abnormalities," Dr. Pokrywka
argued. "In our clinic, we use a particle-based approach in the
prognosis and diagnosis of our patients with CVD risk [because] the
risk is determined by the number of particles, not by the amount of
cholesterol."

Triglyceride levels are also very important, according to Dr.
Pokrywka. "When I look at a lipid panel of a new patient, the first
lipid I always look at is the triglyceride count. We're very focused
on LDL-C in this country, and that's part of the reason I think
we're only preventing one third of the [cardiac] events in our
patients. I look at triglyceride count first because I know as that
goes up, the particle count goes up, too."

High triglyceride levels are included in the definition of metabolic
syndrome, but not in the Framingham Risk Assessment Score, and that
is one of the reasons Dr. Pokrywka thinks metabolic syndrome is a
better predictor of CVD. At the end of his talk, he summed up his
argument by saying, "The diagnosis of metabolic syndrome serves to
identify patients at increased long-term risk for cardiovascular
disease, especially older patients, and it can also be used to
identify patients at higher risk for diabetes and ischemic stroke."

Representing the opposing view was Mary McGowan, MD, medical
director of the Cholesterol Treatment Center at University of
Massachusetts Medical Center, who questioned whether making the
diagnosis of metabolic syndrome provides a true assessment of risk.

"Are we including the right risk factors in our definition?" she
asked. "For one thing, inflammatory markers are not included at all
in the definition of metabolic syndrome," she noted. "Maybe if they
were, it would be a better definition."

C-reactive protein (CRP) is a highly sensitive marker of
inflammation, but it is not included in the definition of metabolic
syndrome, Dr. McGowan pointed out. "CRP has been found to be an
independent predictor of insulin resistance, and the question is,
would the inclusion of CRP in the definition of metabolic syndrome
improve the ability to predict risk?" she wondered. "Moreover,
several studies have found that CRP is a strong, independent
predictor of cardiovascular events, and its predictive value was
equal to that of the metabolic syndrome," she said. "So maybe if CRP
was included in the definition of metabolic syndrome, maybe we'd
have a more robust syndrome," she suggested.

Another potential problem with the metabolic syndrome, according to
Dr. McGowan, is that there are many different ways in which it can
be defined. "For the World Health Organization (WHO), for example,
you have to have diabetes or impaired glucose tolerance to be
diagnosed with metabolic syndrome. Their definition also includes
high waist-hip ratio, high triglyceride, low HDL, high blood
pressure (BP), and microalbuminuria."

On the other hand, the Adult Treatment Panel definition is "very
egalitarian," Dr. McGowan contended. "You only have to have 3 of the
following 5: elevated fasting blood glucose, large waist
circumference, high triglyceride count, low HDL, and high BP.

"So, there are many different ways to diagnose metabolic syndrome,"
Dr. McGowan said, "and this may result in some patients being
falsely reassured, while others may be needlessly or excessively
worried."

Finally, Dr. McGowan wondered if the Framingham Risk Assessment
Score was a better predictive tool than the diagnosis of metabolic
syndrome. She also questioned whether a person diagnosed with
metabolic syndrome would be treated differently if the components of
metabolic syndrome were diagnosed individually. "Does the treatment
of metabolic syndrome differ from the treatment of individual
components?" she asked. "If not, then why diagnose metabolic
syndrome?"

Regarding the first question, Dr. McGowan cited a number of studies
that found no advantage in terms of risk assessment by the unique
components of the metabolic syndrome (obesity and high triglyceride
levels).

"So, I think we already have a better scoring tool than the
metabolic syndrome," she concluded. And regarding the question of
whether the treatment of the syndrome would differ from the
treatment of the individual symptoms, "I would argue that it
wouldn't," she said. "So I would suggest that the clinical emphasis
should be on treating effectively the [individual] cardiovascular
risk factors that are present."

A show of hands at the end of the session revealed that the audience
was equally divided between those who thought that a diagnosis of
the metabolic syndrome is helpful and should continue to be used and
those who thought that the concept should be abandoned because it
has no unique qualities or features with respect to either prognosis
or treatment.

ACPM 2007 Annual Meeting: Session 24. Presented February 26, 2007

An integrative approach helps relieve depression in patients with
cardiovascular disease (CVD), according to results of a study
presented here at the 2007 annual meeting of the American College of
Preventive Medicine.

The study, which was conducted by Valencia Porter, MD, of the
Scripps Center for Integrative Medicine (SCIM) in La Jolla,
California, and colleagues involved a review of the charts of 569
patients who had been enrolled in the "Healing Hearts" program at
SCIM between 1996 and 2003.

Patients diagnosed with CVD often become depressed, and depression
has been shown to hasten disease progression. Therefore, the
investigators hypothesized that preventing and/or relieving
depression could, conceivably, help improve the cardiovascular
health status of these patients.

"Healing Hearts" is a 6-month, integrated rehabilitation program for
people with CVD, which ¡X besides standard medical care, such as
blood pressure control ¡X also incorporates integrative care,
including yoga, exercise, stress management, and nutrition
counseling.

To assess the effects of the program on psychological functioning,
the researchers looked at various measures such as the Beck
Depression Inventory (BDI) and the Short Form (SF)-36 (a
multipurpose health survey with 36 questions, which yields an 8-
scale profile of functional health and well-being) both at baseline
and at the conclusion of the program. These measures were obtained
on 360 patients, 57.8% of whom were men (mean age, 61 years) and
42.2% were women (mean age, 61.4 years).

"These items were collected on the patients initially and after they
went through the program," Dr. Porter told Medscape during an
interview at the conference. "When we looked at the data a number of
years later, we found that [the patients] had improved depression
scores and they also reported feeling better."

An analysis of the data showed an average improvement in BDI score
of 8.4 points (P < .001) and a mean improvement of 74.6 points in SF-
36 score (P < .001) during the 6-month study period.

"We were surprised by these robust improvements in the psychological
scores, because the program originally was not designed specifically
for this," Dr. Porter told Medscape. There were also improvements in
some measures of physical health status [the primary objective of
the program], she explained. These included lower low-density
lipoprotein cholesterol and triglyceride levels, as well as a
decrease in body mass index, she said.

"What these results tell us is that you have to treat the whole
patient, not just their lipids, not just their hypertension," Dr.
Porter told Medscape. "You have to make sure that they have
psychosocial support, they're able to deal with stress, and you have
to help them deal with depression, which is a major issue for these
patients and have a significant negative effect on outcome."

ACPM 2007 Annual Meeting: Poster 16. Presented February 22, 2007

Certain computer-detected heart rate characteristics can aid use of
clinical signs in early diagnosis of neonatal sepsis, researchers
report in the February issue of Pediatric Research.

This monitoring strategy, senior researcher Dr. J. Randall Moorman
told Reuters Health, "does not require new tests or even contact
with the baby, and gives a continuous read-out of the risk of
potentially fatal illness in the near future."

Dr. Moorman, of the University of Virginia, Charlottesville, and
colleagues developed the system by examining abnormal heart rate
characteristics (HRC) during monitoring.

They prospectively recorded clinical data and the HRC index in 76
episodes of proven sepsis and 80 episodes of clinical sepsis in 337
infants.

The team went on to determine relationships of the HRC index with
individual clinical signs of sepsis, laboratory tests, and the total
scoring.

The investigators found that the clinical score and individual
clinical signs were highly significantly correlated with the HRC
index. The clinical score and HRC index added independent
information in predicting sepsis, and were similar in clinical and
proven sepsis.

This monitoring technique "will never replace doctors and nurses,
but it may give them a valuable head start on diagnosis and
treatment of these very vulnerable infants," Dr. Moorman concluded.

A multi-center National Institutes of Health-sponsored study is
currently being conducted to further investigate the approach.

Pediatr Res 2007;61.

Low parental birthweights are associated with an increased risk of
metabolic syndrome in the offspring, a multinational team of
researchers reports from India.

While the link between low birthweights and coronary artery disease
and metabolic syndrome is well established, the inter-generational
link between parental birthweights and chronic disease in offspring
is not clear, Dr. S. R. Veena from the Holdsworth Memorial Hospital,
Mysore, in South India, and colleagues note in the January issue of
Diabetologica.

The investigators included in their study 144 men and 193 women born
between 1934 and 1966 in their hospital, and 223 offspring born to
the men and 283 to the women. A detailed clinical and biochemical
evaluation were carried out to identify metabolic syndrome and its
complications among the offspring.

Among the mother-offspring pairs, the prevalence of coronary heart
disease was over two times higher among offspring of mothers with
birthweights of 2.5 kg or lower as compared to offspring of mothers
with birthweights over 3.5 kg, Dr. Veena and colleagues report.

Also, maternal birth weight was inversely related to systolic blood
pressure in offspring, they add.

In both the mother-offspring and father-offspring pairs, the risk of
metabolic syndrome increased as parental birthweight decreased, the
researchers found. These associations persisted even after
correcting for the birthweight of the offspring, they point out.

There are several possible explanations, the team notes in their
paper.

"One possibility is that the parent and offspring have genes that
both cause low birthweight and insulin resistance as per the 'fetal
insulin hypothesis'," Dr. Caroline Fall told Reuters Health. Dr.
Fall, from the MRC Epidemiology Resource Centre, Southampton, UK, is
one of the co-authors.

"Another possibility is that there are environmental effects
producing epigenetic changes in either parent, that modify gene
expression, causing both lower birthweight in the parent and insulin
resistance in the offspring," she added.

Diabetologica 2007;50: 43-54

A new analysis of the COMET study shows that carvedilol reduces
vascular events to a greater extent than metoprolol, an effect that
the authors suggest likely contributes to the superior therapeutic
profile of carvedilol in the treatment of heart failure.

The current analysis, published in the March 6, 2007 issue of the
Journal of the American College of Cardiology [1], was conducted by
a group led by Dr Willem J Remme (Sticares Cardiovascular Research
Institute, Rhoon, the Netherlands).

They note that carvedilol has a unique pharmacologic profile,
blocking both beta-1 and -2 adrenergic receptors, and has tighter,
more prolonged binding to the beta-1 receptor than metoprolol, which
results in a greater sympathoinhibitory activity. The COMET trial
was conducted to investigate whether these properties would lead to
better outcomes with carvedilol compared with metoprolol tartrate, a
beta-1-selective beta blocker, in more than 3000 heart-failure
patients, and the primary results, published in 2003, did indeed
show improved rates of survival and cardiovascular hospitalizations
in patients receiving carvedilol. But the results have been
challenged by some other heart-failure experts, who have pointed out
that metoprolol was not given at the optimum dose or formulation in
COMET and that the better effect of carvedilol could have been
caused simply by a greater effect on beta-1 blockade alone, which
could be seen with optimum doses of any beta blocker.

The current analysis was conducted to investigate whether vascular
protection could have contributed to the superior effect of
carvedilol in the COMET trial and therefore focused on the vascular
end points of cardiovascular death, stroke, stroke death, MI, and
unstable angina. Results showed a consistently greater effect on
these events with carvedilol than with metoprolol.

Remme et al note: "With the exception of hospitalization for
unstable angina and any strokes, all parameters measured were
significantly reduced by carvedilol. These results strongly suggest
a protective effect of carvedilol against major vascular events.

"As previous analyses have also indicated that carvedilol reduces
the occurrence of sudden death and death due to worsening HF, a
decrease in ischemic events may well contribute to this survival
benefit, in addition to other mechanisms, including hemodynamic
improvement and antiarrhythmic properties of carvedilol," they
write.

Remme told heartwire that some information on vascular events in
COMET has been presented before, but this is a much more detailed
analysis and shows that carvedilol definitely reduces ischemic
events more than metoprolol, which likely contributes to the
mortality benefit shown in the COMET trial. "The mortality benefit
seen with carvedilol in COMET was probably due to several different
factors, including a reduction in remodeling, fewer arrhythmias, and
fewer ischemic events," he commented. He said he could not be sure
exactly what the anti-ischemic mechanism of carvedilol was--it could
be due to the greater sympathoinhibitory effects of carvedilol or to
other properties of the drug. "Carvedilol has several other
properties that could produce an anti-ischemic effect--its blockade
of alpha-1 receptors causes vasodilation, and it also has direct
antioxidant and antiapoptotic effects. There are a wide variety of
mechanisms that could be involved," he noted.

Good choice for other ischemic indications?

Remme says this study is important, as it shows that carvedilol does
have an anti-ischemic profile, which is another reason to choose
this agent over other beta blockers. "If you want to give a beta
blocker to patients with any form of ischemia I would choose
carvedilol. It is not just for heart failure. The ASCOT trial
suggested that beta blockers may not be the best treatment for
hypertension, but if they had used carvedilol instead of atenolol
they might have seen a different result. I wouldn¡¦t use a beta
blocker first-line for the treatment of hypertension for its
antihypertensive effects, not even carvedilol. But if I were going
to use a beta blocker as the second or third antihypertensive, I
would use carvedilol, as its alpha-blocking properties cause
vasodilation, which increases its antihypertensive effects, and now
also because of its anti-ischemic effects," he
commented. "Similarly, in the post-MI setting metoprolol is the most
popular beta blocker, but I would suggest that carvedilol may be
better because of the better anti-ischemic effect. I know that these
are different patient populations from the one we studied, and you
always have to be careful when extrapolating to different
indications, but I think these are reasonable suggestions," he added.

But what about the argument that the superior effect of carvedilol
shown in the trial was due solely to more effective beta blockade in
comparison with the "suboptimal" formulation of metoprolol used?
Couldn¡¦t the reduction in vascular effects also be attributed to
this? Remme claims this whole argument is without merit. "This is a
nonissue in my view. The difference in beta blockade between the
carvedilol and metoprolol groups in COMET was characterized by a
reduction in heart rate of 1.6 beats per minute in the carvedilol
group. This is a very small difference and not enough to account for
the difference in mortality shown in the trial. The same goes for
the vascular effects. I am 100% certain that this is not the reason
for the benefits seen," he told heartwire.

The authors also address this issue in the paper, noting that "in a
post hoc analysis of our data, the effects of carvedilol, compared
with metoprolol, on outcome were independent of any change in heart
rate, and no interaction with heart rate, systolic blood pressure,
or the beta-blocker dose was found." They add: "We therefore
consider the vascular effects of carvedilol the result of its
specific pharmacologic profile, and not the result of more intense
beta-1 blockade than metoprolol in our study."

Remme WJ, Torp-Pedersen C, Cleland JGF, et al. Carvedilol protects
better against vascular events than metoprolol in heart failure.
Results from COMET. J Am Coll Cardiol 2007; 49:963¡V971.

What if a heart-failure drug could lessen the adrenal glands' deluge
of catecholamines to a more normal ebb and flow, complementing the
dam that beta blockers erect at the receptor level? A potential
target for such a therapy might be the increased adrenal levels of a
particular enzyme that helps mediate sympathetic activity, according
to a laboratory study [1]. Inhibition of the enzyme in mouse and rat
models of HF appeared to at least partially restore the normal
metabolic feedback mechanisms controlling epinephrine and
norepinephrine secretion that go out of control in patients with the
syndrome.

The research suggests that the normal dampers on catecholamine
release, which are mediated by á2 adrenergic receptors, are impaired
in HF by the upregulation of adrenal G protein-coupled receptor
kinase 2 (GRK2) but can be restored by GRK2 inhibition, report the
authors, Dr Anastasios Lymperopoulos (Jefferson Medical College,
Philadelphia, PA) and associates. In their study, published online
February 18, 2007 in Nature Medicine, GRK2 inhibition was
accomplished chemically in vitro and by simulated gene therapy in
vivo.

The group's findings suggest that the preservation of normal
epinephrine and norepinephrine responses through GRK2 inhibition can
to some extent reverse the adrenal and ventricular dysfunction
characteristic of HF, according to coauthor Dr Walter J Koch
(Jefferson Medical College). It makes more intuitive sense to
restore a normal homeostatic balance of catecholamines than it does
to block them at the cellular receptor level, he observed for
heartwire.

Lymperopoulos et al "have uncovered a mechanism that may explain
intra- and intercellular maladaptive changes that are involved in
heart failure," writes Dr Stephen B Liggett (University of Maryland,
Baltimore) in an accompanying editorial [2]. "The altered
relationship between the heart and the adrenal gland that occurs
during heart failure appears to be amenable to therapy aimed at
adrenal gland GRK2." Liggett is director of his institution's
cardiopulmonary genomics program.

Such adrenal-targeted sympatholytic therapy, added to beta blockade
and other established HF treatments, would represent an entirely new
approach to managing the syndrome, observed Koch, who heads his
center's laboratory of cardiovascular gene therapy.

He and his group observed significantly increased levels of
epinephrine and norepinephrine and depressed LV function in two
heart-failure models: transgenic mice "programmed" to develop
cardiomyopathy and rats with induced MI.

In a series of experiments with the animals and their isolated and
cultured catecholamine-producing adrenal chromaffin cells, the group
observed evidence for:

• Severe HF-related downregulation of adrenal á2 receptors.

• Increased GRK2 levels in adrenal-gland extracts from the mice and
rats with HF but not in control animals.

• GRK2-mediated alterations in á2-receptor function that interfered
with the receptors' inhibition of catecholamine secretion and
consequent elevation in epinephrine and norepinephrine levels.

• Reversal of á2-receptor dysfunction, reduced catecholamine levels,
and improvements in the animals' myocardial contractility and LV
function associated with GRK2 inhibition.

• Additive catecholamine-reducing effects from the combination of
GRK2 inhibition and administration of the established á2-receptor
agonist moxonidine in the rats with induced HF.

The findings suggest that an inhibitor of GRK2 "would be a very nice
synergistic drug" when administered with beta blockers and might
potentiate the sympatholytic effects of á2 agonists like moxonidine,
a drug that had been abandoned as an HF therapy after it worsened
clinical outcomes in randomized trials, according to Koch.

Moxonidine may not have worked, Koch said, because it targets
receptors that the current data suggest are downregulated in HF. By
the same reasoning, he added, the drug might show a positive effect
in HF if it could be given with a drug that reverses the á2-receptor
impairment--such as a GRK2 inhibitor.

Lymperopoulos A, Rengo G, Funakoshi H, et al. Adrenal GRK2
upregulation mediates sympathetic overdrive in heart failure. Nat
Med 2007; DOI: 10.1038/nm1553. Available at:
http://www.nature.com/naturemedicine.
Liggett SB. Long-distance affair with adrenal GRK2 hangs up heart
failure. Nat Med 2007;13:246-248.
http://www.nature.com/naturemedicine.

A new interactive, cell phone–based technology appears to be
feasible and efficacious in the prevention and management of type 2
diabetes, according to a controlled trial presented here at the 2007
annual meeting of the American College of Preventive Medicine.

"The 'Confidant System' is a cell phone–based biometric system for
real-time health coaching," lead investigator David Katz, MD, MPH,
told Medscape. "The purpose of our study was to demonstrate the
feasibility of using the Confidant System to assist with diabetes
self-care management in a clinic population, as evidenced by
successful implementation, ease of use, and patient and clinician
satisfaction with the system," he said. Dr. Katz is public health
director of the Prevention Research Center at Yale University School
of Medicine in New Haven, Connecticut.

In the Novel Interactive Cell Phone Technology for Health
Enhancement (NICHE) study, 30 patients at 2 community health centers
in Connecticut were assigned to either the intervention group (n =
15) or the control group (n = 15). Subjects at the intervention site
received the Confidant System technology (Confidant-enabled
pedometer, glucometer, and cell phone with remote-access daily
feedback and reminders) and used it for 3 months, along with
standard diabetes management. Subjects in the control group received
only standard diabetes care. The researchers evaluated the system
through feedback using surveys, focus groups, interviews, and
clinical tests.

According to Dr. Katz, a qualitative assessment of clinician and
patient experience after 3 months of use has shown that it is
feasible to incorporate this technology into a primary care
setting. "We found that both patients and providers could use the
Confidant System in this setting," he said.

Although the trial was not powered for clinical outcomes, a
quantitative analysis of the results showed improvements in markers
of glycemic control, as well as diabetes knowledge and self-
efficacy. There was a decrease in the level of glycosylated
hemoglobin (−0.1%; P = .15) and an increase in self-efficacy (P
= .008) in the intervention group compared with the control group.

This new technology is "a step ahead of others," according to Gordon
DeFriese, PhD, professor emeritus of social medicine and
epidemiology at the University of North Carolina at Chapel Hill. Dr.
DeFriese is not associated with the study.

"Previously, there were computer-based and computer-assisted
technologies that provided for the uploading of clinical measures
taken by the patient, but the integration of cell phone technology
incorporating the capabilities of Bluetooth technology, along with
health educational messaging is a major step forward," Dr. DeFriese
told Medscape.

"It enables biomedical measures such as HbA1c, blood pressure,
weight, etc, to be transmitted instantly via Bluetooth technology to
the patient's cell phone, and then immediately to a computer server,
which sends back rapid profiles of recent measures and offers
simultaneous health educational coaching messages, while at the same
time transmitting these clinical measures to one's physician," Dr.
DeFriese said.

He also pointed out that the study conducted by Dr. Katz and
colleagues was "a limited test of acceptance by patients and
clinicians.... It was not a full-scale randomized trial of the use
in a large population of diabetics," he said. "For what the study
was, it was very useful.... This technology, which is being improved
every week, is perhaps a major breakthrough in enabling the patient
with chronic illness to gain a measure of informational control and
immediacy of feedback and reinforcement that has been lacking in
other computer-assisted means of promoting effective disease
management in these populations."

ACPM 2007 Annual Meeting: Poster 38. Presented February 22, 2007

Results from a new study have shown that various genes that play a
role in the molecular clock also regulate enzymes relevant to the
synthesis and disposition of catecholamines, resulting in
alterations in blood pressure and plasma norepinephrine and
epinephrine throughout the day, as well as changes in these
variables in response to stress [1]. The findings provide evidence
for two apparently conflicting explanations for time-dependent
changes in blood pressure, say investigators.

"What we found was that different transcription factors involved in
the core clock had an impact on blood pressure that was quite
distinct and that there was indeed a temporal conditioning of the
response to stress," said senior investigator Dr Garret FitzGerald
(University of Pennsylvania, Philadelphia). "We also made this very
surprising observation that if we knocked out the most nonredundant
transcription factor implicated in the clock, we seem to impact on
an aspect of the stress response that is quite distinct from time.
As we tried to look for a mechanism that brought clock genes into
play, in terms of diurnal variation, we found that several genes
involved in the catecholamine pathway were also under control of the
molecular clock."

The results of the study, published online February 21 in the
Proceedings of the National Academy of Sciences with lead author Dr
Anne M Curtis (University of Pennsylvania), raise the possibility of
modifying blood pressure and the subsequent morning risk of
cardiovascular events by resetting the molecular clock, FitzGerald
told heartwire. As this blood-pressure response is linked to the
internal clock, new means of "phase-shifting" the time of the
maximal increase in blood pressure could potentially decrease the
risk of early-morning MI and stroke, he said.

Molecular clock located in the suprachiasmatic nucleus

The molecular clock for mammals is located in the suprachiasmatic
nucleus of the brain and is made up of positive and negative
transcriptional and translational feedback loops that drive
circadian gene expression. Although the clinical onset of vascular
events occurs more frequently in the morning than at any other time
of day and this circadian variation corresponds to the early-morning
increase in blood pressure, it is unknown whether this increase in
blood pressure is the result of the molecular clock or merely
reflects the physical and emotional stress of getting up and getting
active after a healthy slumber.

To address this question, the researchers used mouse models in which
various core clock genes--Bmal1, Clock, and Npas2--were disrupted,
and they discovered distinct and complementary effects of these
genes on blood pressure and its circadian variation. In addition,
the researchers also showed that genes involved in the production
and catabolism of catecholamines were also under control of the
molecular clock. They subjected the mice to a standardized stress in
response to which catecholamines and blood pressure surge. The
researchers found that the increase in blood pressure and
catecholamines depended on the time of the stress and that the
largest increase occurred at a time that coincided with the early
morning in humans.

"We turned our attention to that particular pathway, as we know that
plasma norepinephrine and epinephrine undergo a diurnal variation
that tracks exactly with blood pressure," said FitzGerald. "We know
also that this system--the 'fight-or-flight response'--is turned on
in response to stress, and so, if you like, there is a mechanistic
commonality between the two."

Investigators also showed that deleting one of the core clock genes
abolished both the catecholamine and blood-pressure response to
stress, regardless of when the stress was applied throughout the
day. This effect was specific only to the catecholamines, as the
stress response of another hormone, a steroid, was unchanged.

"While these different transcription factors impacted on blood
pressure, we found that they also had a similar hierarchy of impact
on plasma catecholamines," explained FitzGerald. "When we knocked
out the Bmal1 transcription factor, we found an effect on the stress
response that was independent of time, that the part of the stress
response it was affecting was the catecholamines and the consequent
rise in blood pressure. What was left untouched was the steroid
response to stress."

Conservation of the steroid response was dramatic but consistent
with earlier results from the group in a different setting. Previous
studies, said FitzGerald, have shown a role for these clock genes in
regulating the recovery from insulin-induced hypoglycemia [2]. They
had assumed that this occurred by abolishing the counterregulatory
hormone response--glucagon and steroids--that are turned on in
response to hypoglycemia. However, the steroid response was left
untouched, and the result reflected control by the clock of a series
of genes relevant to gluconeogenesis. This most recent study is a
second example of the conservation of the steroid response, but in
this particular example, it is maintained with the ablation of the
catecholamine response to stress.

"The nice thing about this present study is that it molecularly
integrates the two apparently conflicting explanations for time-
dependent changes in blood pressure," said FitzGerald.

Curtis AM, Cheng Y, Kapoor S, et al. Circadian variation of blood
pressure and the vascular response to asynchronous stress. Proc Natl
Acad Sci 2007; DOI: 10.1073/pnas.0611680104. Available at:
http://www.pnas.org.
Rudic RD, McNamara P, Curtis AM, et al. Bmal1 and Clock, two
essential components of the circadian clock, are involved in glucose
homeostasis. PLoS Biol 2004; 2:e377.

Researchers are reporting a number of factors that appear to be
associated with an increased risk of developing pathologic gambling
in response to treatment with dopamine agonists among Parkinson's
disease (PD) patients.

Their findings suggest that PD patients who have a younger age at PD
onset, higher novelty-seeking traits, or a personal or family
history of alcohol abuse have a greater risk of developing this
sometimes-devastating response to therapy.

"There may be a certain subgroup of patients that are at slightly
higher risk for developing these behaviors, and we should be looking
out for these patients," lead author Valerie Voon, MD, from the
National Institute of Neurological Disorders and Stroke, National
Institutes of Health, in Bethesda, Maryland, told Medscape.

If one of these traits is present, dopamine agonists should be used
with caution, she said. "It doesn¡¦t mean you can't start the
medications, but certainly we advise that everybody warn patients
with regard to this potential side effect and be much more careful
with those patients in terms of follow-up and education."

Their report appears in the February issue of the Annals of
Neurology.

Novelty-Seeking Temperament

There is growing evidence that dopamine agonists are associated with
an increase in impulse-control behaviors, including pathologic
gambling or shopping and hypersexuality among treated patients. In a
report published last year (Voon V et al. Neurol. 2006;67:1254-
1257), Dr. Voon and colleagues at the Toronto Western Hospital, in
Ontario, looked at the prevalence of repetitive and reward-seeking
behaviors in 297 PD patients using systematic screens and rigorous
definitional criteria. They found a lifetime prevalence of
pathologic hypersexuality of 2.4% and compulsive shopping prevalence
of 0.7%. These, combined with their previously reported data on
pathologic gambling, showing a prevalence of 3.4%, yielded a
lifetime risk for any of these behaviors of 6.1%, rising to 13.7%
among those on dopamine agonists.

There didn¡¦t appear, however, to be a dose relationship between
these disorders and dopamine-agonist treatment, suggesting that
these medications may interact with an underlying vulnerability in
those who develop the behaviors. To look more closely at this issue,
this same group looked at factors associated with pathologic
gambling among 21 patients with idiopathic PD with this problem,
comparing them with 42 controls taken consecutively from patients
who did not appear to have these problems.

However, they did have to exclude 7 of these patients when one of
these impulse-control disorders was found after all. Dr. Voon
explained that it is not uncommon for patients not to have insight
into these behaviors.

They then compared the groups on the basis of clinical features,
comorbid psychiatric and substance-abuse disorders, personality
traits, and impulsivity scores.

Patients with pathologic gambling were found to have a younger age
at PD onset (P = .006), higher novelty-seeking traits (P < .001),
medication-induced hypomania or mania (P = .001), impaired planning
(P = .002), or a personal or immediate family history of alcohol-use
disorders.

In a regression model, younger age at PD onset, higher novelty
seeking, and a personal or immediate family history of alcohol-use
disorders were found to be independently associated with pathologic
gambling.

Thrill-Seeking, Risk-Taking

Novelty-seeking behavior is essentially a temperament: an underlying
trait that is less influenced by environment and more likely to be
heritable, Dr. Voon explained. People with high novelty-seeking
scores tend more to risk-taking or thrill-seeking behaviors and are
more decisive and impulsive.

Interestingly, novelty-seeking rates in this study remained stable
whether or not patients were on a dopamine agonist, she noted.
Alcohol-abuse disorders predated the onset of Parkinson's or were
seen among the patients' family members, she added. "Those 2 traits
would predate the use of dopamine agonists, suggesting to us it is
definitely an underlying vulnerability and may potentially be an
underlying genetic vulnerability."

In general, though, novelty-seeking traits and risk-taking behaviors
such as smoking and alcohol use are low across the board in patients
with PD, she said, "so it's an intriguing and unusual group we're
seeing that actually has these behaviors." It is also not clear what
role the PD itself plays in this, Dr. Voon added, since there was no
association between pathologic gambling and disease stage or
severity.

The finding of an association with the impulsivity-planning score is
also interesting, she added. This score measures the ability to plan
ahead and make choices based on consideration of future
consequences. They found that the medications tended to make
impulsivity planning worse, but novelty-seeking scores did not
alter, suggesting the possibility of some interaction there.

Although further studies are required, the authors
conclude, "Screening for such features and advising those at higher
risk may be warranted."

Ann Neurol. 2007;64:212-216

Polymer implants designed to slowly release the calcium channel
antagonist nicardipine have a beneficial effect on clinical outcome
after severe aneurysmal subarachnoid hemorrhage, German researchers
report in the February issue of Stroke.

"The systemic administration of vasoactive drugs in order to prevent
stroke by cerebral vasospasm following subarachnoid hemorrhage is
characterized by significant side effects." Dr. Peter Vajkoczy told
Reuters Health. "The development of slow-release strategies by which
the vasoactive drug can be applied locally, directly to the vessel
wall, is the logical consequence and a big advancement in stroke
prevention after subarachnoid hemorrhage."

In a proof-of-concept study, Dr. Vajkoczy at the University of
Heidelberg and colleagues randomized 32 patients with severe
subarachnoid hemorrhage who were undergoing aneurysm clipping to
receive or not receive nicardipine-loaded polymers. These were
implanted into the basal cisterns in direct contact with the exposed
proximal blood vessels. In control patients, the basal cisterns were
simply opened and washed out.

The incidence of angiographic vasospasm in proximal vessel segments
was significantly reduced in the implant group, at 7% compared with
73% in the control group. This was also true of most distal vessel
segments.

Computed tomography scans revealed a lower incidence of delayed
ischemic lesions in the nicardipine implant group (14% versus 47%).
The implant group demonstrated more favorable scores on measures of
stroke as well as a significantly lower incidence of deaths (6%
versus 38% control).

The investigators conclude that the approach improves clinical
outcome after severe subarachnoid hemorrhage.

"This is certainly an innovative and important novel strategy for
the prevention of vasospasm-associated stroke in patients suffering
from subarachnoid hemorrhage," continued Dr. Vajkoczy.

"If these results can be confirmed in a larger trial," he
concluded, "the concept of nicardipine-prolonged release implants
will certainly change the future management of these patients
significantly."

Stroke 2007;38:330-336

Current recommendations for diabetic retinopathy screening are not
cost-effective for children with type 1 diabetes who successfully
maintain strict glycemic control with intensive insulin therapy,
report researchers from Yale University School of Medicine, New
Haven, Connecticut.

As Dr. William V. Tamborlane noted in comments to Reuters
Health, "Diabetic retinopathy screening recommendations date back to
when you had worse glycemic control and more rapid onset of
retinopathy."

It would be more cost-effective to limit regular retinopathy
screening to those children who exhibit persistent elevations in
hemoglobin A1C levels, hypertension, or microalbuminuria --
assessments that can be made during regular diabetes clinic visits,
conclude Dr. Tamborlane and colleagues in the February issue of
Diabetes Care.

The Yale group reviewed the results of retinopathy screening eye
exams in 130 children with type 1 diabetes who met American Diabetes
Association (ADA) screening criteria; i.e., they were older than 10
years of age and had diabetes for more than 3 years.

The researchers report that only three eye exams were positive for
diabetic retinopathy. In one of the three, diabetic retinopathy was
misdiagnosed; the other two cases were classified as possible
transient microaneurysms in one eye each.

It is "striking," the authors say, that "none of the children had
any verifiable or sustained evidence of early diabetic retinopathy."

Dr. Tamborlane concluded: "A lot of time, effort and money goes into
screening diabetic children for early eye changes, and, as evidenced
by our study, with very little yield, unless the children have other
risk factors like high blood pressure, chronic elevations of A1C,
and small blood vessel changes in the kidney."

Diabetes Care 2007;30:362-363.

Nepafenac, an NSAID prodrug, administered topically inhibits
diabetes-induced retinal microvascular disease, according to
preclinical study findings reported in the February issue of
Diabetes.

"These results suggest that early non-invasive ocular therapy may
help prevent development of nonproliferative diabetic retinopathy,"
Dr. Timothy S. Kern from Case Western Reserve University, Cleveland,
Ohio told Reuters Health.

Dr. Kern and his associates examined the effect of topical nepafenac
on the development of early stages of diabetic retinopathy and on
metabolic and physiologic abnormalities that contribute to the
retinal disease in streptozotocin-induced diabetic rats.

Topical nepafenac from the onset of diabetes prevented retinal
acellular capillaries, pericyte ghosts, and TUNEL-positive cells,
the authors report, and it inhibited the diabetes-induced increase
in activities of caspase-3 and caspase-6 in the retina of diabetic
rats.

In contrast, nepafenac did not inhibit the ganglion cell loss in the
posterior retina.

"The results of these experiments show that topical ocular
administration of nepafenac has significant effects to inhibit
lesions characteristic of the early stages of diabetic retinopathy
in animals," Dr. Kern said. "This is a result of drug penetration
into the retina, because non-dosed contralateral eyes did not
improve (indicating that systemic exposure was not responsible for
the drug effects noted)."

His team is currently investigating if nepafenac "can inhibit or
even reverse retinal pathology if its administration is delayed
until the retinopathy is already developing," Dr. Kern said.

While results so far are encouraging, Dr. Kern concluded, "these pre-
clinical studies must be reproduced in human clinical trials."

Diabetes 2007;56:373-379

There does not appear to be an independent association between the
use of highly active antiretroviral therapy (HAART) in patients with
HIV and an increased risk of metabolic syndrome, researchers report
in the March 1st issue of Clinical Infectious Diseases.

"Although the prevalence of metabolic syndrome remains high in our
HIV-infected population," lead investigator Dr. Kristin Mondy told
Reuters Health, "much of this risk may now be attributable to an
increased prevalence of traditional cardiovascular disease risk
factors as opposed to therapy-associated factors."

Dr. Mondy of Washington University School of Medicine, St. Louis,
Missouri, and colleagues compared data on 471 HIV patients and a
like number of HIV-negative matched controls who took part in the
National Health and Nutrition Examination Survey (NHANES 2001-2002).

In all, 25.5% of the HIV group had the metabolic syndrome, compared
to 26.5% of controls. Nevertheless, the HIV-infected patients had a
significantly smaller waist circumference, lower body mass index,
lower HDL cholesterol levels, higher triglyceride levels, and lower
glucose levels, than their NHANES counterparts.

HIV-infected patients with metabolic syndrome were more likely to be
diabetic, older, and white and have a high CD4 cell count and body
mass index, compared to patients without metabolic syndrome.
However, the type or duration of antiretroviral therapy was not an
independent risk factor for metabolic syndrome.

"As HIV becomes managed more as a chronic disease," Dr. Mondy
continued, "health problems that are of particular concern to the
general population -- such as obesity, type 2 diabetes, and
hypertension -- will need to be addressed more aggressively in HIV-
infected persons as well."

Clin Infect Dis 2007;44:726-734.

The direct renin inhibitor aliskiren controls mild-to-moderate
hypertension, with side effects similar to that of placebo, a Baylor
College of Medicine team reports. If renin inhibition alone is not
enough, the addition of the angiotensin receptor blocker (ARB)
valsartan provides additional blood pressure lowering effects
without an increase in adverse effects.

Dr. James L. Pool and colleagues point out in the January issue of
the American Journal of Hypertension that while blockade of the
renin-angiotensin-aldosterone system with ACE inhibitors or
angiotensin receptor blockers works well, renin inhibition would be
preferable as it is the rate-limiting step of the system. "Aliskiren
is the first in a new class of orally effective direct renin
inhibitors," they note.

The Houston, Texas, researchers and colleagues in a multicenter
trial randomized 1,123 patients with mild-to-moderate hypertension
to once daily aliskiren 75 mg, 150 mg or 300 mg; once daily
valsartan monotherapy 80 mg, 160 mg or 320 mg; aliskiren plus
valsartan in low/low, medium/medium and high/high dose combinations;
once daily valsartan/hydrochlorothiazide (106 mg/12.5 mg); or
placebo. All patients underwent a 3-4-week placebo run-in period
prior to randomization.

The primary endpoint was change in mean sitting diastolic blood
pressure.

Dr. Pool and colleagues report that aliskiren 300 mg daily
significantly lowered mean diastolic and systolic blood pressure,
with "a safety and tolerability profile comparable to placebo." Its
antihypertensive effect occurred in a dose-response fashion.

Combination aliskiren and valsartan produced a greater (but not
statistically so) antihypertensive effect than monotherapy with
either drug, and was similar to that of
valsartan/hydrochlorothiazide but with fewer adverse effects.

The investigators note that the study was not statistically
powered "to provide conclusive comparisons between the effects of
the aliskiren/valsartan combinations, but was intended to
provide 'proof of concept' for the potential of this combination."

Am J Hypertens 2007;20:11-20

For preventing venous thromboembolism in hospitalized patients,
three times daily dosing of unfractionated heparin is somewhat more
superior than twice daily dosing, results of a study in the February
issue of Chest indicate. However, three times daily dosing may
increase the rate of bleeding in this population.

"While twice-daily (BID) and three-times-daily (TID) dosing regimens
have been studied, the two have never been directly compared," Dr.
Lisa K. Moores, of Walter Reed Army Medical Center, Washington, DC,
and colleagues write.

The researchers conducted a meta-analysis of randomized trials that
compared subcutaneous unfractionated heparin (BID or TID) with
placebo or control for VTE prophylaxis. Overall, 12 trials were
included in the analysis. These involved 7978 patients, including
1664 in the TID arm and 6314 in the BID arm.

The investigators found no significant difference in the overall
rate of VTE after adjusting for baseline risk: BID, 5.41 events per
1000 versus TID, 3.46 per 1000 patient-days (p = 0.87).

The event rate for pulmonary embolism was lower among the TID
patients at 0.53 per 1000 patient-days versus 1.50 for BID, and the
difference approached statistical significance (p = 0.09).

"A total of 52 minor bleeding events and 16 major bleeding events
occurred in the BID group, with 175 minor bleeding events and 17
major bleeding events in the TID arm," Dr. Moores and colleagues
report. "The adjusted event rate for major bleeding was 0.33 per
1000 patient-days in the BID arm versus 0.73 per 1000 patient-days
in the TID arm (p < 0.001)."

Individual patient risk for VTE and bleeding should be assessed
before deciding which dosing regimen to use, the authors advise. The
twice-daily regimen may offer a superior risk/benefit ratio in
patients with high risk for bleeding complications. Those at high
risk for VTE may benefit more from the three-times-daily regimen.

Chest 2007;131:507-516

One of the three galvanizing drug-eluting-stent (DES) studies of the
World Congress of Cardiology 2006 (WCC 2006)--dubbed the Bern-
Rotterdam analysis in the debate that ensued--has now been published
in the February 24, 2007 issue of the Lancet [1]. The study, which
examined late stent thrombosis rates (>30 days poststenting) between
April 2002 and December 2005 in the SIRTAX and Post-SIRTAX
registries in Bern and the RESEARCH and T-SEARCH registries in
Rotterdam, found a cumulative incidence of angiographically
documented stent thrombosis at three years of 2.9%.

Dr Peter Wenaweser (University Hospital, Bern, Switzerland)
presented the results during the WCC 2006 meeting in Barcelona; Dr
Joost Daemen (Erasmus Medical Center, Rotterdam, the Netherlands) is
first author on the paper.

As previously reported by heartwire, the finding from the analysis
that proved to be the flash point for the debate that followed was
that the risk of stent thrombosis did not appear to decline with
time but to occur steadily, at a constant rate of 0.6% per year out
to three years after stent implantation.

"The results of the present study suggest that late stent thrombosis
with drug-eluting stents occurs more frequently than expected and
that rates increase steadily during long-term follow-up. The
sustained occurrence over a long-term period might be explained in
part by the delayed healing response after implantation of drug-
eluting stents, as indicated by delayed reendothelialization and
hypersensitivity reactions to the antiproliferative drugs or, more
probably, to the synthetic polymers."

Key findings, caveats, from Bern-Rotterdam analysis

In all, 8146 patients underwent stenting at the sites included in
the analysis: in both locations, hospitals had adopted policies of
100% DES use, first with the sirolimus-eluting stent (SES; in 3823
patients), followed by the paclitaxel-eluting stent (PES; in 4323
patients). Over the study period, a total of 152 angiographically
documented stent thromboses occurred, of which 61 were late stent
thromboses. Expressed differently, the incidence density of stent
thrombosis was 1.3 per 100 person-years, with a cumulative incidence
of 2.9%.

While rates of early stent thrombosis were similar for the SES and
PES, late stent thrombosis was more common in PES-treated patients
(1.8% vs 1.4%; p=0.031); however, the authors caution that stent
thrombosis rates for the two stents cannot accurately be compared
outside of a randomized clinical trial. Moreover, PES tended to be
used in more complex disease situations, and follow-up in these
patients was not as long as it was for the SES-treated patients.

Of note, of the patients who experienced an early stent thrombosis,
87% were taking dual antiplatelet therapy; by contrast, only 27% of
patients who experienced a stent thrombosis after 30 days were on
dual antiplatelet therapy.

The authors also point out that the true rate of stent thrombosis
was likely underestimated in their study, since only
angiographically proven stent thromboses were included.

In an accompanying Comment, Drs Philip Urban and Edoardo De
Benedetti (La Tour Hospital, Geneva, Switzerland) address the
question of why the stent thrombosis rates in Daemen et al's study
are higher than rates reported in other studies, including recent
meta-analyses of the randomized trials that first led to the
approval of the two stents in the first place [2].

For one, they note, the form of treatment offered to patients at the
sites included in the analysis represent "one extreme," with DES
being used as the default stent in all patients, including those
presenting with ACS (59% of patients).

Total length of stented segments and number of stents used per
patient were both higher in the Bern-Rotterdam study (36 mm and two
stents per patient, respectively) than in the pivotal SES and PES
trials, in which mean stent length was 22 mm for both trials and
mean number of stents per patient was 1.4 in the SIRIUS trial and
1.1 in TAXUS IV.

Optimistic overall

Overall, Urban and De Benedetti are upbeat, citing several reasons.
For one, they argue, "better or safer options do not necessarily
exist today."

Moreover, the natural history of coronary artery disease, even in
the setting of optimal secondary-prevention measures, "remains a
greater threat to patients than do the potential events related to
the stented segment of coronary artery," they suggest.

To heartwire, Urban explained that, in his opinion, the unanswered
questions about DES break down into two separate issues. The first,
he stated, is clinical decision making with current-generation
DES: "Who needs one, who can do without . . . and who has a
contraindication to one," based on anticipated poor compliance with
the dual antiplatelet regimen.

The second issue is how to improve upon current DES technology "to
decrease and hopefully eliminate the very real problem of stent
thrombosis and also the need for prolonged antiplatelet treatment,"
he said.

While ongoing randomized controlled trials comparing different DES,
or DES with CABG, may answer some questions, the stent-thrombosis
issue may ultimately be resolved by newer drugs, polymers, or
resorbable stents, Urban and De Benedetti conclude.

But for the time being, Urban confirmed to heartwire that he does,
indeed, "remain optimistic about the future of DES."

"The data that have become available recently--although some
disagreement persists--suggest that the overall risk of mortality
and MI is probably no different for DES and bare-metal stents, even
if late stent thrombosis does appear to be more of a problem with
DES," he said.

The registry data from Bern and Rotterdam reflect higher stent-
thrombosis rates than seen elsewhere, but they also reflect a higher-
risk patient population, Urban observed, a group that other studies,
as well as the FDA advisory panel, acknowledge to be at increased
risk of adverse events, including stent thrombosis.

"All stakes are bound to be higher in such patients," Urban pointed
out. "Focusing only on stent thrombosis is a little like judging a
powerful antibiotic only on the allergic reactions it induces."

Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary
stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents
in routine clinical practice: Data from a large two-institutional
cohort study. Lancet 2007; 369: 667-678.
Urban P, De Benedetti E. Thrombosis: The last frontier of coronary
stenting? Lancet 2007; 369: 619-621.

Although high blood pressure, obesity, diabetes, and high blood
lipids are often thought of as chronic diseases of adults, new
research indicates that individuals who are at increased risk for
developing these conditions can be detected in the first decade of
life -- as early as age 5 in boys and age 8 in girls.

Researchers, led by Dr. Shumei S. Sun from Wright State University
in Kettering, Ohio, and Dr. Gilman D. Grave from the National
Institute of Child Health and Human Development in Bethesda,
Maryland, analyzed serial BP data obtained from age 2 to adulthood
in 240 men and 253 women from the Fels Longitudinal Study.

"Our data indicate that, to remain free of hypertension or the
metabolic syndrome, with or without hypertension, childhood blood
pressures should remain below the 50th percentile for age and
gender," the investigators report in the February issue of
Pediatrics.

They further report that if average systolic BP readings exceed age-
and gender-specific criterion values at any routine checkup from 5
to 15 years of age for boys or from 8 to 18 years of age for girls,
then the child or adolescent is at increased risk of developing the
metabolic syndrome, with or without hypertension, as an adult.

More specifically, if BP exceeded criterion values at a single
office visit in childhood, the odds ratios for developing
hypertension at age 30 or older ranged from 1.1 for 14- to 18-year-
old boys to 3.8 for 5- to 7-year-old boys, and from 2.7 for 8- to 13-
year-old girls to 4.5 for 5- to 7-year-old girls.

The corresponding odds ratios for the metabolic syndrome, with or
without hypertension, ranged from 1.2 for 14- to 18-year-old boys to
2.6 for 8- to 13-year-old boys, and from 1.5 for 14- to 18-year-old
girls to 3.1 for 5- to 7-year-old girls.

In joint comments to Reuters Health, Drs. Sun and Grave said the
findings are important because they imply that "pediatricians and
other healthcare workers who take care of children should be careful
to measure blood pressures at every well-child visit and to take
notice when blood pressures rise above the 50th percentile of
national norms for age and sex."

"Although this level of blood pressure has traditionally been
considered to lie well within the normal range, our findings
indicate that it may signal metabolic trouble later in life," they
stated.

The findings also imply that "lifestyle interventions -- such as
healthier diets and more physical activity -- to prevent the onset
of the 'deadly quartet' of obesity, high blood pressure, high blood
lipids and high blood sugar should begin in childhood, before
lifestyle changes are difficult to implement."

On the other hand, children whose blood pressures remain below the
50th percentile at all their well-child visits "may be given
a 'clean bill of health'," Drs. Sun and Grave concluded. "Their
healthcare workers can trust with high certitude that these children
will remain metabolically healthy as adults and will not run afoul
of the 'deadly quartet'."

Pediatrics 2007;119:237-246

Increased myocardial scar tissue, especially in the area of the left
ventricular (LV) pacing lead, diminishes the response to cardiac
resynchronization therapy (CRT) for ischemic heart failure,
according to a report in the January European Heart Journal.

"Many factors are important for response to CRT," Dr. Jeroen J. Bax
told Reuters Health, "including LV dyssynchrony, location of scar,
extent of scar, venous anatomy, and atrial fibrillation."

Dr. Bax from Leiden University Medical Center, the Netherlands, and
associates investigated the relationship between the extent of
viable myocardium and scar tissue and CRT response in 51 patients
with substantial LV dyssynchrony prior to CRT implantation.

After 6 months of CRT, changes in LV ejection fraction and LV end-
diastolic and end-systolic volume correlated with the number of
viable myocardial segments at baseline and with the total scar
score, the authors report.

Immediately after implantation of the CRT device, the QRS duration
decreased in patients without scar tissue in the target region, but
QRS duration increased in patients with scar tissue, the results
indicate.

Only the group of patients without scar tissue in the target region
showed improvements at 6-month follow-up in NYHA class, 6-minute
walking distance, quality-of-life score, LV function, and LV
dimension, the researchers note.

Among patients with an overall scar score above the median, 33% were
responders to CRT, the report indicates, compared with 88% of
patients having an overall scar score below the median.

Similarly, only 29% of patients with fewer than 10 viable
ventricular segments (out of 17) were responders, the investigators
say, compared with 80% of patients with 10 or more viable segments.

"In these patients, response to CRT is directly related to the
extent of viable myocardium and inversely related to the extent of
scar tissue," the authors conclude. "Evaluation for viability and
scar tissue may be considered in the selection process for CRT."

Eur Heart J 2007;28:33-41

In line with previous findings, acute muscle contraction or exercise
can restore insulin sensitivity in insulin-resistant skeletal
muscle, according to findings from an animal study.

"Because skeletal muscle accounts for 80 to 90% of glucose
disposal," lead investigator Dr. John P. Thyfault told Reuters
Health, "this means that pre-diabetic or type 2 diabetic patients
can aggressively influence blood glucose levels by increasing their
daily physical activity."

The mechanisms by which exercise restores insulin sensitivity are
unknown, Dr. Thyfault explained. "However, our study indicates that
increased mitochondrial energy flux caused by acute exercise may
play a role in the acutely improved insulin sensitivity."

Dr. Thyfault of the University of Missouri, Columbia and colleagues
found that acute contraction restores insulin-stimulated glucose
uptake to normal levels in muscle of obese Zucker rats.

The normalization of insulin action by contraction of muscle was
associated with increased mitochondrial activity and fatty acid
catabolism, they report in the February issue of the American
Journal of Physiology - Cell Physiology.

In turn, these putative changes in mitochondrial energy metabolism
and/or other contraction-induced events appear to circumvent
upstream impairments in insulin signaling.

Thus, concluded Dr. Thyfault, "Daily physical activity or exercise
acutely improves insulin sensitivity in previously insulin-resistant
skeletal muscle."

Am J Physiol Cell Physiol 2007;292:C729-C739

Performing CABG without cardiopulmonary bypass (CPB) support, as
compared with the standard "on-pump" procedure, did not lower the
incidence of cognitive decline or cardiac events over five years in
a randomized trial, one that confirms over the long haul what has
been increasingly clear from shorter-term studies [1]. For the most
part, the latest Octopus Study report suggests, late outcomes are
about the same with one technique as with the other.

Previously in the trial, cognitive performance at three months
seemed as if it might be better after the off-pump procedure, but
even that trend had disappeared by 12 months, observe the
investigators, Dr Diederik van Dijk (University Medical Center
Utrecht, the Netherlands) and associates. Their current analysis,
which appears in the February 21, 2007 issue of the Journal of the
American Medical Association, does away with what had been a
remaining question, whether the patients treated off-pump might do
better in the long run.

"There may be slight differences and advantages to one type of
revascularization over the other in certain cases, but overall the
results are very comparable--it really depends on what kind of
operation the surgeon feels like doing," Dr Frank W Sellke (Beth
Israel Deaconess Medical Center, Boston, MA) told heartwire.

He said the choice of procedure might influence outcomes in only
about 10% of cases. Patients with diffuse or small-vessel coronary
disease or anatomy that calls for a large number of bypasses are
probably better off with CPB support, according to Sellke, who was
lead author of a relevant 2005 American Heart Association position
statement [2] but was not involved in the Octopus Study. Also, for
patients with heavily calcified aortas, some evidence suggests a
lower risk of stroke or cognitive decline after off-pump procedures
that don't rely on aortic clamping; clamp release, Sellke observed,
can release potentially embolic debris.

Their findings don't necessarily apply to everyone undergoing CABG,
especially those with higher-risk features, caution the authors.
They entered only patients getting nonurgent, first-time, isolated
CABG in whom an off-pump procedure was considered technically
feasible. The series represented only 11% of CABG surgeries
performed at the Octopus Study's three centers during the two-year
recruitment period, the group writes. All surgeries in the study
were performed with Medtronic's Octopus cardiac stabilizer system
designed for off-pump "beating-heart" procedures.

Based on the results of standard neuropsychological tests, available
at a mean of 62 months for 123 off-pump and 117 on-pump patients,
the rate of cognitive decline, as defined by standard criteria, was
50.4% in both groups.


According to more restrictive--and, the authors say, more realistic--
criteria that account for natural fluctuations in individual
cognitive performance, the rates were 33.3% and 35.0%, respectively--
also not significantly different. In this analysis, cognitive
decline was independently associated with older age and lower
educational level but not with sex, diabetes, peripheral vascular
disease, hypertension, or number of bypass grafts.

There were no significant differences in all-cause or CV mortality
or rates of stroke, MI, or repeat revascularization; the composite
rate of such events; the rate of recurrent angina; or overall
quality-of-life measures.

Given the similar rates of cognitive decline, the deficits may be
caused by factors unrelated to CPB, "such as anesthesia and the
generalized inflammatory response that is associated with major
surgical procedures," write van Dijk et al. "It is also possible
that the cognitive decline observed at five-year follow-up is not
caused by the operation but reflects natural aging."

According to the report from van Dijk et al, the Octopus cardiac
stabilizer was invented at the University Medical Center Utrecht,
which receives royalties from Medtronic's worldwide sales of the
device. Coauthor Dr Cornelius Borst (University Medical Center
Utrecht) reports having been a consultant with Medtronic and Dr Erik
WL Jansen (University Medical Center Utrecht) reports having been a
member of the company's scientific advisory board. "Medtronic was
not involved in the study," according to the report.

van Dijk D, Spoor M, Hijman R, et al. Cognitive and cardiac outcomes
5 years after off-pump vs on-pump coronary artery bypass graft
surgery. JAMA 2007; 297:701-708.
Sellke FW, DiMaio JM, Caplan LR, et al. Comparing on-pump and off-
pump coronary artery bypass grafting: numerous studies but few
conclusions: a scientific statement from the American Heart
Association council on cardiovascular surgery and anesthesia in
collaboration with the interdisciplinary working group on quality of
care and outcomes research. Circulation 2005; 111:2858-2864.

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition was
studied as an effective strategy for limiting atherosclerosis, but
development of the ACAT inhibitor furthest along in clinical trials,
pactimibe, ceased after preliminary results of the phase 3 ACTIVATE
(ACAT IntraVascular Atherosclerosis Treatment Evaluation) study were
reported in 2005. The detailed results of ACTIVATE, presented at the
2005 AHA meeting[7] and published simultaneously,[8] showed that in
patients with coronary artery disease, pactimibe not only failed to
reduce progression of atherosclerosis progression compared with
usual care, but it also appeared to have proatherogenic effects. In
addition, although not powered for clinical outcomes, ACTIVATE did
not demonstrate any beneficial effect of pactimibe on cardiovascular
events.

As an ACAT inhibitor, pactimibe was believed by its developer,
Daiichi Sankyo (Tokyo, Japan), to be able to make available more
free cholesterol for reverse cholesterol transport, which
theoretically could reduce lipid accumulation within atherosclerotic
lesions. Now, new ACAT inhibitors are being investigated that may
overcome adverse effects and have more beneficial effect than
pactimibe. At the 2006 AHA, preclinical data were presented by Kowa
Co., Ltd. (Tokyo, Japan) on an ACAT-1 inhibitor, K-604.[9] The agent
has been shown to have IC50 values for human ACAT-1 and ACAT-2 of
0.45 and 102.85 micromol/L, respectively, indicating that it is 229-
fold more selective for ACAT-1. In fat-fed hamsters, a dose of ¡Ý 1
mg/kg was shown to suppress fatty streak lesions without affecting
plasma cholesterol levels, providing direct evidence that
pharmacologic inhibition of ACAT-1 in the arterial walls leads to
suppression of atherosclerosis, researchers believe.[10]

The latest study compared the effect of K-604 with that of the
nonselective inhibitor, pactimibe. ACAT1/2 inhibitory activities
were investigated using Chinese hamster ovary cells overexpressing
human ACAT1/2. K-604 potently and selectively inhibited ACAT-1 more
than ACAT-2 with IC50 values of 0.041 and 9.25 micromol/L,
respectively, vs pactimibe with IC50 values of 3.14 and 4.09
micromol/L.

The antiatherosclerotic efficacy of K-604 and pactimibe (both 30 and
100 mg/kg twice daily administered orally for 12 weeks) were
compared in groups of apoE-knockout mice (15 per cohort). Histologic
analysis of the aortic sinus in the K-604-treated mice compared with
control mice revealed a decrease in macrophage-positive area (30%
and 64%, respectively) and an increase in collagen area (46% and
70%, respectively). So differences were seen in the pactimibe-
treated mice compared with the control mice. However, pactimibe
markedly decreased plasma total cholesterol compared with controls
(39% and 74%, respectively).

The long-term antiatherosclerotic effect of K-604 (30 and 100 mg/kg
twice daily administered orally) was investigated over 24 weeks in
groups of high-fat fed apoE-knockout mice (23 per cohort). K-604
dose-dependently reduced the luminal occlusion in the
brachiocephalic artery compared with controls (20% and 41%,
respectively) without affecting the plasma total cholesterol.

Kowa researchers believe that the morphologic and histologic changes
seen in this study suggest that K-604 may be able to stabilize
vulnerable plaque. Phase 1 studies with K-604 are ongoing.

High-density lipoprotein cholesterol (HDL-C) is a potent and
independent epidemiologic risk factor and is a proven
antiatherosclerotic agent in animal models of atherosclerosis,
acting through the principal mechanisms of accelerating cholesterol
efflux and inhibiting oxidation and inflammation. Much research has
focused on drugs that can raise HDL-C levels in humans more
effectively than lifestyle modification or niacin, the drug most
widely used to increase HDL-C. Emerging targets involved in HDL
metabolism have included liver X receptor and peroxisome
proliferator-activated receptor agonists (PPARs), cholesteryl ester
transfer protein (CETP) inhibitors, HDL mimetics, apoA-I mimetic
peptides, and HDL delipidation and reinfusion.

At the time of the AHA meeting, prospects for CETP inhibitors looked
promising. Early phase 3 data for the compound furthest along in
development at the time, the now abandoned torcetrapib, were not
presented as scheduled after the AHA ruled that Pfizer (New York,
NY), the company developing torcetrapib, had broken an embargo by
revealing some of the results in a news release issued before the
meeting. The results of the study showed that torcetrapib
coadministered with atorvastatin in patients with heterozygous
familial hypercholesterolemia (HoFH) raised HDL-C levels and lowered
low-density lipoprotein-cholesterol (LDL-C) levels significantly
more than atorvastatin alone, although the combination was also
associated with a 2-mm Hg increase in systolic blood pressure.[1]
Detailed results were later presented to investment analysts on
November 3, 2006.

Two days later, however, Pfizer announced that development of
torcetrapib had been discontinued after the independent Data Safety
Monitoring Board monitoring the major phase 3 trial ILLUMINATE
(Investigation of Lipid Level Management to Understand its Impact in
Atherosclerotic Events) recommended terminating the study because of
an imbalance of mortality and cardiovascular events.[2] According to
Pfizer, 82 patients taking the torcetrapib/atorvastatin combination
died, compared with 51 deaths in the group of patients taking
atorvastatin alone. Each arm of the study had 7500 patients.

Investigations continue into the reason for the findings that led to
the discontinuation of torcetrapib and data from the recently
completed phase 3 imaging studies, ILLUSTRATE and RADIANCE (Rating
Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor)
will be further examined for evidence as to why torcetrapib was
associated with increased cardiovascular morbidity and mortality.
The results of these studies will be presented at the 2007 Annual
Scientific Session of the American College of Cardiology in New
Orleans, Louisiana, and are expected to shed light on whether the
clinical findings with torcetrapib apply to CETP inhibitors as a
class. Pfizer has other CETP inhibitors in early clinical trials,
and at the time of writing it is not known whether these or CETP
inhibitors being developed by other pharmaceutical companies will
continue.

Apolipoprotein (apoA-I) is the primary protein constituent of HDL;
it defines its size and shape, solubilizes its lipid components,
removes cholesterol from peripheral cells, activates the
lecithin:cholesterol acyltransferase (LCAT) enzyme, and delivers the
resulting cholesterol esters to the liver (reverse cholesterol
transport). ApoA-I also has anti-inflammatory and antioxidant
effects, and modulates vascular function. A number of genetic
variants of apoA-I are known, including apoA-I Milano. A recombinant
apoA-I Milano/phospholipid complex (ETC216; Pfizer) showed
antiatherosclerotic effects in animals and produced significant
regression in coronary atherosclerosis in humans as measured by
intravascular ultrasound (IVUS).[3] However, apoA-I is a large
protein consisting of 243 amino acids, so it is necessary to
administer it intravenously. In addition, manufacture of apoA-I to
date has been difficult and expensive. Research has therefore been
directed toward finding smaller peptide mimetics that produce
similar results to those seen with apoA-I, but that are easier to
manufacture and administer.

D-4F (Bruin; Los Angeles, California) is an 18-amino-acid peptide
comprised only of D-amino acids, thus resisting degradation by
mammalian gastrointestinal enzymes and allowing oral administration.
(Its name refers to the D-amino acids and the 4 phenylalanines
contained in the compound.) It was shown in vitro to promote
macrophage efflux, bind and sequester fatty acid hydroperoxides and
proinflammatory oxidized phospholipids, and to be highly
antiatherogenic in mouse models.[4,5] These studies suggested that D-
4F could theoretically be clinically useful. From animal studies, it
appeared that type of lesion and time of initiation of this therapy
would be important in achieving its beneficial effects.

At the meeting, Daniel Rader, MD (University of Pennsylvania School
of Medicine, Philadelphia), presented the results of a double-blind,
placebo-controlled, phase 1 study that evaluated the safety,
tolerability, pharmacokinetics, and pharmacodynamics of a single
oral dose of D-4F or matching placebo in patients with coronary
heart disease (CHD).[6] The study showed that a single oral dose of
D-4F is absorbed and well tolerated. Bioavailability of D-4F is low,
but improved when food is delayed for 2 hours post dose. An
important incidental observation was that HDL anti-inflammatory
function improved significantly after a single dose of D-4F.

The trial enrolled men and postmenopausal women aged 21-75 years
with stable CHD or CHD equivalent status as defined by National
Cholesterol Education Program (NCEP). Subjects had to have been
stable for > 4 weeks on a regimen of statin therapy. Overall, a
total of 36 men and 14 women, average age 60 years, overweight, with
average body mass index 31.3 kg/m2 were recruited. Sixteen had CHD,
35 subjects had type 2 diabetes, and 6 subjects had other
atherosclerotic cardiovascular diseases; 2subjects had > 20% CHD
risk.

Ten subjects per dose group were randomized to D-4F 30 mg, 100 mg,
300 mg, or 500 mg diluted in 30 mL of 25% sucrose-water solution or
matching placebo (8 patients on D-4F, 2 on placebo in each group).
Treatments were given after ¡Ý 12 hours of fasting and ¡Ý 2 hours
before a meal or any concomitant medications; in the 500-mg subgroup
given food to improve bioavailability, treatment was given within 10
minutes prior to a standardized AHA-approved low-fat breakfast. In
all cases the subjects fasted for 2 hours after study drug
administration, with the exception of the 10 subjects receiving 500
mg or matching placebo with a standardized meal. Blood samples were
taken at 0, 15, and 30 minutes, and at 1, 2, 4, 6, 8, and 24 hours
after each single dose of D-4F. Safety measures were made at Days 2,
7, 14, and 28.

Investigators found that D-4F was detectable in plasma at each dose
with a Tmax of 30 minutes, 1 hour, and 2 hours in subjects treated
with 30, 100, and ¡Ý 300 mg, respectively. The AUC(0-t was 27.81
ng*h/mL and 54.71 ng*h/mL for the 300- and 500-mg dose groups,
respectively, and 17.96 ng*h/mL for the 500-mg dose given with food
(P = .06 for 500 mg fed vs fasting).

There were no clinically significant changes in clinical or
laboratory safety parameters measured. Among all subjects, 42%
experienced an adverse event, The most common adverse events were
seasonal allergies (9.5%). Three adverse events were considered to
be possibly treatment related. No serious adverse events were
recorded.

There were no changes in plasma HDL-C (data not presented) and no
significant changes in apoA-I levels vs placebo over 24 hours.

The effect of a single administration of D-4F on HDL function was
measured using the monocyte chemotaxis assay. This cell-based assay
measures monocyte chemotactic activity generated in an artery wall
cell coculture by a standard control LDL in the absence and presence
of the test HDL. The monocyte chemotactic activity determined in the
absence of the test HDL is normalized to 1.0. The value obtained
when the test HDL is added is then compared with the monocyte
chemotactic activity in the absence of HDL. If the value after
adding the test HDL is greater (ie, HDL inflammatory index > 1.0),
the test HDL is classified as proinflammatory. If the value obtained
after addition of the test HDL is less (ie, HDL inflammatory index <
1.0), the HDL is classified as anti-inflammatory. Thirty of the 40
study subjects were found to have proinflammatory HDL despite all
being on stable statin therapy.

Administration of D-4F resulted in a significant improvement in the
HDL anti-inflammatory index at 2, 4, and 8 hours compared with
baseline (P < .01 for all time points), whereas the placebo group
showed no significant change. At 4 hours, the improvement in HDL
inflammatory index was significant compared with the placebo group
(P = .02). By 24 hours, it had returned to baseline. These results
suggest that even a single dose of D-4F improved the HDL anti-
inflammatory function in these subjects. HDL inflammatory index was
even seen to improve in a group of subjects with nondetectable
plasma D-4F. "It is possible that D-4F is doing something there,
even though it is not detectable on the assay," Dr. Rader said. He
noted that the maximal anti-inflammatory effect occurred at the
maximal plasma concentration, indicating that there may be a
relationship between plasma concentration and effect on HDL function.

"The general concept is that D-4F is not an HDL-raising approach,
but it is allowing HDL to be more functional," Dr. Rader explained.

Exact plans for further development of D-4F "are not exactly sure,"
according to Dr. Rader. "I think the concept of applying it to the
acute setting, as has been suggested for apoA-I Milano and other
synthetic HDL-type therapies, could make sense," he suggested.

In 2005, Novartis (Basel, Switzerland) reported that it had licensed
D-4F from Bruin. Novartis has said that the drug, designated APP018,
is in exploratory phase 1 studies and that regulatory filing would
not be expected before 2010.

Inhibition of microsomal triglyceride transfer protein (MTP) was
identified as a promising approach to reducing low-density
lipoprotein cholesterol (LDL-C) some years ago. MTP mediates
triglyceride absorption and chylomicron secretion from the intestine
and very-low-density lipoprotein (VLDL) secretion from the liver by
linking lipid molecules with apolipoprotein B (apoB).[1] Inhibition
of MTP reduces the level of all apoB-containing lipoproteins,
including LDL. Several classes of MTP inhibitors identified as
effective in vitro and in vivo reached clinical trials and were
shown to be effective at lowering LDL-C in humans. However, their
use was associated with a high incidence of adverse events,
particularly hepatic and gastrointestinal (GI), including fatty
liver. As a result, clinical development of most MTP inhibitors
ceased at or before phase IIa of study.

Recently, MTP inhibitors have started to re-enter clinical studies,
at doses or in formulations aimed at utilizing their efficacy but
avoiding their side effects. At the American Heart Association (AHA)
2006 Annual Scientific Session held in Chicago, Illinois, the
results of early clinical trials with 2 of these drugs were
presented. The first is a novel formulation of a small-molecule MTP
inhibitor and the second is an MTP inhibitor that was previously
abandoned in clinical trials, but is now being tested at lower,
potentially nontoxic doses in combination with a cholesterol
absorption inhibitor.

SLx-4090 is a novel, orally administered MTP inhibitor that is being
developed by Surface Logix (Brighton, Massachusetts) for the
treatment of dyslipidemia and familial hypercholesterolemia. SLx-
4090 is a potent, small-molecule inhibitor of MTP that has been
designed to act selectively in the enterocytes lining the GI tract.
It prevents the formation of chylomicrons which are used to
transport triglyceride and cholesterol into the systemic
circulation. The novelty of SLx-4090 is that it is selective for
enterocytes and is not absorbed into the systemic circulation, and
thus allows activity against fat uptake while avoiding toxicity at
other sites of MTP expression including the liver, heart, testis,
ovary, and eye.

In preclinical studies, SLx-4090 was compared with a potent,
selective, systemically available MTP inhibitor that failed
development at phase 2. Animal studies were used to investigate the
effects of acute dosing on postprandial triglyceride levels and of
chronic dosing on fasting triglyceride levels. SLx-4090 had similar
efficacy to the control compound, producing significant reductions
in both postprandial and fasting triglyceride levels. At efficacious
doses, no SLx-4090 was detected in plasma after 6 weeks of
treatment. Compared with the control drug, there was no buildup of
fat in the liver and no increase in the levels of liver enzymes
(alanine aminotransferase [ALT] and aspartate aminotransferase
[AST]). No toxicity was seen in animals in single doses up to 2000
mg/kg and on chronic dosing up to 500 mg/kg in dogs and 1000 mg/kg
in rats.

At a special session at this year's AHA featuring novel therapies
and first human-use trials, results from 2 phase 1 studies of SLx-
4090 in humans were presented by William Prince, MB ChB, PhD, Chief
Development Officer at Surface Logix.[2] The results from these
studies confirmed that SLx-4090 is well tolerated and is a potent
inhibitor of MTP, lowering triglycerides and LDL-C while raising
levels of high-density lipoprotein cholesterol (HDL-C) with chronic
dosing. SLx-4090 was not detectable in human plasma.

Phase 1A Study
The initial phase 1 trial indicated that SLx-4090 was well
tolerated, with no serious adverse events, and demonstrated a
significant impact (> 60%) on lowering triglyceride levels compared
with placebo.[2] The single-center, randomized, double-blind,
placebo- controlled, escalating single-dose study was carried out in
3 cohorts of 8 healthy male volunteers (total of 24 patients; age 18-
55 years, body mass index [BMI] 19-30 kg/m2) who were assigned to
the following doses (with 2 placebo and 6 active doses at each
session):

Group 1: placebo, SLx-4090 at 5, 10, and 50 mg


Group 2: placebo, SLx-4090 at 100, 200, and 300 mg


Group 3: placebo, SLx-4090 at 400, 600, and 800 mg
The mean age of the men in the study was 40 years; mean BMI was 25
kg/m2 with average baseline triglycerides 80-100 mg/dL.

Pharmacokinetic and pharmacodynamic sampling was performed out to 24
hours post-dose to measure plasma lipid and lipoprotein
concentrations after dietary consumption. In Groups 1 and 2, SLx-
4090 was followed by a meal (containing about 33% fat) at 4 hours
post dose, but in Group 3, SLx-4090 was dosed immediately before
breakfast (0 hours). Safety and tolerability were assessed by vital
signs, adverse events, and clinical chemistry and hematology.

In Group 3, single 400-mg and 800-mg doses of SLx-4090 effectively
reduced postprandial increases in triglycerides. After single doses
of 400 and 800 mg, the mean maximal percentage increase over
baseline in postprandial triglycerides was less than half of that
seen with placebo. The difference at 4, 5, 6, and 7 hours post dose
was significant at 4 hours for 600 mg and 800 mg (P < .03) --
  "impressive in this small number of subjects," Dr. Prince commented.

No adverse events were reported following the 5, 10, 50, 100, 200,
or 800 mg of SLx-4090. Eight of 13 adverse events were reported by 1
subject on placebo, SLx-4090 at 400 mg or 600 mg (Table 1). No
flatulence was reported at doses of 600 or 800 mg. In addition, no
SLx-4090 was detected in plasma samples at any dose at a lower limit
of quantitation (LOQ) of 10 ng/mL.

Phase 1b Study
On the basis of the results of the phase 1a study, SLx-4090 was
advanced into a phase 1b repeat-dose study to investigate safety and
tolerability, including bowel movement frequency and stool reports.
[2] Pharmacokinetics, pharmacodynamics, and lipid profiles were
secondary objectives. The study began in August 2006 and was
scheduled to be completed by December 2006. According to Dr. Prince,
the initial results confirmed the profile seen in the first study.

This randomized, double-blind, placebo-controlled, dose-escalating
study involved 4 cohorts of 12 healthy men aged 18-55 years. All
subjects received placebo on Day 1. On Days 2-15, 3 subjects in each
cohort remained on placebo and 9 started on active treatment with
SLx-4090 at an initial dose of 50 mg 3 times daily (TID), rising to
100 and 200 mg TID, given with meals at 0800, 1200, and 1800 hours.
On most days, subjects received a breakfast of normal fat content
(about 35%), but on Day 6 they had a low-fat breakfast and on Day 10
a high-fat breakfast.

Similar reductions in postprandial triglyceride elevations after the
first dose, after lunch, and after the evening meal were seen with
50-mg and 200-mg doses of SLx-4090 compared with placebo. A 50%
reduction in postprandial triglycerides, as calculated by the AUC0-
24h, was seen with doses of both 50 mg and 200 mg.

After the high-fat meal and a greater postprandial rise in
triglycerides, the 100-mg dose of SLx-4090 produced a substantial
reduction in postprandial rise in triglycerides, greater than that
seen with a normal meal. "It is encouraging that this drug works
with a normal meal, a low fat meal [data not presented], and after a
high fat challenge," Dr. Prince said.

At the time of the presentation, adverse events had not been fully
analyzed, since the study was still ongoing; however, no adverse
events related to the bowel had been reported with the 50- and 100-
mg doses over the 14 days of administration. Some bowel effects have
been seen at 200 mg, but these have not been sufficient to justify
discontinuing treatment, Dr. Prince reported. Early results [not
presented] also showed a reduction in LDL-C and an increase in
HDL/LDL ratio, "which is very encouraging and supports data from
earlier animal studies," Dr. Prince commented.

Dr. Prince noted that because of the initial results showing the
efficacy of the lower dose, the 100- and 200-mg doses of SLx-4090
are no longer being used.

"It is exciting that this novel compound performed so well in this
phase 1 study," commented Dr. Prince. He noted that, as was
consistent with his preclinical results, "no drug was detected in
the plasma at doses up to 800 mg and no adverse events occurred that
were distinguishable from placebo. This is particularly notable, as
it has historically been difficult to design an MTP inhibitor that
acts selectively in the GI tract with no adverse impact on liver or
liver function."

Commenting on SLx-4090 Studies
Dr. Prince and his colleagues believe that they have proved the
concept of an MTP inhibitor that was nonbioavailable, nontoxic, and
efficacious. SLx-4090 is being taken further into clinical studies
looking at various lipid disorders. Phase 2a studies directed at
patients with dyslipidemia complicated by high triglyceride levels
are scheduled to begin early in 2007.

"Based on the impact of SLx-4090 in lowering LDL cholesterol and
raising HDL cholesterol in preclinical studies, we strongly believe
that a safe, efficacious, enterocyte-specific MTP inhibitor could
play a significant role by providing clinicians another route to
manage lipid disorders for patients who do not respond to currently
available treatment options," Dr. Prince predicted.

Speaking as the AHA-designated discussant for this study, Daniel
Rader, MD (University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania) commented that these studies
showed "very nicely" that, in humans, SLx-4090 was not absorbed and
therefore not detectable in plasma and that it "blunted, but did not
eliminate increases in triglycerides after dietary fat challenge,
without major GI-related side effects with 2 weeks of
administration, as expected by mechanism of action." Dr. Rader
concluded that intestinal-specific MTP inhibition is likely to be an
effective treatment for severe hyperchylomicronemia and predicted
that it may also improve other plasma lipids. "It may reduce LDL
cholesterol by decreasing intestinal cholesterol absorption," he
proposed, and "theoretically it could raise HDL cholesterol by
reducing postprandial intestinal lipoproteins." This needs further
study, he noted.

Dr. Rader cautioned that intestinal-specific MTP inhibition may not
reduce LDL-C or increase HDL-C substantially, as it might be
primarily focused on the intestinal chylomicrons. He also warned
about adverse GI-related effects: "I still think the potential is
there to cause fat malabsorption and steatorrhea. It will be very
important to confirm the therapeutic window," he stressed.

Intestinal-specific therapeutic approaches using small molecules
that are not absorbed but act specifically on the enterocyte may
have potential as other types of novel therapies, Dr. Rader
suggested. "The intestine is a major source of HDL biosynthesis, and
small molecules that are not absorbed but act to upregulate
apolipoprotein A-I (apoA-I) or acyl-coenzyme A:cholesterol
acyltransferase-1 (ACAT1) in the intestine could be very
interesting, novel approaches to raising HDL biosynthesis and
increasing levels of HDL cholesterol," he theorized. "I would love
to see this concept further developed," he added.

Dr. Rader also pointed out that the reduction in fat absorption
produced by SLx-4090 could result in weight loss. Surface Logix has
said that it is already exploring the potential of SLx-4090 in both
obesity and diabetes.

AEGR-733: Clinical Investigation Into Drug in New Combination Resumed
AEGR-733 is an MTP inhibitor that in prior studies showed positive
efficacy data but appeared to have dose-limiting side effects.
Originally designed and synthesized as BMS-201038 by Bristol-Myers
Squibb (New York, NY), the drug was shown in a rat model of
hypertriglyceridemia to decrease plasma triglycerides and VLDL by
approximately the same degree as atorvastatin.[3] However, it also
produced elevations in liver enzymes (AST and ALT) sufficiently high
to halt development in 2001.

Now being developed as AEGR-733 by Aegerion (Bridgewater, New
Jersey), it is being investigated at a lower dose that the company
believes will produce clinically meaningful LDL-C lowering while
minimizing hepatic and GI adverse effects. AEGR-733 is being
developed in combination with other nonstatin lipid-lowering
therapies to be used in patients who cannot tolerate or who do not
respond sufficiently to statin therapy.

Interim results from an ongoing phase 2 clinical trial of AEGR-733,
alone and in combination with the cholesterol absorption inhibitor
ezetimibe, were presented at the meeting by Fredrick F. Samaha, MD
(University of Pennsylvania School of Medicine) and colleagues.[4]
To date, the study shows that low-dose MTP inhibition with AEGR-733
monotherapy provides clinically significant reductions in LDL-C and
that AEGR-733 has additive LDL-C lowering efficacy when combined
with ezetimibe. According to Dr. Samaha and colleagues, low-dose
AEGR-733 plus ezetimibe provides > 30% reduction in LDL-C and
therefore may play an important role in the management of
hyperlipidemic statin-intolerant patients.

The prospective, double-blind, active controlled, multicenter,
randomized trial enrolled men and women aged 18-70 years (mean age
55 years) with baseline LDL-C 130-250 mg/dL and baseline
triglyceride levels < 400 mg/dL. All patients on prior lipid-
lowering therapies were washed out 4 weeks prior to randomization.
After a ¡Ý 2-week low-fat diet run-in period, patients were
randomized to 1 of 3 arms: (1) AEGR-733 alone, (2) ezetimibe 10 mg
alone, or (3) AEGR-733 plus ezetimibe 10 mg. Patients randomized to
AEGR-733 alone or in combination were treated initially with 5 mg
for 4 weeks and then force-titrated to 7.5 mg for 4 weeks, followed
by an additional 4 weeks at 10 mg for a total of 12 weeks of
treatment. Patients randomized to ezetimibe received 10 mg over the
entire 12 weeks of treatment. A total of 84 patients (mean age 55
years, baseline LDL-C 164-169 mg/dL) were randomized in the study.

The study included a prespecified interim analysis of AEGR-733 doses
of 5 mg and 7.5 mg to guide starting doses for development of future
trials. This analysis showed that the effects of AEGR-733 and
ezetimibe on LDL-C, the primary efficacy endpoint of the study,
appeared to be additive. Compared with reductions of 19.9% and 18.6%
with ezetimibe and AEGR 733 monotherapy, respectively, patients
treated with a combination of 10 mg of ezetimibe and 5 mg of AEGR-
733 achieved an LDL-C reduction of 34.5% after 4 weeks.

Over the next 4 weeks, when the dose of AEGR-733 was increased to
7.5 mg, similar results were seen to those in the first 4 weeks,
with additive effects of AEGR-733 and ezetimibe significantly
greater than that of ezetimibe alone.

Secondary efficacy endpoints included changes in total cholesterol,
triglycerides, non-HDL-C, and HDL-C. Similar decreases seen in the 2
monotherapy groups for total cholesterol, non-HDL-C, and apoB over 0-
4 weeks appeared to be additive with combination therapy. A modest
decrease in HDL-C was seen only in the patients on AEGR-733, not
ezetimibe, at 0-4 weeks, with greater reduction in HDL-C over 4-8
weeks. "We do not know why the HDL cholesterol decreases with MTP
inhibition," Dr. Samaha admitted. On the basis of findings from
prior studies, it does not appear to be an effect on apoA
production, he noted. "Levels decreased in this study with MTP
inhibitor, but we do not know whether it is a reflection of
increased catabolism or increased uptake," he said. "This is an area
that requires further investigation."

No significant effects on triglycerides were seen in any of the 3
treatment strategy groups at 0-4 weeks. At 4-8 weeks, larger
reductions in triglycerides occurred in patients receiving the MTP
inhibitor, but little change was seen with ezetimibe.

All adverse events were captured and the GI symptom rating scale was
used to quantify GI-related side effects. Of the total, 75%-85% of
the subjects tolerated short-term treatment with AEGR-733. More
adverse events were reported in patients on the MTP inhibitor alone
or in combination, primarily attributable to transaminase elevations
(11%-18% of patients on AEGR-733 vs 4% of patients on ezetimibe).
All patients except 1 experienced transaminase level elevations 2-3
¡Á the upper limit of normal (ULN). One patient experienced a 5 ¡Á ULN
transaminase elevation and the therapy was discontinued after 2
sequential transaminase elevations. No bilirubin elevations were
reported. Dr. Samaha observed that transaminase elevations occurred
early in the majority of patients, during initial exposure to AEGR-
733, "so this is clearly dose response effect," he said.

There were no significant differences between treatment groups with
regard to adverse events in rates of muscle- or GI-related side
effects, all of which were rare, Dr. Samaha reported. Among the
patients who received ¡Ý 1 dose of study drug, a slightly higher
number of patients had to discontinue AEGR-733 monotherapy compared
with ezetimibe alone, but there were no significant differences for
the 2-drug combination. Most of the study drug discontinuations for
the MTP inhibitor were related to transaminase elevations.

"These results are a demonstration of the potential broad
applicability of AEGR-733 in treatment as a monotherapy and in
combination with current lipid lowering therapies," Dr. Samaha
commented. "There is a clear unmet medical need in the management of
hypercholesterolemia and this class of compounds, known as MTP-
inhibitors, has the potential to play an important role as treatment
patterns continue to evolve in the direction of combination therapy."

Final study results of this trial are expected in the first quarter
of 2007. Aegerion plans to initiate additional phase 2 trials in
early 2007. One will examine the LDL-C-lowering efficacy of various
doses of AEGR 733 given in combination with atorvastatin vs the
agents used as monotherapy. Another study will be conducted in 50
healthy volunteers given an initial dose of 1 of 5 US Food and Drug
Administration (FDA)-approved lipid-lowering therapies followed by a
7-day period on AEGR-733. On study Day 8, subjects will receive the
second oral dose of the same lipid-lowering medication that was
given on Day 1 and a last dose of AEGR-733. The FDA-approved lipid-
lowering therapies used in the study will be atorvastatin 20 mg,
ezetimibe 10 mg, simvastatin 20 mg, pravastatin 20 mg, and
micronized fenofibrate 145 mg, each given to 10 subjects.

Aegerion has recently licensed a second MTP inhibitor compound,
implitapide, and plans to begin additional phase 2 testing in 2007.
Implitapide was originally developed by Bayer (Leverkusen, Germany)
and reached phase 3 before development was finally discontinued.
Aegerion also has an agreement with Pfizer (New York, NY) and the
University of Pennsylvania under which Aegerion may develop other
MTP-based therapies.

The latest round of randomized clinical trials established the
principle that the target level for low-density lipoprotein
cholesterol (LDL-C) should be lower than previously thought and
endorsed in the guidelines, on the order of 70 mg/dL instead of 100
mg/dL. However, a large proportion of patients with elevated LDL-C
fail to achieve a target of < 70 mg/dL, despite being on optimum
statin therapy or sometimes because they are statin intolerant. A
number of other therapeutic options are available for combination
therapy with a statin, such as ezetimibe, nicotinic acid, fibrates,
and bile acid sequestrants, and clinical experience with these
combinations continues to be reported. Despite these current
treatment options, however, research continues with the aim of
identifying and testing other LDL-C-lowering therapies with greater
effect. As reviewed below, several presentations at the American
Heart Association (AHA) 2006 Annual Scientific Session highlighted
the latest research in this burgeoning area.

Squalene synthase inhibitors are believed to have potential
advantages over statins, which inhibit 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase. HMG-CoA catalyzes the conversion of
HMG-CoA to mevalonate and thus serves as the primary rate-limiting
enzyme in the hepatic biosynthesis of cholesterol. Squalene synthase
acts downstream of mevalonate, catalyzing the dimerization of
farnesyl-pyrophosphate to squalene. This is the first step in the
cholesterol biosynthetic pathway that is solely committed to the
production of cholesterol, and researchers believe that blockade at
this site may avoid the effects associated with decreased formation
of isoprenolated intermediates and metabolites in the pathway beyond
HMG-CoA reductase.[1]

Squalene synthase inhibitors have been studied for number of years
but did not previously progress beyond early clinical studies. Now a
drug in this class has reached phase 3 clinical trials. First proof-
of-concept clinical data on lapaquistat acetate (lapaquistat; TAK-
475) alone and in combination with atorvastatin in patients with
hyperlipidemia were presented at the AHA meeting by researchers from
Takeda (Tokyo, Japan), the company developing lapaquistat worldwide.

Preclinical studies showed that lapaquistat and its 2 active
metabolites, M-I and M-II, are biologically active and in both in
vitro and in vivo models demonstrate inhibition of de novo
cholesterol synthesis and subsequent upregulation of LDL receptor
mRNA expression. Inhibition of hepatic triglyceride synthesis was
also seen in these models.[1] Early pharmacokinetics showed that the
drug is rapidly absorbed following oral dosing, metabolized
hepatically, and the metabolites are subsequently excreted in the
feces. The pharmacokinetics are compatible with once-daily dosing.
Early studies in healthy subjects showed that lapaquistat produced
reductions in LDL-C.

Lapaquistat Monotherapy
At the AHA meeting, Piper and colleagues, from Takeda Global
Research and Development Centre (Europe) in London (UK), reported
the results of a phase 2 study that evaluated different doses of
lapaquistat compared with atorvastatin in patients with primary
hypercholesterolemia.[2] Lapaquistat produced significant reductions
in LDL-C, total cholesterol, and apolipoprotein B (apoB), although
these reductions were not as great as seen with atorvastatin. Unlike
atorvastatin, however, significant increases were seen in high-
density lipoprotein cholesterol (HDL-C) at higher doses of
lapaquistat.

This randomized, double-blind, placebo and actively controlled,
parallel-group study was conducted in subjects with LDL-C levels ¡Ý
130 mg/dL and ¡Ü 210 mg/dL, with mean triglyceride levels ¡Ü 350
mg/dL. Patients were not taking other lipid-lowering drugs and had
no history of cardiovascular disease or diabetes. After 6 weeks of
following a standardized National Cholesterol Education Program
(NCEP) diet, 321 patients (60% male, 99% white, mean age 53.2 years)
whose LDL-C remained elevated were randomized to 1 of 5 once-daily
treatments:

Lapaquistat 25 mg;
Lapaquistat 50 mg;
Lapaquistat 100 mg;
Atorvastatin 10 mg; or
Placebo.
Treatment was given over 8 weeks, with 2-week follow up.

Baseline LDL-C levels were similar in all treatment groups (mean
160.7 mg/dL). At the end of treatment, a dose-response effect was
seen for lapaquistat on LDL-C levels, the primary efficacy endpoint,
with significant decreases vs placebo (P < .001) for all lapaquistat
doses (Table 1). Atorvastatin produced the greatest reduction in LDL-
C.

In addition, statistically significant changes were seen in
secondary lipid parameters with all lapaquistat doses, with the
greatest responses associated with the 100-mg dose and with
atorvastatin. HDL-C increased with all doses of lapaquistat, and at
the 50-mg and 100-mg doses, the increases were significant and
greater than that produced by atorvastatin.

Overall, the tolerability and safety profile of lapaquistat were
similar to those of atorvastatin and placebo. The researchers
reported that:

There were no deaths during the treatment or follow-up periods.

The most frequently reported adverse events in all the groups were
headache and back pain.

The withdrawal rate due to adverse events was low, only 4 subjects
(1 on placebo and 1 in each of the lapaquistat groups).

No pattern of treatment-emergent events emerged for lapaquistat,
atorvastatin, or placebo and none of the adverse events reported
appeared to be dose related when comparing the lapaquistat cohorts.

There were no differences in blood pressure, electrocardiogram, or
weight change between groups.

Raised levels of creatine kinase and liver enzymes, alanine
aminotransferase (ALT), and aspartate aminotransferase (AST), were
seen in 1 patient each on lapaquistat 100 mg; both of these
increases were transient and resolved without treatment.
Combination Therapy With Atorvastatin
Researchers believe that the novel mechanism of action of
lapaquistat has potential in combination therapy for hyperlipidemic
patients, and another phase 2 study of the addition of lapaquistat
to stable atorvastatin therapy in patients with primary
hypercholesterolemia was presented by researchers from Takeda North
America (Lincolnshire, Illinois).[3] A total of 172 patients with
LDL-C > 100 mg/dL after 4 weeks of treatment with atorvastatin (10
or 20 mg) were randomized to additional treatment with lapaquistat
100 mg or placebo for an additional 6 weeks.

In the patients who took additional lapaquistat, a further reduction
in LDL-C was seen within 2 weeks of randomization that persisted for
the duration of the study. No change in LDL-C was seen in the
patients on additional placebo. At the last visit, LDL-C was reduced
by 19.1% in subjects on atorvastatin plus lapaquistat compared with
an increase of 0.7% for atorvastatin plus placebo (P < .001) (Table
2). Significant decreases from baseline (P < .05) compared with
placebo were also seen in total cholesterol, triglycerides, and apoB
with additional lapaquistat. HDL-C increased slightly in both the
lapaquistat and placebo groups (1.4% and 1.6%, respectively).

Lapaquistat was well tolerated; most side effects were mild or
moderate and not considered related to the study drug. There were no
deaths (13% placebo, 20% lapaquistat + atorvastatin), serious
adverse events considered related to study drug, or changes in liver
enzymes. The most frequent adverse events in both groups were
nasopharyngitis, back pain, and arthralgia.

The data from these 2 studies provide evidence to support continued
investigation of lapaquistat. The phase 3 clinical trial program is
ongoing in > 7000 dyslipidemic patients in Australia, Canada,
Europe, South Africa, South America, and the United States. The
placebo-controlled studies in patients with primary
hypercholesterolemia include a US study of lapaquistat vs placebo,
and multicenter studies comparing lapaquistat vs simvastatin alone
or in combination, vs ezetimibe, and as add-on in patients already
on atorvastatin, rosuvastatin, or a high-dose statin. Lapaquistat
will also be investigated as add-on treatment to already treated
patients with homozygous familial hypercholesterolemia, and in
patients with type 2 diabetes.

Population-based studies have shown that microvascular disease in
diabetic patients can predict CVD not only in type 1 but also in
type 2 diabetes and even in nondiabetic subjects. This association
may be stronger in women, but no studies have clearly shown a
difference in the association between retinopathy and cardiovascular
mortality between the sexes.

The current trial is an 18-year, population-based cohort study
conducted in one country, in patients with type 2 diabetes to
examine the value of 3 categories of retinopathy in predicting CHD,
CVD, and all-cause mortality in men and women with diabetes.

Study Highlights

Included were Finnish men and women 45 to 64 years old with type 2
diabetes identified through a national drug reimbursement register.
Excluded were those with type 1 diabetes or prior CVD (myocardial
infarction, stroke, or peripheral vascular disease).
The final population for analysis included 425 men and 399 women
with baseline ophthalmoscopic examination documented.
All baseline laboratory specimens were taken after a 12-hour fast at
0800 hours.
Ophthalmoscopic examination was performed after pharmacologic
dilatation of pupils by 2 experienced diabetologists.
Fundoscopic findings were classified as "no
retinopathy," "background retinopathy" (microaneurysms,
microinfarcts, hard exudates, or hemorrhages), and "proliferative
retinopathy" (neovascularization or previous laser coagulation).
Death was ascertained using the death register and copies of death
certificates. Hospital records and autopsy reports were also used.
Primary outcomes were mortality (all-cause, CVD, and CHD) using the
International Classification of Diseases, Ninth Edition, codes.
At baseline, mean age was 57 years, mean glycated hemoglobin level
was 10%, and mean duration of diabetes varied from 7 to 13 years.
15% to 29% of men were current smokers compared with 4% to 10% of
women.
Overall, men with retinopathy smoked less, received insulin more
frequently, were leaner, and had higher high-density lipoprotein
cholesterol, lower triglycerides, higher urinary proteins, and
longer duration of diabetes.
Women with retinopathy received insulin more frequently, had higher
systolic blood pressure, higher urinary protein, and longer duration
of diabetes.
During 18 years of follow-up, 67.5% of men and 67.9% of women died,
and of those who died, 61.7% of men and 67.5% of women died of CVD,
and 46.3% of men and 45.0% of women died of CHD.
Event rates for men were 32, 32, and 65 per 1000 person-years for no
retinopathy, background retinopathy, and proliferative retinopathy,
respectively.
Event rates for the same categories of retinopathy in women were 33,
51, and 98 per 1000 person-years of follow-up, respectively.
Adjusted Cox model HRs of all-cause, CVD, and CHD mortality in men
were 1.34, 1.30, and 1.18, respectively, for background retinopathy
and 3.05, 3.32, and 2.54 for proliferative retinopathy,
respectively.
Adjusted HRs for women were 1.61, 1.71, and 1.79, respectively, for
background retinopathy and 2.92, 3.17, and 4.98, respectively, for
proliferative retinopathy.
Background retinopathy had an impact on CVD mortality in women but
not in men.
The impact of proliferative retinopathy was similar in both sexes,
but in women, the association was dramatically seen earlier, in the
first half of the follow-up period.
The association between retinopathy and mortality was independent of
conventional CVD risk factors such as family history and also of
glycemic control, duration of diabetes, and proteinuria.

Pearls

In women with type 2 diabetes, background and proliferative
retinopathy both predict all-cause, CVD, and CHD mortality, and the
effect is seen within 10 years.
In men with type 2 diabetes, only proliferative retinopathy predicts
all-cause, CVD, and CHD mortality.

VHD is a common medical condition. In recent years, the patient
population with VHD has changed because a better understanding of
its pathophysiology exists. Also, the incidence of rheumatic valve
disease has declined in industrialized countries because of the
development of streptococcus infection prophylaxis. However, the
increase in life expectancy has caused degenerative valve disease to
become more prevalent. And, the 2 most frequent valvular diseases
are calcific AS and mitral regurgitation (MR). Diagnosis of VHD
remains dominated by echocardiography. The treatment of VHD is
complex and must be individualized according to each valvular
disease. Therefore, the European Society of Cardiology published
these comprehensive practice guidelines to help clinicians manage
this challenging disorder.

Study Highlights

A clinical examination detects VHD in asymptomatic patients; an
electrocardiogram and chest x-ray is usually obtained, with
echocardiography as the key technique to confirm the diagnosis of
VHD and to assess its severity and prognosis.
Treatment of VHD usually involves surgical valve replacement, and
each incidence of VHD has its own indications.
Aortic regurgitation (AR)
Surgical intervention indications include symptomatic patients;
asymptomatic patient with resting left ventricular ejection fraction
(LVEF) of ¡Ü 50%; patients undergoing coronary artery bypass graft
surgery (CABG) or surgery of ascending aorta, or on another valve;
asymptomatic patients with resting LVEF > 50% with severe left
ventricular (LV) dilatation; patients who have aortic root disease
with maximal aortic diameter valve ¡Ý 55 mm for most patients.
Medical therapy includes nitroprusside and inotropic agents prior to
surgery in patients with poorly tolerated acute AR; in patients with
chronic severe AR and heart failure, angiotensin-converting enzyme
(ACE) inhibitors are the treatment of choice when surgery is
contraindicated.
In asymptomatic patients with high blood pressure, the use of
vasodilators such as ACE-inhibitors or dihydropyridine calcium
channel blockers is warranted.
AS
Surgical indications include patients with severe AS and any
symptom; patients with moderate to severe AS undergoing CABG or
surgery of ascending aorta, or on another valve; patients with
symptoms or signs of LV dysfunction.
Asymptomatic patients with severe AS are only recommended in select
patients at low operative risk (eg, those with a blend of calcified
valve with rapid increase in peak aortic velocity of ¡Ý 0.3 m/second
per year).
Nonsurgical candidates may be treated with digitalis, diuretics, ACE-
inhibitors, or angiotensin-receptor blockers if they are
experiencing heart failure.
MR
Urgent surgery is indicated in symptomatic patients with acute MR;
surgery is indicated in asymptomatic patients with severe LV
dysfunction (end systolic dimension, > 45 mm and/or LVEF, ¡Ü 60%);
asymptomatic patients with preserved LV function and either atrial
fibrillation or pulmonary hypertension.
In acute MR, nitrates and diuretics are indicated. When heart
failure develops, ACE-inhibitors have a benefit, along with beta-
blockers and spironolactone.
Anticoagulant therapy (target international normalized ratio between
2 and 3) should be given in patients with MR and permanent or
paroxysmal atrial fibrillation or whenever there is a history of
systemic embolism or evidence of left atrial thrombus and during the
first 3 months following mitral valve repair.
Mitral stenosis (MS):
Currently, percutaneous mitral commissurotomy (PMC) is the treatment
of choice when surgery is contraindicated or high risk or for
patients with favorable characteristics. Intervention is indicated
for patients with clinically significant MS and inpatients with high
thrombus-embolic risk or high risk for hemodynamic decompensation.
The most important contraindication to PMC is left atrial thrombus.
Diuretics or long-acting nitrates can improve dyspnea, while beta-
blockers or calcium channel blockers are useful in improving
exercise tolerance.
Tricuspid stenosis:
Intervention on the tricuspid valve is usually performed at the time
of intervention on the other valves in patients who are symptomatic
despite medical therapy.
Tricuspid regurgitation (TR):
Conservative surgery with annuloplasty is preferable to valve
replacement; the need for valve replacement is determined at the
time of surgical correction.
Severe TR should be corrected; and diuretics improve signs of
congestion.

Pearls

Because of the decline of acute rheumatic fever and the increase in
life expectancy, degenerative valve disease has become the
predominant cause of VHD in industrialized nations. The most
frequent valvular diseases are calcific AS and MR.
Treatment of VHD still relies on surgical prosthetic valve
technology; however, the development of conservative surgical
approaches and the introduction of percutaneous interventional
techniques are promising alternatives.

Proliferative retinopathy in male and female patients with type 2
diabetes may predict coronary heart disease (CHD), but in women,
background retinopathy predicted all-cause, cardiovascular disease,
and CHD mortality, according to the results of a study reported in
the February issue of Diabetes Care.

"Population-based studies have shown that microvascular
complications predict cardiovascular disease (CVD) mortality not
only in type 1 and type 2 diabetic subjects but even in nondiabetic
subjects and in general population samples, controlling for the
effect of glucose status," write Auni Juutilainen, MD, of the
University of Kuopio in Finland, and colleagues. "These observations
suggest similar underlying pathogenic processes in microvascular
complications and in atherosclerotic CVD in diabetes. It has been
suggested that microvascular processes might be especially important
in the development of coronary heart disease (CHD) in women."

To evaluate the predictive value of retinopathy for all-cause, CVD,
and CHD mortality by sex, the investigators performed an 18-year
follow-up study of 824 Finnish subjects with type 2 diabetes (425
men and 399 women) who were free of CVD at baseline. Based on
standardized clinical ophthalmoscopy, findings were classified
as "no retinopathy," "background retinopathy," and "proliferative
retinopathy." The primary outcomes were all-cause, CVD, and CHD
mortality.

In men, adjusted Cox model hazard ratios (HRs) of all-cause, CVD,
and CHD mortality were 1.34 (95% confidence interval [CI], 0.98 -
1.83), 1.30 (95% CI, 0.86 - 1.96), and 1.18 (95% CI, 0.74 - 1.89),
respectively, for background retinopathy and 3.05 (95% CI, 1.70 -
5.45), 3.32 (95% CI, 1.61 - 6.78), and 2.54 (95% CI, 1.07 - 6.04),
respectively, for proliferative retinopathy. In women, the
corresponding HRs were 1.61 (95% CI, 1.17 - 2.22), 1.71 (95% CI,
1.17 - 2.51), and 1.79 (95% CI, 1.13 - 2.85), respectively, for
background retinopathy and 2.92 (95% CI, 1.41 - 6.06), 3.17 (95% CI,
1.38 - 7.30), and 4.98 (95% CI, 2.06 - 12.06), respectively, for
proliferative retinopathy.

"Proliferative retinopathy in both sexes and background retinopathy
in women predicted all-cause, CVD, and CHD death," the authors
write. "These associations were independent of current smoking,
hypertension, total cholesterol, HDL [high-density lipoprotein]
cholesterol, glycemic control of diabetes, duration of diabetes, and
proteinuria. This suggests the presence of common background
pathways for diabetic microvascular and macrovascular disease other
than those included in the conventional risk assessment of CVD."

The primary study limitation is evaluation of retinopathy based on
fundoscopy, giving rise to the possibility that subtle changes may
have been missed.

"A sex difference was observed in our study in the association of
background retinopathy with all-cause, CVD, and CHD death, with a
significant association in women but not in men," the authors
conclude. "The sex difference observed in the association of
background retinopathy with macrovascular disease warrants closer
examination."

The costs of publication of this article were defrayed in part by
the payment of page charges, mandating that it must therefore be
hereby marked "advertisement" solely to indicate this fact.

Diabetes Care. 2007;30:292-299

The European Society of Cardiology has issued its first ever
European guidelines on the management of valvular heart disease
(VHD), published in the February 6 issue of the European Heart
Journal. Chairperson of the task force that produced the
recommendations, Alec Vahanian, MD, of the Bichat Hospital in Paris,
France, told heartwire that although national guidelines for VHD
existed in some European countries, there was nothing that pulled
current advice together.

One reason for the lack of guidelines is that there is very little
clinical trial evidence in the field of VHD compared with other
areas of cardiology, Dr. Vahanian said. "But we were fortunate in
that we had the results of the EuroHeart Survey, so we could see
what was happening in practice across Europe, and we were able to
stress some of the more important points in these new
recommendations."

Dr. Vahanian said the new guidelines are "very similar" to US
recommendations on VHD, which were updated last summer. "The two
were produced independently but we have come up with pretty similar
documents overall, with just minor differences on areas where there
is not much trial evidence," he noted.

Risk Stratification Essential in the Elderly
Dr. Vahanian outlined some of the highlights of the new guidelines.
First, it is important to note that the prevalence of VHD is
increasing, primarily because of the aging population, with
consequent rises in degenerative heart disease such as aortic
stenosis (AS), he noted.

"We wanted to stress the importance of risk stratification in the
elderly," Dr. Vahanian says. Too often, the elderly are not
considered candidates for surgery simply because they are old, "but
we shouldn't just discount them on the basis of age alone." The
operative risks can vary widely depending on age, comorbidities, and
other things, he notes, so each patient should be individually
assessed.

Another issue identified by the task force is the question of what
to do with the increasing numbers of asymptomatic patients, which
are due to widespread use of echocardiography. "These patients are
difficult to manage," says Dr. Vahanian, "and we wanted to emphasize
the importance of performing stress tests on these patients. Stress
testing is underused in Europe compared with the US."

An Integrative Approach and Fewer Invasive Interventions
Another theme in the new European guidelines is an emphasis on less
invasive interventions, where possible, Dr. Vahanian said. And there
is encouragement toward an "integrative approach" to valve disease,
so that decisions about treatment are not made on the basis of a
single echo criterion, he noted. "There is no magic number. An echo
criterion should not be taken in isolation. We need to add evidence
before building a strategy and then deciding on an approach."

And the document is also stressing the need to educate and inform
patients to help in the decision-making process. "For example, when
choosing the type of prosthesis for a valve replacement, the patient
needs to be involved in the decision and needs to be educated with
regard to issues such as the prevention of endocarditis and use of
anticoagulation," he notes.

The task force is also emphasizing the value of a multidisciplinary
approach to VHD. "For example, when we send a patient with valve
disease or a prosthesis to a dentist for a tooth extraction, there
should be a discussion among the health professionals about how best
to manage the case," says Dr. Vahanian.

Eur Heart J. 2007;28:230-268.

Both paclitaxel- and sirolimus-eluting stents show "a trend toward
more favorable outcome" in diabetics with occluded coronary arteries
compared with bare-metal stents, Dutch investigators report in the
January issue of the European Heart Journal. However, the question
of whether one drug-eluting stent is superior to the other remains
unclear.

Dr. Patrick W. Serruys and colleagues at Erasmus Medical Center in
Rotterdam analyzed 2-year outcomes of 708 patients with diabetes
mellitus enrolled in the RESEARCH and T-SEARCH registries. One in
four of the diabetics were insulin-dependent.

The patients received a bare-metal stent, a paclitaxel-eluting stent
or a sirolimus-eluting stent to open occluded coronary vessels.

The investigators report that the relative risk for target vessel
revascularization and major adverse events was not significantly
different in the paclitaxel-eluting stent compared with the bare-
metal stent, after adjusting for independent predictors of adverse
events.

The paclitaxel-eluting stent had a non-significant lower incidence
of target vessel revascularization and major adverse events compared
with sirolimus-eluting stent in non-insulin-dependent diabetics at 2
years. The rate of adverse events was higher with sirolimus-eluting
stent at 1 year.

The 2-year cumulative mortality was comparable in all three groups.
However, mortality rate during the second year was 5.8% in the
sirolimus-eluting stent group compared with 1.2% in the paclitaxel-
eluting stent group (p = 0.007).

The investigators observed that the incidence of stent thrombosis
was 4.4% in the sirolimus-eluting stent group compared with 2.4% in
the paclitaxel-eluting stent group and 0.8% in patients who received
bare metal stents. The higher mortality rate with sirolimus-eluting
stent may be related to the increased incidence of stent thrombosis
in patients treated with the sirolimus-eluting stent.

The Dutch team notes that, overall, "there was no significant
difference between sirolimus-eluting stent and paclitaxel-eluting
stent in each of the clinical endpoints, and neither in the non-
insulin-dependent diabetes mellitus group, which are hypothesized to
be better off with paclitaxel-eluting stent."

"The present study suffers from the inherent limitations of a non-
randomized trial," Dr. Serruys' team notes. "More larger-scale and
randomized trials are needed to elucidate the best treatment for
patients with diabetes mellitus and the possible superiority of one
drug-eluting stent compared to another, also taking into account the
long-term adverse events like stent thrombosis," the Dutch
investigators conclude.

Eur Heart J 2007;28:26-32

A new study by Finnish researchers has shown a relationship between
the risk for fatal stroke and fine and ultrafine particulate air
pollution, but the relationship was only significant during the warm
season.

Their results have implications for the elderly population, first
author Jaana Kettunen, from the Environmental Epidemiology Unit at
the National Public Health Institute in Kuopio, Finland, said in a
release from the American Heart Association (AHA), beginning with
the need for doctors to inform their elderly patients about this
risk.

"We suggest that on high pollution days, elderly people should avoid
spending unnecessary time in traffic, whether it is in a vehicle or
walking, especially if they suffer from cardiovascular diseases, to
lower their exposure to pollutants," Kettunen said. "They should
also avoid heavy outdoor exercise on high air-pollution days."

Their results were published online February 15 in Stroke and will
appear in the March issue.

Risk From Fine and Ultrafine Particles

Previous studies have shown an association between particulate air
pollution and all-cause mortality as well as cardiovascular
morbidity and mortality, the researchers note. An association has
also previously been reported between fatal and nonfatal stroke and
daily variation in outdoor concentrations of inhalable particles —
that is, those less than 10 µm in diameter.

However, toxicological and epidemiological evidence suggests that
ultrafine particles, those less than 0.1 µm in diameter produced
mostly by combustion, are especially harmful. In this study,
researchers examined the effects of a variety of particle
sizes, "including, for the first time to our knowledge, ultrafine
particles (< 0.1 µm) on stroke."

Levels of particulate and gaseous air pollution were measured
between 1998 and 2004 at central outdoor monitoring sites in
Helsinki, Finland, where pollution is actually relatively low
compared with other areas where these links have been shown. The
researchers then looked at the association between daily levels of
these particles and stroke fatalities in patients 65 years of age
and older.

In that time period, there were 1304 fatal strokes in the warm
season (May to September) and 1961 in the cold season (October to
April).

"We found that during the warm season, there was a positive
association between stroke mortality among the elderly and current-
day levels of fine particles," Kettunen said in the AHA
release. "There was a 6.9% increase in stroke death for every 6-
µg/m3 increase in fine particles. In addition, there was a 7.4%
increase in stroke mortality for every 6-µg/m3 increase of previous-
day fine-particle levels."

The associations were robust and independent of other pollutants,
they note. They also found associations for previous-day ultrafine
particles and carbon monoxide, but these associations were less
robust and dependent on each other, they noted. There was no
association with coarse particles.

During the cold season, there was no association on any of these
analyses between stroke death and fine particles, ultrafine
particles, or carbon monoxide.

Interestingly, particle concentrations were actually lower in the
warm months than the cold ones; they speculate that the lack of
association with stroke mortality during cold weather may relate to
higher summer ventilation rates, leading to greater indoor exposure
to particles during the summer months, or the increased time spent
out of doors in the warmer months with a more active lifestyle.

"Our results suggest that the levels of combustion-originating
particles rather than coarse particles explain the association
between particulate matter and stroke," the authors conclude. "Thus,
regulatory efforts should be focused on reducing of emissions of
combustion particles. The monitoring of the outdoor concentrations
of the smaller-size fractions should also be considered."


Stroke. Published online February 15, 2007