CARDIOVASCULAR NEWS
A new group of antithrombotic compounds could
have advantages over current therapies. The new
agents are peptides called pepducins and were
designed to inhibit the thrombin receptors PAR1
and PAR4 on platelets. Thrombin is the most potent
activator of platelets, and antagonists of these
2 receptors (PAR1 and PAR4) might be useful to
prevent the thrombotic and proliferative complications
of acute coronary syndromes. The pepducins work
by inhibiting signaling through G-protein-coupled
receptors (GPCRs), which are found throughout
the body and have key roles in both normal physiology
and disease. They are thus the targets for more
than 50% of all prescribed drugs, but so far all
GPCR agonists or antagonists act on the extracellular
side of the receptors. These new pepducins are
novel in that they are the first known compounds
to penetrate the cell and act as intracellular
inhibitors of GPCRs. These new pepducins might
overcome the limitations of current antithrombotic
therapies. Infusion of the anti-PAR1 and anti-PAR4
pepducins into mice extended bleeding time and
protected against systemic platelet activation.
New drugs targeting the thrombin PAR receptors
have the potential to be both safe and efficacious.
They will be efficacious because thrombin is the
most potent agonist of platelet activation, and
blocking the thrombin receptors PAR1 and PAR4
is safer than a direct thrombin antagonist such
as heparin or hirudin because the anti-PAR drug
would allow fibrin formation to be unperturbed.
Anti-PAR1/4 agents should also be safer than the
anti-GPIIb/IIIa drugs by allowing platelet aggregation
to proceed via the other secondary agonists and
the collagen receptor, which should reduce the
incidence of severe hemorrhage. However, these
anti-PAR1 and anti-PAR4 compounds will need to
be tested further for toxicity and pharmacologic
activity in animals, and if successful in these
tests they will enter clinical trials, probably
first in patients with acute coronary syndromes.
The authors hope they will be superior to aspirin
and clopidogrel in reducing complications of MI
or unstable angina. The pepducins are not yet
in development by any pharmaceutical company.
Nature Medicine September 23, 2002 AOP
Researchers have discovered proteins that appear
to control the size and function of the heart.
A tumor-suppressor gene called PTEN was known
to control the size of organs in a fly model.
Experiments were carried out on mice manipulating
PTEN. Suppression of PTEN caused hypertrophy in
the mouse hearts as well a dramatic decrease in
contractile function. PTEN and proteins called
P13K have known functions in the immune system
and many other tissues. PTEN works as a negative
regulator of P13K in determining heart size: in
these experiments, P13K unsuppressed by PTEN produced
large hearts. When P13K was blocked, the mice
developed hearts only half the normal size. They
also demonstrated that the function of these hearts
could be controlled through an interaction of
PTEN with P13K. Basically, when P13K was removed,
their hearts functioned normally. The researchers
have been able to genetically uncouple PTEN and
P13K, creating hearts in mice that are large but
highly contractile or small and failing. P13K
was previously known as a regulator of migration
of white blood cells in the setting of infection.
The authors were surprised that the same molecule
that controls neutrophil migration turned out
to a regulator of heart function as well. P13K
acts downstream of G protein-coupled receptors,
the main receptors in the heart that control contraction,
including beta-adrenergic and acetylcholine receptors.
It’s thought that in heart failure and hypertension,
pathologic changes are mediated by these receptors.
Plans are under way to investigate the role of
P13K in animal models of heart failure. Similarly,
there may be a role for this protein in acute
ischemic insult. During ischemia, contractility
is dramatically reduced and begins to recover
during reperfusion. Animal experiments are currently
underway to see if shutting down P13K during acute
myocardial infarction improves cardiac function.
The hope is that manipulating the same proteins
in humans may prevent pathologic cardiac problems
such as hypertrophy and mechanical dysfunction.
Cell 2002;110:737 (AOP September 20, 2002)
Autologous skeletal myoblast transplantation
for treatment of postinfarction heart failure
is feasible and relatively safe. The procedure
appears to restore contractility in some segments.
Preclinical studies, have shown that myoblasts
differentiate into cells that resemble myocytes
and that they form fibers, induce angiogenesis
to provide a blood supply, and improve function
and contractility within infarcted tissue. Because
the patient’s own skeletal myoblasts are used,
some of the problems encountered in obtaining
other types of cells for myocardial regeneration
are avoided with this technique. Autologous skeletal
myoblasts can be easily obtained, extracted from
a muscle biopsy, and then expanded in culture,
and finally reinjected into an area of myocardial
infarct. Siminiak and colleagues in Poland carried
out autologous skeletal mypblast transfer in 10
patients with previous myocardial infarction.
They injected the cells directly into scarred
tissue while the patient’s chest was open during
bypass surgery, choosing an area of the infarction
that would not be revascularized by the procedure.
Injected segments had been shown to be either
akinetic or dyskinetic on dobutamine stress echo.
Patients at relatively low risk were purposely
selected, and each received about 20 million cells.
Follow-up dobutamine stress echo showed an increase
in contractility in several injected segments.
There was however 1 death that occurred 7 days
postoperatively. Autopsy revealed a new site of
infarction in a part of the left ventricle that
had previously been normokinetic. Their first
2 patients experienced sustained ventricular fibrillation
(VF) postoperatively. Both were treated with oral
amiodarone, which was discontinued by 5 months.
After these cases, prophylactic infusion of amiodarone
was given in all subsequent patients, and there
were no subsequent episodes of arrhythmia. Menasché
et al in France first reported their series of
10 patients at the American Heart Association
Meeting in 2001 and VF was also observed in 4
patients. The possibility that arrhythmias might
be related to the procedure itself raises the
issue of safety. About 90% of transplanted cells
die almost immediately. Such a small number of
surviving cells would be unlikely to affect function.
In a new phase 2 trial planned by the French group,
patients are being randomized to a low dose of
400 million cells and a high dose of 800 million
cells. Target enrollment for the trial is 300
patients. The forthcoming study is primarily designed
to address whether or not skeletal myoblast transfer
can or cannot improve function in postinfarction
heart failure.
European Society of Cardiology Congress 2002.
Berlin
Manipulating gene expression in the failing
heart has therapeutic promise, but until now efficient
and homogeneous cardiac gene delivery has required
an open-chest approach. Investigators examined
the hypothesis that vector delivery promoted by
echo contrast microbubbles will be maximized by
injection of the vectors into the aortic root
with brief balloon occlusion above the sinuses,
while at the same time prolonging diastole and
vasodilating with acetylcholine (ACh) to maximize
coronary exposure. After incubation with albumin-coated
perfluorocarbon microbubbles, an adenovirus encoding
a reporter gene was infused into the aortic root
of rats. To maximize delivery, the aortic root
was transiently occluded with a balloon catheter
during a brief ACh-induced asystole. Ultrasound
was used to image the delivery and disrupt the
microbubbles. Aortic occlusion with concomitant
ACh increased myocardial gene expression for virus
+ microbubbles by >2.5-fold, from 925±165 to 2358±376
relative units (RU; P<0.01). This delivery system
also produced substantial expression with vector
alone (1473±549 RU). All uptakes were significant
compared with 433±332 RU without virus. The study
concluded that an adenoviral delivery system combining
echo contrast with a catheter-based technique
to maximize coronary perfusion increases gene
delivery compared with echo contrast alone. This
novel method permits efficient percutaneous gene
delivery in closed-chest animals. (Circulation.
2002; 106:1756)
Experimental data suggest that bone
marrow–derived cells may contribute to the healing
of myocardial infarction (MI). 10 patients who
were treated by intracoronary transplantation
of autologous, mononuclear bone marrow cells (BMCs)
in addition to standard therapy after MI were
analyzed After standard therapy for acute MI,
10 patients were transplanted with autologous
mononuclear BMCs via a balloon catheter placed
into the infarct-related artery during balloon
dilatation (percutaneous transluminal coronary
angioplasty). Another 10 patients with acute MI
were treated by standard therapy alone. After
3 months of follow-up, the infarct region (determined
by left ventriculography) had decreased significantly
within the cell therapy group (from 30±13 to 12±7%,
P=0.005) and was also significantly smaller compared
with the standard therapy group (P=0.04). Likewise,
infarction wall movement velocity increased significantly
only in the cell therapy group (from 2.0±1.1 to
4.0±2.6 cm/s, P=0.028). Further cardiac examinations
(dobutamine stress echocardiography, radionuclide
ventriculography, and catheterization of the right
heart) were performed for the cell therapy group
and showed significant improvement in stroke volume
index, left ventricular end-systolic volume and
contractility (ratio of systolic pressure and
end-systolic volume), and myocardial perfusion
of the infarct region. These results demonstrate
for the first time that selective intracoronary
transplantation of autologous, mononuclear BMCs
is safe and seems to be effective under clinical
conditions. The marked therapeutic effect may
be attributed to BMC-associated myocardial regeneration
and neovascularization.
(Circulation. 2002;106:1913.)
Peripheral blood mononuclear cells
(PBMNCs), platelets, and polymorphonuclear leukocytes
(PMNs) contain various angiogenic factors and
cytokines. Unilateral hindlimb ischemia was surgically
induced in athymic nude rats, and fluorescence-labeled
human blood cells (PBMNCs, platelets or PMNs)
were intramuscularly implanted into the ischemic
limbs. Laser Doppler imaging revealed markedly
increased blood perfusion in PBMNC+platelet-implanted
limbs (44% increase, P<0.001) compared with control
implantation of human umbilical vein vascular
endothelial cells. The addition of PMNs to PBMNCs+platelets
attenuated blood perfusion (27% decrease, P<0.01).
Neocapillary densities were increased by implantation
of PBMNCs+platelets or platelets alone (3.5-fold
and 2.4-fold, respectively; P<0.001), whereas
PMNs inhibited (32%, P<0.05) PBMNC+ platelet-mediated
capillary formation. There was no incorporation
of implanted PBMNCs into neocapillaries, whereas
PBMNCs and platelets accumulated around arterioles
after implantation. Cellular extract from PBMNCs+platelets,
in which vascular endothelial growth factor (VEGF),
basic fibroblast growth factor, platelet-derived
growth factor-AB, and transforming growth factor-ß
were detected, markedly stimulated tubule formation
of human umbilical vein vascular endothelial cells.
Anti-VEGF neutralizing antibody markedly inhibited
tubule formation and in vivo vessel formation.
Neutrophil elastase inhibitor blocked the antiangiogenic
action of PMNs, whereas inhibitors of oxygen metabolites
had no effect. The study demonstrated that implantation
of PBMNCs and platelets into ischemic limbs effectively
induce collateral vessel formation by supplying
angiogenic factors (mainly VEGF) and cytokines,
suggesting that this cell therapy is useful as
a novel strategy for therapeutic angiogenesis.
(Circulation. 2002;106:2019) .
The potential role of oral anticoagulant
therapy as secondary prevention is highlighted
in the Warfarin, Aspirin, Reinfarction Study (WARIS
II). In this open-label study, patients hospitalized
in 20 Norwegian centers for acute myocardial infarction
were randomly assigned to long-term treatment
with either warfarin (at a dose targeted to achieve
an international normalized ratio [INR] of 2.8
to 4.2), 160 mg of aspirin daily, or 75 mg of
aspirin daily plus warfarin (INR, 2.0 to 2.5).
The primary outcome-a composite of death, nonfatal
reinfarction, or thromboembolic stroke-occurred
in 20% of the patients in the aspirin-only group,
16.7 % of those in the warfarin-only group, and
15% of those in the combination-therapy group.
The overall risk reduction was 29% in the combination-therapy
group (P=0.001 for the comparison with the aspirin-only
group) and 19% in the warfarin-only group (P=0.03).
The incidence of nonfatal major hemorrhage among
the patients receiving warfarin (either alone
or in combination) was three to four times that
among the patients receiving aspirin alone.
(N Eng J Med. 2002;347:969 – 974).
In a study of about 6600 cardiac
surgeries performed in California hospitals, female
children had 51% higher odds of death than male
children. The study, which reviewed hospital discharge
data between 1995 and 1997, showed that when other
factors are held equal, female sex is a risk factor
for higher mortality among children undergoing
surgery for congenital heart disease. The surgeries
were adjusted for risk, and the end-point was
in-hospital death versus alive at discharge. The
investigators used logistic regression analysis
to evaluate the effect of sex on in-hospital mortality,
controlling for age, race and ethnicity, type
of insurance, home income, type of admission,
date and month of surgery, hospital case volume,
and the type of procedure. Among 6593 cases, there
were 345 in-hospital deaths, for an overall mortality
rate of 5.23%. They found that crude mortality
rates did not differ significantly between the
sexes, 4.98% for males and 5.54% for females.
The rates were highest in neonates at 16.5%, falling
to 5.57% for infants, and 1.75% for children over
1 year old. Compared with the males, though, fewer
of the female children were neonates, and the
females more often had lower-risk procedures such
as ASD closure and fewer high-risk procedures
such as the Norwood operation than the males.
Multivariate logistic regression accounting for
these differences showed the females actually
had a higher risk of in-hospital mortality, with
an odds ratio of 1.51 (P<0.01). The investigators
state that the reason for this difference is unclear,
but is unlikely to be due to variations in service
utilization during hospitalization, since the
risk-adjusted length of stay and hospital charges
were similar between the groups. The authors note,
however, that females in this study had a higher
incidence of comorbid conditions, including Down
syndrome, pulmonary hypertension, and failure
to thrive. Thus, they speculate that the sex difference
in surgical outcomes discovered in the present
study may be due to other biological differences
between young males and females that were not
characterized in this administrative data set.
Circulation 2002;106:1514 (AOP
September 17, 2002)
Data from the CARMEN trial indicate
that left ventricular remodeling in patients with
mild chronic heart failure (HF) can be significantly
improved by the early administration of carvedilol
in combination with an ACE inhibitor. The Carvedilol
ACE Inhibitor Remodeling Mild CHF Evaluation (CARMEN)
trial is the first large-scale study directly
comparing the effects of a beta blocker with an
ACE inhibitor in this condition. In 65 institutions
in 13 European countries, a total of 572 patients
with mild HF (ejection fraction [EF] < 39%) were
randomized in a double-blind design into 3 study
arms, receiving 18 months of treatment on top
of their current HF therapy (diuretics, digoxin,
nitrates): Carvedilol in combination with enalapril;
Carvedilol alone; Enalapril alone. The objective
of the trial was to evaluate the efficacy of carvedilol
alone or a combination of carvedilol with enalapril
vs enalapril alone, in terms of left ventricular
remodeling, tolerability, and safety. The primary
study end point, the change in LV-end-systolic-volume
index, was assessed by echocardiogram at the initiation
of treatment and at 6 and 18 months of follow-up.
In patients receiving carvedilol plus ACE inhibitor
and in those taking carvedilol alone the researchers
found a highly significant improvement of LV-remodeling
and a significant reduction in heart size. Patients
on enalapril only, in contrast, did not show a
benefit. All 3-treatment arms had similar safety
and tolerability profiles and no significant difference
in mortality and morbidity. It was pointed out
that the observed effect was only seen with Carvedilol.
Other beta blockers may not show the same effect.
European Society of Cardiology Congress 2002.
Berlin
retion and all-cause mortality and
mortality caused by cardiovascular (CV) disease
and non-CV disease in the general population was
examined. In the period 1997 to 1998, all inhabitants
of the city of Groningen, the Netherlands, aged
between 28 and 75 years (n=85 421) were sent a
postal questionnaire collecting information about
risk factors for CV disease and CV morbidity and
a vial to collect an early morning urine sample
for measurement of urinary albumin concentration
(UAC). The vital status of the cohort was subsequently
obtained from the municipal register, and the
cause of death was obtained from the Central Bureau
of Statistics. Of these 85 421 subjects, 40 856
(47.8%) responded, and 40 548 could be included
in the analysis. During a median follow-up period
of 961 days (maximum 1139 days), 516 deaths with
known cause were recorded. We found a positive
dose-response relationship between increasing
UAC and mortality. A higher UAC increased the
risk of both CV and non-CV death after adjustment
for other well-recognized CV risk factors, with
the increase being significantly higher for CV
mortality than for non-CV mortality (P=0.014).
A 2-fold increase in UAC was associated with a
relative risk of 1.29 for CV mortality (95% CI
1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for
non-CV mortality. Urinary albumin excretion is
a predictor of all-cause mortality in the general
population. The excess risk was more attributable
to death from CV causes, independent of the effects
of other CV risk factors, and the relationship
was already apparent at levels of albuminuria
currently considered to be normal.
(Circulation. 2002;106:1777.)
Observational studies have suggested
that psychological stress increases the incidence
of sudden cardiac death. Whether emotional or
physical stressors can trigger spontaneous ventricular
arrhythmias in patients at risk has not been systematically
evaluated. Patients with implantable cardioverter-defibrillators
(ICDs) were given diaries to record levels of
defined mood states and physical activity, using
a 5-point intensity scale, during 2 periods preceding
spontaneously occurring ICD shocks (0 to 15 minutes
and 15 minutes to 2 hours) and during control
periods 1 week later. ICD-stored electrograms
confirmed the rhythm at the time of shock. A total
of 107 confirmed ventricular arrhythmias requiring
shock were reported by 42 patients (33 men; mean
age, 65 years; 78% had coronary artery disease)
between August 1996 and September 1999. In the
15 minutes preceding shock, an anger level ž3
preceded 15% of events compared with 3% of control
periods (P<0.04; odds ratio, 1.83; 95% confidence
intervals, 1.04 to 3.16) Other mood states (anxiety,
worry, sadness, happiness, challenge, feeling
in control, or interest) did not differ. Patients
were more physically active preceding shock than
in control periods. Anger and physical activity
were independently associated with the preshock
period. Anger and physical activity can trigger
ventricular arrhythmias in patients with ICDs.
Future investigations of therapies aimed at blocking
a response to these stressors may decrease ventricular
arrhythmias and shocks in these patients.
(Circulation. 2002;106:1800.)
Off-pump coronary artery bypass
surgery has been demonstrated to reduce morbidity
in elective patients. However, high-risk patients
might benefit the most from this surgical procedure.
Investigators evaluated the effectiveness of on-pump
and off-pump coronary artery bypass surgery on
early clinical outcome in a consecutive series
of overweight patients. From April 1996 to April
2001, data on 4321 patients undergoing coronary
surgery (mortality 1.4%) were prospectively entered
into the Patient Analysis and Tracking System.
Data were extracted for all patients with a body
mass index ž25 kg/m2. A risk-adjusted analysis
was performed to assess the effect of surgical
technique in the whole overweight cohort. 2844
patients were identified (2261 male, median age
63, interquartile range 56 to 68). Patients undergoing
on-pump surgery (76.3%) were less likely than
those undergoing off-pump surgery to have hypercholesterolemia
or left main stem disease and were, on average,
less obese. However, they were more likely to
have unstable angina and to have had a previous
myocardial infarction, and they had more extensive
coronary disease and received more grafts (all
P<0.05). Unadjusted analyses, taking account only
of consultant team, showed significant benefits
of off-pump surgery in terms of hospital deaths,
arrhythmias, inotropic use, use of intra-aortic
balloon pump, blood loss, transfusion requirement,
postoperative hemoglobin, chest infections, neurological
complications, intensive care unit and hospital
stay (all P<0.05). After adjustment for confounding
prognostic factors, the benefits of off-pump surgery
were still significant for death in hospital,
transfusion requirement, postoperative hemoglobin,
neurological complications, intensive care unit
and hospital stay (ORs 0.35 to 0.79, P<0.05).
These results suggest that off-pump surgery is
safe and effective and is associated with a reduced
in-hospital mortality and morbidity in overweight
patients when compared with conventional coronary
surgery with cardiopulmonary bypass and cardioplegic
arrest.
(Circulation. 2002;106:1764)
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