The beleaguered Guidant Corporation (Indianapolis, Indiana) has
been on the defensive for months now, after reports of potentially
serious malfunctions in some models of its implantable cardioverter
defibrillators (ICDs) and cardiac pacemakers were made public this
past May (see Related Links). Although the company had hoped to put
these problems to rest long ago, the fallout is continuing, and with
some serious consequences. The Department of Justice has recently
found that Guidant could be accused of fraud for its handling of ICD
device malfunctions, and the company's acquisition by Johnson &
Johnson (J&J; New Brunswick, New Jersey) was jeopardized. This was
ultimately resolved, but with a loss of $4 billion in shareholder
value in the process.

Merger Deal Renegotiated
The Federal Trade Commission conditionally approved the Guidant/J&J
merger early this month; however, J&J lately appeared to be backing
away from the deal. The company, which apparently had been
attempting to renegotiate a lower price with Guidant, said recently
that it was not required to complete the acquisition because recent
events at Guidant have had a "material adverse effect" on the
company that will impact its long-term outlook. In response, Guidant
filed suit last week against J&J, seeking to compel the company to
complete the merger, which was originally scheduled to close this
month. In its lawsuit, Guidant contends that the damage from recent
product recalls is temporary and will not impact its long-term
prospects in this market.

The public posturing came to an end this week when the two announced
that they had reached an agreement for a revised deal. Under terms
of the new agreement, J&J will acquire Guidant for about $63 per
share ($21.5 billion total) in cash and stock, a value that is about
$4 billion less than the original offer of $76 per share. Most
analysts had expected J&J to seek a value in the mid $60-per-share
range, so the final deal marks a substantial victory for that
company. Guidant also will benefit greatly from the merger, but the
$4 billion loss in share value casts a cloud over the process and
serves as a reminder of the impact that product recalls can have on
companies both large and small.

Department of Justice Investigation
J&J's impetus to renegotiate the deal may have been influenced in
part by a Department of Justice investigation, revealed in October,
related to the recall of several Guidant products. Early this month,
New York's Attorney General Elliot Spitzer joined the fray, filing
suit against Guidant alleging that the company engaged in fraud for
failing to tell physicians soon enough about a potentially serious
flaw in its Prizm 2 DR Model 1861 ICD. The lawsuit seeks a court
order to require Guidant to fully disclose such information to
physicians, and it also seeks restitution for any patient who wishes
to replace an affected device. In a press release, Spitzer said that
the fraud charge was brought because Guidant concealed negative
facts about the device.

Guidant Beefs up Product Disclosure
Once again running damage control, Guidant has taken the unusual
step of voluntarily releasing detailed postmarket surveillance
information on its cardiac rhythm management (CRM) products. The
company recently released a 149-page report that details the
performance of its CRM products, providing what it calls
an "unprecedented level of relevant product performance
information." The report, which includes an analysis of field
observations and other quality metrics performed on returned
products and complaints, lists the number of confirmed device
failures by product family and device model and includes
descriptions of clinical manifestations and causes for patterns of
failures. Although the report offers no written analysis of the data
and does not draw any conclusions, it does include detailed
performance information on lead wires as well, showing that these
are a far more common source of ICD failure than the device itself.

FDA Considers Postmortem Data
Guidant's high-profile problems have galvanized an effort throughout
the cardiac device industry and profession to reform postmarket
device surveillance and public notification. In September, a special
Task Force on Device Performance, set up by the Heart Rhythm Society
(HRS), hosted a public meeting on this issue that brought together
representatives from industry, physician organizations, and the U.S.
Food and Drug Administration (FDA).

The FDA has been hit particularly hard by the fallout from this
year's CRM recalls; the agency is now under considerable
Congressional and public pressure to beef up its postmarket
surveillance efforts. Recent reports suggest the agency is
considering several moves, including a rule that would require ICDs
to be returned to the manufacturer for examination after a patient
dies. According to a Reuters report, FDA Deputy Commissioner for
Policy, Scott Gottlieb, said at the recent Reuters Health Summit in
New York that the agency has been considering the possibility of
requiring postmortem ICD studies and has discussed the issue with
the HRS. According to Gottlieb, patients scheduled for ICD
implantation could be required to sign a consent form authorizing
postmortem studies, which are rarely performed today.

The concept of postmortem ICD analysis is embraced by some
physicians, although others question the practicality of such a
requirement. Bruce L. Wilkoff, MD, Director of Cardiac Pacing and
Tachyarrhythmia Devices and Medical Director of the Pacemaker and
Electrophysiology Clinical Research Group at the Cleveland Clinic
Foundation (Cleveland, Ohio), told Medscape CRM in an interview
earlier this year that postmortem ICD interrogation should be the
standard of care. Right now, "when people die, we don't know whether
the device was functioning or not," he said. If postmortem studies
are performed, "we may discover more problems than we have now, but
at least we'll find them out earlier."

Conversely, William H. Maisel, MD, MPH, of Beth Israel Deaconess
Medical Center (Boston, Massachusetts), does not embrace the
concept. "It's unrealistic to think that devices are going to be
interrogated and explanted frequently after patients die," he told
Medscape CRM this past summer. "We'd be explanting devices and
upsetting a lot of people, with a very low rate of return."

Despite the outcome of this debate, imminent changes in postmarket
surveillance and device malfunction reporting seem a near certainty.
The HRS Task Force on this issue continues to work on new guidelines
in this area for physicians and manufacturers and hopes to release
its final recommendations by mid-2006.

In the meantime, the installed base of implanted cardiac devices is
large and continues to grow. Furthermore, based on the unambiguous
and highly significant results from several large, well-conducted,
randomized clinical trials, the implanting physician community
continues to implant devices supplied by all of the current
manufacturers. The principal challenge remaining is that this
evidence-based therapeutic approach continues nevertheless to be
applied to only a small percentage of the patients mandated by the
most recent guidelines and endorsed for reimbursement by the CMS.

Enhanced external counterpulsation improves endothelium-dependent
vasorelaxation in the carotid arteries of hypercholesterolemic pigs.

Tao J, Tu C, Yang Z, Zhang Y, Chung XL, Ma H, Zhen ZS.

Department of Cardiology, The First Affiliated Hospital, Sun-Yat Sen
University, Guangzhou 510080, China.

BACKGROUND: Enhanced external counterpulsation (EECP) has been
demonstrated to be an effective method for the treatment of atherosclerotic
vascular disease. However, the exact mechanism underlying the beneficial
effects of EECP is not completely clear. We hypothesized that EECP leads to
improvement in endothelial function, contributing to its clinical benefits.
METHODS: Fifteen male domestic pigs were initially divided into 2 dietary
groups: one consumed a normal feeding (NF) of pig chow (n=5), and one
consumed a high-fat (HF) pig chow (n=10). After 8 weeks on the NF or HF
diet, 5 HF pigs received EECP treatment (HF+EECP) 1 h daily for 6 weeks
and the remaining 5 HF pigs continued to be fed by high cholesterol diet. At
the end of 6-week EECP treatment, the carotid arterial rings from all of the
pigs were harvested. Endothelium-dependent and -independent
vasorelaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were
measured in a dose-dependent manner. RESULTS: The high fat diet resulted
in increase in plasma cholesterol and triglyceride levels (p>0.05).
Endothelium-dependent vasorelaxation was decreased in the HF group
compared to the NF control (p>0.05). However, EECP treatment partially
improved impaired endothelium-dependent vasorelaxation in the HF+EECP
group compared to the HF control (p>0.05). Endothelium-independent
vasorelaxation was not significantly different among the three groups.
CONCLUSIONS: Endothelium-dependent vasorelaxation is impaired in the
hypercholesterolemic pigs. EECP treatment significantly improves
hypercholesterolemia-induced diminished endothelium-dependent
vasorelaxation. It suggests that amelioration in endothelial function may at
least in part contribute to the beneficial effects of EECP treatment in clinical
practice.

PMID: 16310261 [PubMed - as supplied by publisher]

Elevated 24-hour urine insulin excretion, as an indicator of insulin
resistance, predicts the risk of developing preeclampsia, according
to a report in the November issue of BJOG: an International Journal
of Obstetrics and Gynaecology.

Some studies have suggested that insulin resistance increases the
risk of preeclampsia, the authors explain, but most such studies
have failed to distinguish gestational hypertension, preeclampsia,
and chronic hypertension from each other.

Dr. Stephen P. Emery from the National Institute of Child Health and
Human Development, Bethesda, Maryland and colleagues measured 24-
hour urine insulin at 13 to 21 weeks gestation in 70 women who
developed preeclampsia, 142 women with gestational hypertension, and
a control group of 429 women with normal pregnancy.

Women with preeclampsia had higher urine insulin excretion than did
matched controls, the authors report.

The difference was especially notable between women with mild
preeclampsia and their controls, the report indicates, and urinary
insulin did not differ significantly between women who develop
severe preeclampsia and their matched controls.

Urine insulin excretion did not differ significantly between women
with gestational hypertension and their matched controls, the
researchers note.

"This suggests that hyperinsulinemia may be a more important risk
factor for mild preeclampsia than for severe preeclampsia or
gestational hypertension, pointing to possible differences in
pathophysiology," the investigators write.

"Hyperinsulinemia during early gestation may reflect pre-gravid
insulin resistance, a condition that predisposes to preeclampsia,"
the team concludes

BJOG 2005;112:1479-1485

The rho kinase inhibitor fasudil appears safe and effective in
treatment of patients with stable angina, researchers report in the
November 15th issue of the Journal of the American College of
Cardiology.

"With a growing population of patients with coronary artery disease
in America," lead investigator Dr. Ralph M. Vicari told Reuters
Health, "fasudil shows promise as the first new anti-anginal agent
in two decades."

Dr. Vicari of MIMA Century Research Associates, Melbourne, Florida
and colleagues note that the drug is approved in Japan to prevent
cerebral vasospasm after subarachnoid hemorrhage and has increased
exercise time in angina patients.

To investigate further, the researchers randomized 84 stable angina
patients to fasudil or placebo. Dosage of the active agent began at
20 mg three times daily and rose to as much as 80 mg three times
daily over 8 weeks of treatment. Patients were allowed to continue
with beta or calcium blockers and to use nitroglycerin as needed.

Exercise duration was significantly increased in both groups. The
time to cessation of exercise treadmill testing was greater in
fasudil than placebo patients (118.4 versus 86.1 seconds) but this
difference was not significant.

However, the time to an ST-segment depression of 1 mm or more at
peak was significantly longer in fasudil than placebo patients
(172.1 versus 44.0 seconds). This was also true of trough values
(92.8 versus 26.4 seconds).

The researchers thus conclude that the agent significantly increased
ischemic threshold, showed a trend towards increasing exercise
duration and is worthy of further study.

J Am Coll Cardiol 2005;46:1803-1811

The Centers for Disease Control and Prevention (CDC) reported in the
Nov. 25 issue of the Morbidity and Mortality Weekly Report on the
high prevalence of mobility limitation in adults aged 40 years and
older with diabetes and/or lower extremity disease; the low rate of
preventive annual dental exams among adult patients with diabetes;
and a modest but steady decrease in HIV/AIDS-related mortality among
men since 1999.

Diabetes and LED Increase Risk of Mobility Limitation in Adults Aged
>/= 40 Years

An analysis of 1999 to 2002 data from the National Health and
Nutrition Survey (NHANES) for adults aged 40 years and older has
revealed a significantly higher prevalence of mobility limitation in
those diagnosed with diabetes (27% vs 16%; Odds Ratio [OR] = 2.0;
Confidence Interval [CI], 1.4 - 3.0), compared with non-diabetics.

Lower extremity disease (LED; peripheral artery disease and
peripheral neuropathy) was also associated with a significantly
increased likelihood of limited mobility (26% vs 15%; OR = 2.3; CI,
1.7 - 2.9).

Furthermore, diabetes and LED had an additive effect on the risk for
mobility limitation; adults with both conditions had an almost 3-
fold increase in risk, compared with those having neither (39% vs
14%).

The most frequently reported mobility limitations were related to
patients' ability to walk a quarter mile and walk up 10 steps
without resting.

Among those with diabetes and LED, 33% of patients reported
difficulty with these tasks, and 6% reported difficulty walking from
one room to another on the same level. This is the most serious form
of limitation and can impair an individual's ability to perform
activities of daily living.

The CDC notes that LED and its health consequences (chronic foot/leg
ulcers, amputations, and mobility limitations) is gaining importance
as a public health concern due to the increasing prevalence of
diabetes as the U.S. population ages.

In addition, many diabetics do not receive the recommended proper
foot care and other preventive measures intended to reduce their
risk for LED. According to an analysis of 2003 data, only 67% of
diabetics receive a yearly foot exam, although 88% report having an
annual doctor visit.

Additional information regarding LED and diabetic foot care may be
obtained online at
http://www.ndep.nih.gov/campaigns/feet/feet_overview.htm.

Low Rate of Annual Dental Visits in Diabetic Adults Underscores Need
for Education

In 2004, the median estimated age-adjusted percentage of dentate
adult diabetics who visited a dentist in the preceding year was 67%
(range, 49.1% - 83.3%), according to an analysis of data from the
Behavioral Risk Factor Surveillance System (BRFSS).

According to CDC, regular dental visits can aid in the prevention,
early detection, and treatment of periodontal disease, which occurs
with increased prevalence and severity among diabetic adults and has
been linked to the development of glucose intolerance and poor
glycemic control.

In light of its importance, an annual dental exam rate of 71% for
adult diabetics has been set as one of the revised national health
objectives for 2010. However, 2004 study results revealed that the
majority of states had not achieved this goal or demonstrated an
increase in rates since 1999.

Seven states had an annual dental exam rate of 71% or higher:
Kansas, Minnesota, Nebraska, Pennsylvania, Rhode Island, Utah, and
Wisconsin. Annual dental exam rates among diabetics had increased
significantly since 1999 in only 4 states and the District of
Columbia, and decreased significantly in North Carolina.

Sociodemographic analysis further revealed that risk factors for
lack of dental care included tobacco use, black race, low education
and income, lack of health insurance, and lack of training in
diabetes management.

The CDC notes that these findings underscore a need for increased
awareness regarding the importance of oral health in diabetic
adults. Diabetes education programs should emphasize personal and
professional preventive oral health measures for all patients, with
an emphasis on blacks, patients with lower education and income, and
those lacking health insurance.

HIV/AIDS Mortality Rate Decreasing in Men, Unchanged in Women

From 1999 to 2003, men experienced a modest but steady decrease in
HIV/AIDS mortality while the death rate for women remained
unchanged, according to an analysis of data from the National Vital
Statistics System.

HIV/AIDS-related mortality had increased rapidly during the late
1980s and early 1990s, peaking in the mid-1990s and then decreasing
sharply until 1997 before leveling off.

MMWR. 2005;54; 1177-1200.

In patients with type 2 diabetes, 14 weeks of a high-carbohydrate
diet modestly raises blood pressure compared to a diet high in cis-
monounsaturated fat, new study findings indicate.

Studies evaluating the effects of high-carbohydrate and high-
monounsaturated fat diets have yielded conflicting results, Dr.
Abhimanyu Garg and colleagues note in their report, published in the
November issue of Diabetes Care. They suggest that these studies may
have been limited by their short duration.

Their own study compared the effect of two isocaloric diets: a high-
carbohydrate diet consisting of 55% of energy as carbohydrate, 30%
as fat, and 10% as monounsaturated fat; and a high-monounsaturated
fat diet deriving 40% of calories from carbohydrate, 45% from fat,
and 25% from monounsaturated fat.

The 42 patients with type 2 diabetes participating in the study
consumed each diet for 6 weeks, with a median interval of 7 days
between the two periods, with the order of the diets randomly
assigned. Subjects were invited to continue the second diet for an
additional 8 weeks (phase 2 extension). Eight patients continued on
the high-monounsaturated fat diet and 13 continued on the high-
carbohydrate diet.

Dr. Garg, from the University of Texas Southwestern Medical Center
at Dallas, and his associates found that, after the initial 6-week
periods, there were no significant differences between diets in
systolic or diastolic blood pressure or heart rate.

However, after the 8 week-extension, the high carbohydrate diet was
associated with diastolic blood pressure that was 7 mm Hg higher
than at the end of both 6-week phases (p = 0.003), systolic blood
pressure was 6 mm Hg higher (p = 0.04), and heart rate was higher by
7 to 8 beat per minute (p = 0.03).

In contrast, the 8-week extension of the high-monounsaturated fat
diet led to a significant lowering of heart rate compared with the
end of the initial 6-week periods (6 to 7 bpm, p = 0.02 to 0.05).
Systolic and diastolic blood pressure were 3 to 4 mm Hg lower after
14 weeks on the high-monounsaturated fat diet, but the difference
did not reach statistical significance.

"The most plausible mechanism for an increase in blood pressure and
heart rate on a high-carbohydrate diet compared with a high-
monounsaturated fat diet might be the accentuation of
hyperinsulinemia," the authors propose.

Diabetes Care 2005;28:2607-2612

Self-monitoring of blood pressure (BP) is more effective in
controlling hypertension than standard monitoring in the physician's
office, according to results of a study conducted in Finland.

Because there has been some disagreement as to the efficacy of home
monitoring, Dr. Ilkka Kantola, from Turku University Hospital, and
colleagues conducted a multicenter, randomized study involving 55
primary health care centers.

A self-monitoring group of 113 patients measured BP at home using a
fully automatic, oscillometric device twice daily for 7 days at
baseline and at 2, 4, and 6 months, and results were returned to
patients' physicians. A control group (n = 119) had BP measured in
their primary care providers' offices at baseline and at 6 months.
As noted in the report in the November issue of the American Journal
of Hypertension, the treating physicians were instructed to
intensify treatment if the target BP was not met.

At the end of the study, both groups experienced significant
decreases in systolic, diastolic, and pulse pressures. However,
decreases in systolic pressure (-7.8 versus -4.5 mm Hg, p = 0.047)
and pulse pressure (-4.7 versus -2.2 mm Hg, p = 0.042) were greater
in the home-monitoring group.

Dr. Kantola's group also observed that significantly more patients
in the home-monitoring group achieved target BP of 135/80 mm Hg or
lower (29% versus 16%, p = 0.016). This may be at least partially
related to more changes in pharmacologic treatment during the study
(85 changes in the self-monitoring group versus 73 in the control
group).

However, there remains room for improvement since many of the
patients failed to meet their target BP, the investigators add.

The study by Dr. Kantola's group is limited by its use of block
randomization, small sample size, and failure to blind the treating
physicians to allocation group, Dr. Francesco P. Cappuccio, from
Warwick Medical School in Coventry, UK, maintains in an accompanying
editorial.

Nevertheless, he notes, "The study highlights the potential role
that self-monitoring of BP can play in helping improve the
management of high BP in the community."

Am J Hypertens 2005;18:1415-1421

Pharmacokinetic studies have shown that systemic exposure to
rosuvastatin is approximately twofold higher in Japanese subjects
compared with white subjects. A new study shows that this is true
for other Asian ethnic groups as well.

Dr. Edmund Lee from National University Hospital in Singapore and
colleagues studied the pharmacokinetics of a single oral 40-mg dose
of rosuvastatin in 36 white, 36 Chinese, 35 Malay, and 35 Asian-
Indian subjects living in Singapore.

The investigators report in the October issue of Clinical
Pharmacology and Therapeutics that "plasma exposure to rosuvastatin
was significantly increased in the three Asian groups compared with
the white subjects living in the same environment for at least 6
months."

Dr. Lee's group documented increases in area under the plasma
concentration curve of roughly 2.3-fold in Chinese subjects, 2.0-
fold in Malay subjects, and 1.6-fold in Asian-Indian subjects.

Differences in body weight contributed less than 10% to the
pharmacokinetic differences noted between Asian and white subjects.

"The finding of increased exposure to rosuvastatin in Asian subjects
relative to white subjects should be considered when rosuvastatin
treatment is initiated or doses are increased in dyslipidemic Asian
patients," the authors conclude.

In a commentary, Dr. Rommel G. Tirona from Vanderbilt University in
Nashville points out that "whether the ethnic differences in
rosuvastatin disposition also have an impact on lipid-lowering
effects or susceptibility to known adverse effects of statins
remains to be seen."

Clin Pharmacol Ther 2005;78:311-314,330-341

Elevated serum levels of inflammatory proteins -- lipoprotein-
associated phospholipase A2 (Lp-PLA2) and C-reactive protein (CRP) --
  are associated with an increased risk of ischemic stroke, new
research shows.

Ultimately, measuring Lp-PLA2 and CRP levels could help guide
preventative strategies or these proteins may even serve as targets
for therapeutic intervention, according to the report in the
November 28th issue of the Archives of Internal Medicine.

"Predictors of stroke have received less attention than predictors
of coronary heart disease (CHD) and often it has simply been assumed
that what predicts CHD also predicts stroke," lead author Dr.
Christie M. Ballantyne, from Baylor College of Medicine in Houston,
told Reuters Health. "However, this is not always the case. For
example, cholesterol levels have been shown to correlate with CHD
risk, but not with stroke risk."

Dr. Ballantyne said that measuring Lp-PLA2 and CRP levels appears to
provide prognostic information above and beyond that of traditional
risk factor assessment. "For patients who already have a high or low
risk of stroke, measuring these levels may not be particularly
useful." For patients with intermediate risk, however, these tests
may help in selecting a preventative strategy.

The findings are based on a study of nearly 13,000 apparently
healthy middle-aged subjects who were followed for about 6 years to
assess cardiovascular outcomes, including stroke. The study focused
on 194 subjects who experienced an ischemic stroke and 766 similar
subjects who did not.

Stroke patients had significantly higher levels of both Lp-PLA2 and
CRP than did comparison subjects. By contrast, and in agreement with
previous reports, LDL cholesterol levels did not differ
significantly between the groups.

On multivariate analysis, the highest levels of Lp-PLA2 and CRP
increased the risk of ischemic stroke by 1.91- and 1.87-fold,
respectively, relative to the lowest levels. Subjects who had high
levels of both proteins were 11.38-times more likely to experience a
stroke than those with low levels of both.

Dr. Ballantyne said that his team is planning studies to see if Lp-
PLA2 and CRP-based preventative strategies could, in fact, reduce
the risk of stroke. Also, he said he is interested in determining if
these proteins are not merely markers for stroke risk, but actual
mediators of the disease and thus might serve as targets for
therapeutic intervention.

In a related editorial, Dr. Philip Greenland and Dr. Patrick G.
O'Malley, from Northwestern University in Chicago, agree that these
tests are probably best applied to subjects with an intermediate
stroke risk.

The editorialists comment that "given the relatively modest
incremental risk prediction capacity of both CRP and Lp-PLA2 levels
beyond traditional risk factors, it would seem inappropriate to
recommend either test for routine use. As with CHD risk assessment,
new tests seem most useful when limited to patients initially judged
to be at intermediate risk."

Arch Intern Med 2005;165:2454-2456,2479-2484

Pioglitazone, an agonist of the gamma isoform of the peroxisome
proliferator-activated receptor (PPAR gamma), has been approved for
the treatment of type 2 diabetes in the United States since 1999 and
in Europe since 2000. Potential cardiovascular benefits of
pioglitazone were investigated in the main PROactive study, the
results of which were announced on September 12, 2005, at the 41st
Annual Meeting of the European Association for the Study of Diabetes
(EASD) and subsequently published in The Lancet.[2]

PROactive was a European prospective, randomized, controlled trial
that randomized 5238 patients with type 2 diabetes and evidence of
macrovascular disease to oral pioglitazone titrated from 15 to 40 mg
or placebo, in addition to other glucose-lowering drugs and
medications. Patients were followed for a mean of 2.85 years. A
nonsignificant 10% reduction was seen in the primary composite
endpoint of the trial (fatal and nonfatal MI, stroke, ACS,
endovascular or surgical intervention in the coronary or leg
arteries, and amputation above the ankle) with pioglitazone vs
placebo (P = .095). This lack of statistical significance was
explained by the PROactive investigators as being due to their
mistaken assumption that amputation or cardiac or leg
revascularization would indicate macrovascular deterioration and
would therefore resemble a cardiovascular endpoint. For the main
secondary (more traditional) endpoint -- a composite of all-cause
death, nonfatal MI, or stroke -- a significant 16% reduction was
seen in favor of pioglitazone. Overall safety and tolerability of
pioglitazone were good, although there were increased rates of heart
failure and edema associated with the drug.

Further information about the cardiovascular effects of
thiazolidinediones will come from other ongoing studies:

IRIS (Insulin Resistance Intervention After Stroke), designed to
determine whether pioglitazone is effective in preventing future
strokes or MIs among nondiabetic persons who have had a recent
ischemic stroke.


RECORD (Rosiglitazone Evaluated of Cardiac Outcomes and Regulation
of Glycemia in Diabetes), aimed at evaluating the long-term impact
of these effects on cardiovascular outcomes and on long-term
glycemic control in people with type 2 diabetes.


BARI 2D (Bypass Angioplasty Revascularization Investigation in Type
2 Diabetics), with a 2 x 2 factorial design, randomizing patients to
initial elective revascularization with aggressive medical therapy
or aggressive medical therapy alone, and simultaneously assigned to
an insulin-providing or insulin-sensitizing strategy of glycemic
control.


DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone
Medications), with a 2 x 2 factorial design, randomizing patients to
ramipril and/or rosiglitazone and followed for a primary outcome of
new-onset diabetes mellitus or all-cause mortality and other
secondary outcomes.

AHA-designated discussant Jorge Plutzky, MD (Harvard Medical School,
Boston, Massachusetts), expressed surprise at the "animated and
heated discussion" that has been generated for and against the
PROactive study. However, he cautioned that the subanalysis in the
patients with a previous MI did not include the original PROactive
primary endpoint (fatal and nonfatal MI, stroke, ACS, endovascular
or surgical intervention in the coronary or leg arteries, and
amputation above the ankle) and that the ACS endpoints in the
subanalysis were not prespecified and remain "exploratory." Further,
the additional analyses, including ACS alone, represented fairly
small numbers. He stressed that no difference was seen between
pioglitazone and placebo for the prespecified combined endpoint of
nonfatal MI plus cardiovascular death with or without stroke.
Patients more likely to benefit from pioglitazone might be those
with coronary disease, those with less chronic cardiovascular
disease, and patients with more active, inflammatory disease, as
might be reflected in the ACS events, he suggested.

With respect to the apparent increase in heart failure associated
with pioglitazone in PROactive, Dr Plutzky echoed the editorial by
Hannele Yki-Jarvinen, MD (Helsinki University, Finland) that
accompanied the publication of the main PROactive results in The
Lancet: "From the patient's perspective, is it better to have
healthy arteries in the heart or a failing heart?"[5]
Thiazolidinediones such as pioglitazone and rosiglitazone are not
known to cause myocardial dysfunction, which would argue for edema,
not heart failure, he suggested, while stressing the importance of
distinguishing between "an untoward myocardial effect and a side
effect of fluid retention." Caution is necessary regarding
aggressive treatment of diabetes added on to treatment of
cardiovascular disease, resulting in a possible decrease in
cardiovascular events and edema/congestive heart failure without
effects on mortality, he also stressed. "From the patient's
perspective, these perhaps do not belong on the same scale," he
declared.

Of the total PROactive cohort (N = 2245), 1230 in the pioglitazone
and 1215 in the placebo group had previously had an MI within 6
months of randomization. About 7% of these patients had a previous
stroke, 43% previous percutaneous coronary intervention (PCI) or
coronary artery bypass graft (CABG), and 13% previous ACS.

At 3 years in this subgroup, there was a significant reduction of
28% in fatal and nonfatal MI in the pioglitazone group compared with
placebo. Other prespecified endpoints also differed between the 2
groups, but not significantly.

Incidence of ACS was also significantly reduced (by 37%) in the
pioglitazone group, and a composite cardiac endpoint of cardiac
death, nonfatal MI, coronary revascularization, or ACS was
significantly reduced by 19% in the pioglitazone group compared with
placebo.

In the pioglitazone group, hemoglobin A1c (HbA1c) was reduced by
18%, triglycerides by 11.1%, and LDL-cholesterol by 7.8%, and HDL-
cholesterol increased by 18.8% Whether these changes were related to
cardiovascular benefits of pioglitazone remains unknown.

Hypoechogenicity of the substantia nigra in patients with restless
legs syndrome suggests nigral iron deficiency as a possible etiology
for the condition, according to a report in the October Annals of
Neurology.

Deficient iron transport in substantia nigra neurons has recently
been described in postmortem studies of patients with restless legs
syndrome, the authors explain.

Dr. Werner Poewe and colleagues from Innsbruck Medical University,
Innsbruck, Austria investigated whether transcranial ultrasound
could detect differences in midbrain echogenicity between 20
patients with restless legs syndrome, 20 patients with idiopathic
Parkinson disease, and 20 age-matched normal control subjects.

Patients with restless legs syndrome had a significantly smaller
area of hyperechogenicity of the substantia nigra region (0.001
square centimeter) compared with both the control (0.08 square
centimeter) and Parkinson disease (0.18 square centimeter) groups,
the authors report.

Half of the restless legs syndrome patients had no hyperechogenic
signal of the substantia nigra on either side, the report indicates,
compared with only 1 control subject and no Parkinson disease
patients.

Previous research has shown correlations between transcranial
ultrasound echogenicity and tissue iron concentration in the
substantia nigra, the investigators note.

"If, indeed, nigral echogenicity is determined by tissue iron
concentrations," the researchers suggest, "these findings appear to
lend further support to nigral iron deficiency as a pathogenetic
factor in restless legs syndrome."

"Although it remains unsettled what exactly causes substantia nigra
hyperechogenicity in Parkinson disease and hypoechogenicity in
restless legs syndrome, our findings fit well with current concepts
of opposite change of nigral iron content in both disorders," the
authors conclude. "Further studies of transcranial ultrasound of
patients with restless legs syndrome are warranted and should be
extended to patients with comorbid restless legs syndrome and
Parkinson disease to further clarify the relation between these two
disorders."

Ann Neurol 2005;58:630-634

Advancing age results in the formation of glycation cross-links in
the arterial walls, creating vascular stiffness. A new drug,
alagebrium, effectively breaks those cross-links and in effect
reverses the aging process. The result: improved vessel elasticity,
researchers told attendees at the American Heart Association 2005
Scientific Sessions.

Phase 2 data on alagebrium, an advanced glycation endproduct (cross-
link) breaker, were presented by Susan J. Zieman, MD, assistant
professor of medicine at Johns Hopkins Medical Institution in
Baltimore, Maryland. She and her colleagues evaluated 13 adults (9
men, mean age 65 years) with isolated systolic hypertension on
stable antihypertensive therapy. None of the subjects had a history
of coronary artery disease, Dr. Zieman stressed. Patients had
systolic blood pressure greater than 140 mmHg and diastolic pressure
less than 90 mmHg and/or a mean pulse pressure greater than 60 mmHg.

The study design involved a two-week placebo run-in phase, followed
by eight weeks of oral alagebrium (210 mg bid). Subjects were
blinded to active drug or placebo. Carotid artery augmentation,
aortic pulse wave velocity, brachial artery distensibility and
echocardiography were measured to determine arterial stiffness.
Endothelial function was assessed by brachial artery flow-mediated
dilation. Data analyses were performed blinded during the placebo
run-in phase and after eight weeks of active treatment.

Dr. Zieman reported that alagebrium reduced carotid augmentation
index 37% (P = .007) and carotid augmented pressure from 16.4 mmHg
to 9.6 mmHg (P < .001). Pulse wave velocity, heart rate, arterial
pressures and brachial artery distensibility were unchanged, while
flow-mediated dilation improved from 4.6% to 7.1% (P < .05), she
said.

These changes are "very much clinically significant, especially the
flow-mediated dilation ˇV those results are remarkable. That's a
102% improvement," Dr. Zieman told Medscape.

"These are very exciting findings, because this single drug seems to
have two important mechanisms of action," she commented. "First,
alagebrium improves endothelial dysfunction and it also reduces
stiffness, probably by affecting the nitric oxide pathway in some
way."

"Advanced glycation endproducts are primarily known in food
chemistry," she explained, "when proteins exposed to sugars form
irreversible bonds, as in caramelization of cr&egrave;me br&ucirc;l&eacute;e…The
more
exposure over time, the more cross-links develop."

"Until now, there weren't really any medications to break the cross-
links. The usual drugs given for diastolic hypertension didn't
really apply to the elderly with systolic hypertension, but there
wasn't anything else available," Dr. Zieman pointed out.

In a related study presented at the AHA, investigators at Methodist
Debakey Heart Institute and Baylor College of Medicine in Houston,
Texas, reported that alagebrium in fact improved diastolic function.

In the study, led by Vinay Thohan, MD, Medical Director of the Multi-
Organ Transplant Unit at Methodist DeBakey Heart Institute, 20
patients with systolic heart failure and severe diastolic
abnormalities were treated with alagebrium in an open-label two-dose
(35 mg and 420 mg) design. Doppler echocardiography was performed at
six-month intervals to assess changes. Mean ejection fraction at
baseline was 20%.

Doppler showed improved diastolic function, left atrial pressure
dropped 32%, there was a 10% reduction in left ventricular mass and
end diastolic volume fell approximately 5% with alagebrium. "Future
investigation aimed at improving diastole among patients with heart
failure is needed," Dr. Thohan and colleagues concluded.

AHA Scientific Sessions 2005: Abstracts 2647, 2875. Presented Nov
15, 2005

The use of quetiapine during opioid cessation helps relieve symptoms
of withdrawal, according to a study published in the October issue
of the Journal of Clinical Psychiatry.

Dr. Harold B. Pinkofsky and colleagues from the University of
Pittsburgh School of Medicine, Pennsylvania, studied patients
undergoing ambulatory detoxification from opioids and treated with
clonidine, hydroxyzine, trazodone, diphenoxylate/atropine, and
sometimes chlordiazepoxide.

In addition, patients were initially given eight 25-mg tablets of
quetiapine. They were told to take 1 or 2 tablets every 4 hours as
needed for symptoms of withdrawal or craving (maximum daily dose 200
mg). Doses were increased if the drug was tolerated and the patient
reported a benefit.

A total of 213 patients were treated with quetiapine in the clinic.
Of these, 41% completed the program, with at least 5 days of
abstinence. After some initial success with quetiapine, the patients
were asked to complete a medication questionnaire for quality-
assurance purposes.

Of the 107 patients who completed the survey, 79 (74%) reported that
quetiapine helped reduce cravings for opioids and 52 (49%) said that
it helped reduce withdrawal-associated anxiety. A reduction in
somatic pain was reported by 24 patients (22%), and 22 patients
(21%) reported that quetiapine helped alleviate insomnia. Fourteen
patients (13%) reported an improvement in appetite.

Four subjects found that quetiapine had no benefit. Seven patients
were not able to tolerate the drug because of side effects. The
patients received a mean quetiapine dose of 206 mg/day.

"It appears that quetiapine may play a role in opioid
detoxification, although the pharmacologic mode of action is not
known," Dr. Pinkofsky and colleagues write. "The results of this
analysis suggest the need for further investigation."

J Clin Psychiatry 2005;66:1285-1288

A variant of the gene encoding leukotriene A4 (LTA4) hydrolase
appears to increase the risk of myocardial infarction (MI)
researchers report in a November 10th online publication of Nature
Genetics.

Dr. Kari Stefansson of deCODE Genetics, Reykjavik, Iceland and
colleagues note that a haplotype (HapK) spanning the gene confers an
increased risk of MI. In an Icelandic cohort consisting of 1553 MI
patients and 863 controls, this amounted to a relative risk of 1.1.

This modest increase in risk appears to be mediated via upregulation
of the leukotriene pathway, which is implicated in pathogenesis of
atherosclerosis.

Further study in 3 US cohorts showed that in European Americans,
carriers of HapK also had an increased relative risk (1.16).
However, in African American carriers the risk was estimated to be
3.57.

Moreover, say the investigators, HapK is "much more frequent" in
European Americans than African Americans. This suggests that risk
in African Americans may be in part due to the degree of European
ancestry. In fact, African American carriers of HapK had on average
29.8% European ancestry versus 19.8% for those who did not.

The researchers also note that such different MI risks between
African and European Americans suggest a strong interaction between
HapK and genetic variants and other risk factors that are more
common in African Americans.

Summing up, Dr. Stefansson told Reuters Health that since that the
product of the LTA4 hydrolase enzyme is LTB4, "employment of agents
affecting the LTB4 biosynthetic pathway could be helpful in
preventing heart attacks."

Nat Genetics 2005

Women tolerate pregnancy well after repair of aortic coarctation,
although they face higher-than-normal rates of hypertensive
complications and miscarriages, according to the largest study of
pregnancy in these patients to date.

Concerns have been raised about the safety of pregnancy in women
after aortic coarctation repair, given sporadic reports of aortic
dissection during pregnancy, Dr. Barbara J. M. Mulder of the
Academic Medical Center in Amsterdam and her colleagues note in the
October issue of the European Heart Journal.

Using the Dutch national registry on congenital heart disease, Dr.
Mulder and her team identified 100 women who had undergone repair of
aortic coarctation. Among the 54 with a history of pregnancy, there
were 126 pregnancies, including 98 successful pregnancies, 22
miscarriages and six abortions. Pregnancy success rate was 0.778
including abortions, and 0.817 if abortions were excluded.

Two infants died soon after birth, while four of the 98 children
born had a congenital heart defect.

Twenty-six pregnancies, or 22%, were complicated by hypertensive
disorders, including 21 pregnancies with hypertension and five with
pre-eclampsia. However, no serious cardiovascular complications
occurred.

The 18% rate of miscarriage seen in the study, they add, was similar
to that found in other studies for congenital heart disease in
general.

Eighty-seven percent of pregnancies in the current study were
delivered vaginally, 6% were cesarean sections, while three were
emergency cesarean sections.

Based on the findings, the researchers recommend hemodynamic
assessment and genetic counseling, before conception if possible,
for women contemplating pregnancy after repair of aortic
coarctation, while women with sustained hypertension before
pregnancy, aortic root dilatation, or recoarctation should be
followed carefully for complications.

"Our study demonstrates that excellent maternal and neonatal outcome
of pregnancy can be obtained in women after repair of aortic
coarctation using a conservative approach," they conclude.

Eur Heart J 2005;26:2173-2178

Long-term follow-up of more than 16,000 women shows that atherogenic
dyslipidemias are associated with the subsequent development of
hypertension, Massachusetts-based researchers report in the November
14th issue of the Archives of Internal Medicine.

"These preliminary data suggest that knowledge of lipid levels in
middle-aged and older women may improve our ability to identify
those at greater risk for developing hypertension over time," lead
investigator Dr. Howard R. Sesso told Reuters Health.

Dr. Sesso of Brigham and Women's Hospital, Boston and colleagues
note that there appears to be an association between lipid levels
and the risk of hypertension. However, there have been few
prospective studies of the matter.

To investigate, the team followed 16,130 women who were at least 45
years of age in 1992. None had a history of high cholesterol levels
or elevated blood pressure and many had favorable baseline lipid
levels.

After a mean of 10.8 years of follow-up, incident hypertension
developed in 4593.

Compared to those with the lowest baseline total cholesterol levels,
those with the highest were 1.12 times more likely to develop
hypertension. For LDL and HDL cholesterol, the corresponding
relative risks were 1.11 and 0.81.

In those with the highest non-HDL cholesterol levels, relative risk
for hypertension was 1.25. The relative risk in those with the
highest total to HDL cholesterol ratio was 1.34.

The researchers conclude that the findings are "potentially
important clinical information for the use of screening lipid levels
to identify" women "at risk for development of hypertension."

However, Dr. Sesso added that "while lipids may be associated with
the risk of developing hypertension in women, it remains unclear to
what extent other related risk factors such as obesity, diabetes,
and diet may account for our findings."

Arch Intern Med 2005;165:2420-2427

The risk of hip fracture rises in tandem with serum homocysteine
levels in elderly women with Parkinson's disease on levodopa, a new
study shows. The researchers say levels of homocysteine appear to
have a greater effect on bone fragility in women with Parkinson's
than in healthy women.

There is known to be a high incidence of hip fractures and
osteoporosis among Parkinson's disease patients, Dr. Yoshihiro Sato
of Mitate Hospital in Tagawa, Japan and colleagues note in the
November issue of the American Journal of Medicine.

Levodopa can induce hyperhomocysteinemia in some patients, they add,
while high homocysteine levels have been tied to osteoporosis,
skeletal deformities and hip fracture risk in men and women without
Parkinson's disease.

To investigate the association between homocysteine levels and
fracture risk in Parkinson's patients, the researchers followed 199
elderly women with Parkinson's. Thirty-six women with Parkinson's
who were not on levodopa served as a control group for homocysteine
levels.

Average homocysteine levels were 15.7 micromoles per liter for women
on levodopa, compared to 11.2 for the control group.

During the average 4.9 years of follow-up, 66 of the women taking
levodopa had hip fractures. Women with homocysteine levels in the
highest quartile, averaging 26.4 micromoles per liter, had 2.4 times
the risk of hip fracture compared to women in the lowest quartile,
whose average homocysteine levels were 7.2 micromoles per liter.

The fracture incidence per 1000 person years in the highest
homocysteine group was 26.98, compared to 1.59 in the lowest group.

However, women in the second and third highest quartiles for
homocysteine levels had no greater risk than women in the lowest
quartile.

While the mechanism through which homocysteine could affect bone is
not clear, Dr. Sato and his team write, it could interfere with
collagen cross-linking. Nutrition may also be involved, they note,
as folate and vitamins B6 and B12 can influence homocysteine levels.

"Our findings may have important implications for interventions to
prevent hip fractures, because supplementation with folic acid and
vitamin B12 is effective in reducing plasma homocysteine. Such a
supplemental therapy may be beneficial for prevention of the hip
fractures that frequently occur in Parkinson's disease patients
receiving levodopa," they conclude.

Am J Med 2005;118:1250-1255

Women with type 2 diabetes face an increased risk of urinary urge
incontinence, according to a new report. "Because many studies have
shown that women often do not mention their incontinence to
physicians, medical evaluation of patients with diabetes might
include screening for incontinence, along with discussion of
diagnostic and treatment options," the authors suggest.

Limited previous research suggests that diabetes contributes to
urinary dysfunction, Dr. Karen L. Lifford from Harvard Medical
School, Boston, Massachusetts and colleagues explain in November's
Journal of the American Geriatrics Society, but there have been no
prospective studies of diabetes and incident incontinence.

The team used data from the Nurses Health Study to compare the risk
of prevalent and incident incontinence in women with type 2 diabetes
with that in women without diabetes.

Between 1996 and 2000, the incidence rate of incontinence was 10.5%
in women with diabetes and 7.0% in those without diabetes, the
authors report.

After controlling for age, women with diabetes had a 28% greater
risk for prevalent incontinence than women without diabetes, and a
21% increased risk of incident incontinence. This risk was more
pronounced for larger quantities of leakage, the results indicate.

Longer duration of diabetes increased the risk of incontinence
further, the researchers note, so that women with diabetes for more
than 10 years had nearly a 50% greater risk of incident
incontinence. Moreover, women with microvascular complications of
diabetes had more than double the risk of developing incontinence
compared with those without microvascular complications.

Results were similar after excluding obese women, subjects with a
prior stroke, those reporting substantial functional limitations,
and those who were nonsmokers.

"Overall, in this population of women, 17% of incontinence of any
quantity and nearly 15% of severe incontinence can be avoided with
the prevention of diabetes," the investigators suggest.

As they point out, "Diabetes is a largely preventable condition, and
studies have indicated that weight loss may decrease diabetes, as
well as urinary incontinence."

"In particular," the researchers add, "given the increasing risk of
incontinence with increasing duration of diabetes, even delaying
onset of diabetes could substantially reduce the medical, emotional,
and financial burdens of incontinence for older women."

J Am Geriatr Soc 2005;53:1851-1857

As body mass index (BMI) increases, the sensitivity of using the
standard B-type natriuretic peptide (BNP) cut-off point of 100 pg/mL
or greater for diagnosing heart failure (HF) decreases, a new study
shows.

The findings, presented here at the American Heart Association 2005
Scientific Sessions, suggest that a lower cut-off of 54 pg/mL or
greater could improve the sensitivity of BNP measurements in
severely obese patients, said Lori B. Daniels, MD, a cardiology
fellow at the University of California, San Diego.

"Obese patients tend to have lower levels of BNP, even when in heart
failure," Dr. Daniels told Medscape. "As a result, a severely obese
patient with a BNP of 80 pg/mL may be sent home, when in fact the
patient is in heart failure."

To find out what threshold would identify 90% of patients in various
weight classes with HF, the researchers studied 1,368 patients who
were enrolled in the prospective BNP Multinational Study presenting
to the emergency department with dyspnea.

BNP was measured on arrival, and two cardiologists blinded to the
results adjudicated the HF diagnosis based on a various factors,
including x-rays, echocardiograms, history and physical
examinations, and all lab work except BNP, afterward.

Patients were divided into three categories based on BMI: lean (< 25
kg/m2), overweight (25-35 kg/m2), or severely or morbidly obese (>
35 kg/m2).

In the severely or morbidly obese patients, a cut-off of 54 pg/mL
would have caught 90% of patients in HF, the study showed.

In both the overweight and lean patients, the standard cut-off point
of 100 pg/mL would have detected more than 90% of patients actually
in HF, but in severely obese patients, the cut-off point of 100
pg/mL limited the sensitivity to 77%.

Mariell L. Jessup, MD, medical director of the heart
failure/transplant program at the University of Pennsylvania Health
System in Philadelphia, told Medscape that while determining optimal
BNP cut-off points in different classes of patients is
important, "much more important is realizing that BNP is just part
of the puzzle.

"A specific patient's BNP value is not as important as factoring in
all the different variables [such as x-ray and echocardiogram
results] that can point to a heart failure diagnosis," she said.

AHA 2005 Scientific Sessions: Abstract 3512. Presented Nov. 16, 2005

Bradycardia patients with pacemakers who have atrial fibrillation
(AF) episodes lasting longer than one day are at three-fold
increased risk of arterial embolism, Italian researchers report.

Dr. Allesandro Capucci of Civile Hospital in Piacenza told Reuters
Health the findings show that "atrial tachycardias and not only AF
may be related to embolic events." The findings were "surprising,"
he added.

AF is common among bradycardia patients, Dr. Capucci and his
colleagues note in their report in the November 15 issue of the
Journal of the American College of Cardiology, while 6% to 10% of
bradycardia patients experience an embolic event annually.

They conducted the current observational, multicenter study to
evaluate factors associated with the risk of arterial embolism among
bradycardia patients implanted with pacemakers. They followed 360
men for a median of 22 months, or a total of 1,166 patient years. At
the study's outset, 31.0% of patients were taking antiplatelet
therapy while 36.4% were on anticoagulants.

The annual incidence of any embolic event was 1.2%, and 0.6% for
stroke. Ischemic disease increased the risk of having an embolic
event seven-fold, as did having had a prior embolic event. Patients
with diabetes were five times more likely to have an embolic event,
while hypertension increased the risk four-fold.

Also, the researchers found, AF episodes detected by the pacemaker
device that lasted longer than 24 hours were tied to a 3.1-fold
increased risk of an embolic event.

"Atrial fibrillation duration longer than one day could certainly be
a simple parameter to be used in clinical practice to guide
anticoagulation therapy," Dr. Capucci and colleagues write.

Monitoring of daily device diagnostics could be useful for this
purpose, they add. Currently, Dr. Capucci told Reuters Health, this
is generally only done to correlate clinical findings with AF types.

Just 32.2% of patients with indications for anticoagulation therapy
were receiving it at the start of the study, while 41.2% were on the
drugs by study's end, they note. Nine of the 14 patients who had
arterial embolism were on anticoagulants.

"Anticoagulation therapy was underused in our patient population;
moreover, arterial embolic events were observed also in
anticoagulated patients. This datum suggests either a stricter
international normalized ratio monitoring or an addition of
antiplatelet therapy," the researchers conclude.

J Am Coll Cardiol 2005;46:1913-1920

Losing weight may be more important than exercise when it comes to
being heart healthy in young adulthood, Rhode Island researchers
reported here at the American Heart Association 2005 Scientific
Sessions.

"It is better to be a normal weight than to be fat and fit," Charles
Eaton, MD, professor of family medicine at Brown University Medical
School in Pawtucket, Rhode Island, told Medscape. "There is a large
population of Americans who are overweight. The question is whether
it is better to lose weight or become fit."

Not surprisingly, this study showed that participants who were
highly fit and had a normal body mass index (BMI) had the best risk
factor profiles for coronary heart disease (CHD), while those with
low fitness levels or who were overweight or obese had the worst
profiles.

However, the researchers also found that low-fit normal weight
participants had better risk profiles for CHD than those who were
highly fit, but overweight or obese.

Researchers used cross-sectional data from the National Health and
Nutrition Examination Survey (NHANES) and studied 2,178 young
adults, aged 20 to 49 years, with different levels of fitness. All
participants had blood work-ups for total cholesterol (TC), high-
density lipoprotein cholesterol (HDL-C), glucose, insulin,
fibrinogen, and homocysteine levels. Blood pressure, height, and
weight were recorded using standard protocols. Fitness categories,
based on the norms for age and sex, were used to define low,
moderate, and high levels of cardiovascular fitness.

BMI was measured and categorized as normal (< 25 kg/m2), overweight
(25 - 30 kg/m2), and obese (> 30 kg/m2).

The researchers looked at the relationship between BMI level and
cardiovascular
fitness level to determine whether it is better to be fat and fit or
thin and unfit.

When comparing the group of participants who were obese/fit vs the
group that was thin/unfit, researchers found statistically
significant differences between groups in the TC/HDL-C ratio (P
= .0001) as well as HDL-C (P = .0078), TC (P = .0598) and non-HDL-C
(P = .0082) levels.

There also were trends toward differences in systolic blood pressure
and white blood counts in the obese/fit vs the thin/unfit, but the
differences did not reach statistical significance (120 mm Hg vs 112
mm Hg, respectively; P = .0869; and 7.24 vs 6.23, respectively; P
= .0869).

There were no significant differences in the homeostasis model
assessment (HOMA) index, a marker for insulin resistance, or in
homocysteine or diastolic blood pressure levels between the two
groups.

While this was a cross-sectional study that measured risk factors at
one time point, the findings show that for most markers it was
better to be thin and fit than fat and unfit, Dr. Eaton said. "High
fitness and normal BMI subjects had the best cardiovascular disease
risk factors. Those who were obese and unfit had the worst
cardiovascular risk factors."

But, he noted, the study results also suggest that it is better to
be normal weight and unfit than obese and fit.

The results, however, are not in line with other studies on this
subject and other preliminary studies have had mixed results. This
study, he said, probably would have required a larger number of
participants to reach statistical significance for some markers.

Nevertheless, "This study adds to the dialogue that weight is more
important than fitness," he told Medscape. "If you are overweight it
is better to get down to normal weight than be overweight and fit."

In addition, the data, he cautioned, are preliminary and no firm
clinical statement can be made at this time. Dr. Eaton called for
further longitudinal studies to determine whether dieting or
exercise will bring more beneficial results in reducing CHD risk
factors in the overweight or obese population.

"This study raises important questions as to whether or not being
fat and fit is okay," Robert Eckel, MD, president of the American
Heart Association and professor of medicine at the University of
Colorado Health Science Center in Denver, told Medscape. "The
biomarker report here is not as favorable as that previously
reported.

"Being both normal weight and fit remain the best recommendation for
prevention of cardiovascular disease and diabetes," he added.

AHA 2005 Scientific Sessions: Abstract 3611. Presented Nov. 13, 2005

An implantable hemodynamic monitoring device that continuously
measures intracardiac pressure on an outpatient basis can improve
outcomes among New York Heart Association (NYHA) class III/IV
patients by 33% compared with standard medical care alone,
researchers report.

Six-month follow-up results from the Chronicle Offers Management to
Patients with Advanced Signs and Symptoms of Heart Failure (COMPASS-
HF) trial also demonstrated that use of the ambulatory monitoring
device on top of optimal therapy was associated with a 33% reduction
in worsening HF compared with optimal therapy alone.

The results of the single-blinded, randomized controlled study,
presented here at the American Heart Association 2005 Scientific
Sessions, "demonstrate the benefits of remotely monitoring
hemodynamics and congestion in heart failure patients using an
implantable monitor," said principal investigator Robert C. Bourge,
MD, director of the division of cardiovascular disease at the
University of Alabama at Birmingham.

Dr. Bourge told Medscape that the implantable hemodynamic monitor
(Chronicle; Medtronic, Minneapolis, Minnesota) is implanted
subcutaneously, similar to a pacemaker, with a pressure-sensing lead
extending into the right ventricular outflow tract. The monitor
continuously tracks intracardiac pressure, body temperature, patient
activity, and heart rate, and the measurements are then transmitted
from the patient's home to the clinician's office via a secure
online connection.
COMPASS-HF was designed to determine whether a management strategy
based on continuously monitored intracardiac pressures in patients
with heart failure already receiving optimal medical care improves
patient morbidity. The study randomized 274 patients receiving
standard heart failure care, including standard drug and device
therapy, daily weight measurements, and regular access to heart
failure clinicians, to standard care alone (control group) or
standard care complemented by continuous hemodynamic monitoring
(monitor group).

The current analysis included 200 patients (99 control and 101
monitor) that completed six-month follow-up; 85% of patients
enrolled had NYHA functional class III heart failure at baseline.

Dr. Bourge and colleagues reported that improvement in the clinical
composite score, which took into account changes in NYHA class,
major clinical events, and hospitalizations, was higher in the
monitor patients compared with controls (46% vs 35%, respectively).

In addition, significantly fewer patients in the monitor group than
in the control group experienced worsening heart failure, as
measured by the clinical composite score (34% vs 51%, respectively;
P = .035).

Patients randomized to the monitor group had fewer incidents of
hospitalization for heart failureˇVrelated conditions (27.7% vs
44.4%) and fewer deaths (5.9% vs 8.1%). Investigators also reported
that NYHA class improved in 46.5% of patients in the monitor group,
compared with 38.5% of controls, and worsened in 3.0% of monitor
patients vs 5.2% of controls.

James D. Bergin, MD, medical director of the heart failure/cardiac
transplant program at the University of Virginia Health System in
Charlottesville, said that "the fewer number of patients
hospitalized in the treated group does suggest the technique may
hold promise.

"But the study was single-blinded, which makes subjective end points
a little more difficult [to interpret]," he told Medscape. "It would
be nice to see this applied to a larger group in a double-blind
fashion."

The trial was supported by Medtronic, the maker of the Chronicle
monitor.

AHA 2005 Scientific Sessions: Abstract 3015, Presented Nov. 14, 2005

As body mass index (BMI) increases, the sensitivity of using the
standard B-type natriuretic peptide (BNP) cut-off point of 100 pg/mL
or greater for diagnosing heart failure (HF) decreases, a new study
shows.

The findings, presented here at the American Heart Association 2005
Scientific Sessions, suggest that a lower cut-off of 54 pg/mL or
greater could improve the sensitivity of BNP measurements in
severely obese patients, said Lori B. Daniels, MD, a cardiology
fellow at the University of California, San Diego.

"Obese patients tend to have lower levels of BNP, even when in heart
failure," Dr. Daniels told Medscape. "As a result, a severely obese
patient with a BNP of 80 pg/mL may be sent home, when in fact the
patient is in heart failure."

To find out what threshold would identify 90% of patients in various
weight classes with HF, the researchers studied 1,368 patients who
were enrolled in the prospective BNP Multinational Study presenting
to the emergency department with dyspnea.

BNP was measured on arrival, and two cardiologists blinded to the
results adjudicated the HF diagnosis based on a various factors,
including x-rays, echocardiograms, history and physical
examinations, and all lab work except BNP, afterward.

Patients were divided into three categories based on BMI: lean (< 25
kg/m2), overweight (25-35 kg/m2), or severely or morbidly obese (>
35 kg/m2).

In the severely or morbidly obese patients, a cut-off of 54 pg/mL
would have caught 90% of patients in HF, the study showed.

In both the overweight and lean patients, the standard cut-off point
of 100 pg/mL would have detected more than 90% of patients actually
in HF, but in severely obese patients, the cut-off point of 100
pg/mL limited the sensitivity to 77%.

Mariell L. Jessup, MD, medical director of the heart
failure/transplant program at the University of Pennsylvania Health
System in Philadelphia, told Medscape that while determining optimal
BNP cut-off points in different classes of patients is
important, "much more important is realizing that BNP is just part
of the puzzle.

"A specific patient's BNP value is not as important as factoring in
all the different variables [such as x-ray and echocardiogram
results] that can point to a heart failure diagnosis," she said.

AHA 2005 Scientific Sessions: Abstract 3512. Presented Nov. 16, 2005

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Use of rosuvastatin appears to be a more cost effective means of
lowering LDL cholesterol than is treatment with atorvastatin,
according to European and US researchers.

In the October 10th issue of the International Journal of
Cardiology, Dr. Mark Hirsch of AstraZeneca UK Limited, in
Macclesfield, and colleagues note that the considerable cost of
lipid-lowering interventions makes it particularly important to
identify agents with the best cost-effectiveness ratio.

To see how rosuvastatin and atorvastatin compare in this regard, the
researchers examined pooled data from three double-blind trials. In
all, 389 patients had been randomized to rosuvastatin 10 mg and 393
received atorvastatin 10 mg.

Over the course of the 12-week study period, treatment with
rosuvastatin cost 1.85 euros per one percent reduction in LDL
cholesterol. For atorvastatin, the corresponding cost was 2.37 euros.

The average cost per patient treated to reach European LDL goals was
130.18 euros for rosuvastatin and 242.44 euros for atorvastatin. For
US LDL goals, the cost was 115 euros for rosuvastatin and 163 euros
for atorvastatin.

The researchers also note that more rosuvastatin patients reach
guideline goals on their starting dose, thus "reducing the costs
incurred by titration visits and monitoring."

The team notes that the two statins have the same acquisition cost,
but rosuvastatin is more efficacious than atorvastatin in lowering
LDL cholesterol. They call for further studies, but conclude
that "our findings after 12 weeks of statin therapy may also apply
to longer-term treatment."

Int J Cardiol 2005;104:251-256

Use of the new chemically synthesized agent pitavastatin appears to
reduce tubulointerstitial damage in certain patients with diabetic
nephropathy, Japanese researchers report in the November issue of
Diabetes Care.

As senior investigator Dr. Hikaru Koide told Reuters
Health, "pitavastatin can ameliorate injury in the renal tubules in
patients with early diabetic nephropathy from the viewpoint of
urinary fatty acid-binding protein excretion -- an index of renal
tubular injury."

Liver-type fatty acid binding protein (L-FABP) is expressed in renal
proximal tubules and is reported to be a useful marker for
progression of glomerulonephritis, Dr. Koide of Koto Hospital, Tokyo
and colleagues explain. Using levels of L-FABP as a marker, the team
initially studied 58 patients with type 2 diabetes and 20 healthy
controls.

All of the diabetic patients except 12 without nephropathy showed
significantly higher urinary L-FABP levels than did controls.

Of the diabetic patients, 20 with microalbuminuria were randomized
to receive pitavastatin 1 mg per day or placebo.

At 12 months, in the active treatment group, urinary albumin
excretion was significantly reduced from baseline (32 versus 110
mcg/minute). This was also true of L-FABP levels (8.8 versus 18.6
mcg/g creatinine). Little change was seen in placebo patients.

The researchers note that the effect was independent of cholesterol-
lowering action, and they speculate that the results may be "in part
due to reducing oxidative stress: however, the precise mechanisms
remain unclear."

Summing up, they conclude that "urinary L-FABP levels appear to be
associated with the progression of nephropathy, and pitavastatin may
be effective in ameliorating tubulointerstitial damage."

Diabetes Care 2005;28:2728-2732

For men, blood pressure in young adulthood is inversely related to
gestational age at birth, according to a report in the November 21st
online issue of Circulation: Journal of the American Heart
Association. Further studies are needed to determine if this holds
true in women as well.

"We hypothesized that preterm birth would be associated with high
blood pressure later in life, but we did not expect the risk to be
as high as it was," lead author Dr. Stefan Johansson, from the
Karolinska Institute in Stockholm, told Reuters Health.

"It is well known that low birth weight in term babies is associated
with high blood pressure and we thought that preterm birth would
provide a similar degree of risk. But, we found that preterm birth
provides a higher risk than just being small at term," he noted.

The findings stem from a study of 329,495 Swedish men who were born
between 1973 and 1981 and had blood pressure measurements recorded
20 years later upon conscription for military service. Term,
moderately preterm, very preterm, and extremely preterm births were
defined as a gestational age of 37 to 41, 33 to 36, 29 to 32, and 24
to 28 weeks, respectively.

The risk of high systolic blood pressure increased steadily from 25%
for moderately preterm birth to 93% for extremely preterm, relative
to term birth. Small for gestational age was only a risk factor for
high blood pressure among subjects with a gestational age of at
least 33 weeks.

Decreasing gestational age was also linked to increasing risks of
high diastolic blood pressure, but the association only reached
statistical significance for subjects born moderately preterm.

The mechanisms responsible for the link between gestational age and
blood pressure are unclear, but "could involve structural changes in
the vascular tree," Dr. Johansson said. "Functional alterations,
involving hormones and neuroendocrine effects, could also play a
role."

"One of the messages from this study is that children born preterm
should have their blood pressure checked at follow-up visits, at
least when they reach school age, because it may be important to
consider other risk factors for cardiovascular disease as they are
growing," Dr. Johansson said.

Circulation 2005