Circulation. 2008;118:2485-2487
doi: 10.1161/CIRCULATIONAHA.108.191130
(Circulation. 2008;118:2485-2487.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation: The A4 Study
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The mainstay of treatment for atrial fibrillation has historically
been pharmacological, using drugs to control either the rhythm
or the rate. However, nonpharmacological approaches have been
effective at restoring sinus rhythm in drug-refractory patients,
raising the possibility of using catheter ablation earlier in
the management cascade than previously envisaged. Nonrandomized
or single-center studies suggesting the superiority of catheter
ablation over antiarrhythmic drug treatment have been reported.
We performed a prospective randomized controlled trial involving
112 patients in 4 centers, 2 in North America and 2 in Europe,
comparing a strategy of additional antiarrhythmic drugs (59
patients) with catheter ablation (53 patients) for patients
with paroxysmal atrial fibrillation who had previously failed
at least 1 antiarrhythmic drug. At the 1-year follow-up, 13
of 55 patients (23%) and 46 of 52 patients (89%) had no recurrence
of atrial fibrillation in the antiarrhythmic drug and ablation
groups, respectively (
P<0.0001). Symptom score, exercise
capacity, and quality-of-life scores were significantly higher
in the ablation group. This multicenter randomized trial demonstrates
that catheter ablation of atrial fibrillation is superior to
antiarrhythmic drug therapy in patients with paroxysmal atrial
fibrillation who have previously taken and failed antiarrhythmic
drugs. The substantial improvement in quality of life, symptoms,
and physical performance in this series of relatively young
and healthy patients constitutes an important benefit that may
support earlier use of catheter ablation in this context. See
p
2498.
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Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis: Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)
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Considerable interest has focused on the development of therapies
that raise systemic levels of high-density lipoprotein (HDL)
cholesterol. Despite substantial elevation of HDL cholesterol,
the cholesteryl ester transfer protein inhibitor torcetrapib
failed to slow progression of atherosclerosis and was associated
with excess mortality in clinical trials. This has fueled speculation
that the functionality of HDL is impaired in the setting of
cholesteryl ester transfer protein inhibition. Although torcetrapib
substantially elevated HDL cholesterol but had no effect on
percent atheroma volume, in this post hoc analysis an inverse
relationship was observed between changes in levels of HDL cholesterol
and percent atheroma volume. Disease regression at the highest
levels of HDL cholesterol suggests that HDL particles can retain
their functional activity, in terms of lipid mobilization, in
patients treated with cholesteryl ester transfer protein inhibitors.
The lack of efficacy is likely to reflect some form of off-target
toxicity, such as activation of the renin-angiotensin-aldosterone
axis. As a result, additional cholesteryl ester transfer protein
inhibitors that lack such adverse effects may have a beneficial
influence on cardiovascular disease risk. This possibility requires
confirmation in prospective randomized clinical trials. See
p
2506.
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Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity: A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials
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The cholesteryl ester transfer protein (CETP) inhibitor torcetrapib
has been shown to increase cardiovascular event rates despite
conferring a significant high-density lipoprotein cholesterol
increase. Hypotheses have been put forward to explain this unanticipated
result, relating either to the mechanism of CETP inhibition
per se or to off-target adverse effects of the torcetrapib molecule.
We pooled the data from 2 large vascular imaging trials with
torcetrapib and confirmed that the use of torcetrapib induces
electrolyte changes, increase in blood pressure, and increased
carotid intima-media thickness progression. The blood pressure
changes were related to both the electrolyte changes and the
increased carotid intima-media thickness progression. In contrast,
torcetrapib-induced high-density lipoprotein increase was unrelated
to either electrolyte changes or carotid intima-media thickness
progression. The difference in carotid intima-media thickness
progression between treatment groups was attenuated after adjustment
for off-target effects (blood pressure and electrolyte changes)
but not after adjustment for effects related to CETP inhibition
(low-density lipoprotein cholesterol and high-density lipoprotein
cholesterol changes). Although it cannot be excluded that the
mechanism of CETP inhibition was detrimental by itself, our
findings suggest that off-target toxicity of the torcetrapib
molecule has contributed to the adverse outcome seen with torcetrapib.
Interactions with different types of antihypertensive medications
suggest mineralocorticoid excess as a possible mechanism. Evidence
is accumulating that other CETP inhibitors which are currently
being developed do not display this type of off-target toxicity.
Our study therefore supports a careful further development of
these modalities, albeit with an unremittingly strong focus
on their safety profile. See p
2515.
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Angiotensin II Type 2 Receptor Stimulation: A Novel Option of Therapeutic Interference With the Renin-Angiotensin System in Myocardial Infarction?
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Interference with the renin-angiotensin system is a very common,
well-established, and successful concept of treatment in cardiovascular
disease. All currently available and approved renin-angiotensin
system–interfering drugs (angiotensin-converting enzyme
[ACE] inhibitors, angiotensin II type 1 [AT
1] receptor [AT
1R]
blockers, renin inhibitors, aldosterone antagonists) aim at
inhibition of the unfavorable effects of an overactivated renin-angiotensin
system signaling via the AT
1R. However, the renin-angiotensin
system not only harbors the renin/ACE/AT
1R-aldosterone axis,
which, when overstimulated, is involved in a huge variety of
pathologies ranging from hypertension to end-organ damage or
local processes in myocardial infarction and stroke; in fact,
it also possesses a tissue-protective axis involving ACE
2, Ang
1–7,
and the AT
2 receptor (AT
2R), which seems to counteract detrimental
effects mediated via the AT
1R but also inflammation, hyperproliferation,
or fibrosis in general. At present, no pharmacological tool
is available to specifically stimulate this beneficial ACE
2/Ang
1–7/AT
2R
axis in vivo. The novel nonpeptide AT
2R agonist compound 21
may be such a drug. The study presented here is the first to
test the therapeutic potential of direct AT
2R stimulation in
a model of myocardial infarction. Compound 21 significantly
improved cardiac function and resulted in a smaller scar size
independent of any hemodynamic changes. Because compound 21
is a nonpeptide with a sufficient bioavailability (
30%), it
may be a suitable lead compound for the development of a drug
for the blood pressure–independent treatment or prevention
of end-organ damage in humans. See p
2523.
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Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease: The Framingham Offspring Study
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We tested whether elevated levels of the hemostatic and vascular
dysfunction biomarker von Willebrand factor predicted incident
cardiovascular disease in a community sample over 11 years of
longitudinal follow-up, and in particular, among those with
type 2 diabetes mellitus or insulin resistance (measured with
the homeostasis model). After adjustment for age, sex, blood
pressure, smoking, body mass index, total and high-density lipoprotein
cholesterol, and treatment with aspirin, insulin, antihypertensives,
and lipid-lowering medications, the hazard ratio for cardiovascular
disease was 1.32 in the highest quartile of the von Willebrand
factor distribution relative to the lowest (
P=0.04 for trend).
Additional adjustment for type 2 diabetes mellitus or insulin
resistance somewhat weakened the association. We stratified
the models by diabetes status or the top quartile of the homeostasis
model of insulin resistance distribution ("insulin resistant")
versus the lower 3 quartiles. Von Willebrand factor was associated
with cardiovascular disease among participants with diabetes
mellitus (
P=0.04 for trend) but not among nondiabetics (
P=0.5)
and similarly among insulin-resistant (
P=0.01) but not insulin-sensitive
(
P=0.9) participants. Elevated levels of von Willebrand factor
were an independent risk factor for cardiovascular disease,
especially in people with diabetes mellitus or insulin resistance,
in whom endothelial or hemostatic dysfunction may be a novel
therapeutic target for prevention of cardiovascular disease.
See p
2533.
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Predictive Value of Myocardial Perfusion Single-Photon Emission Computed Tomography and the Impact of Renal Function on Cardiac Death
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Although it is known that a substantial portion of death in
patients with chronic kidney disease (CKD) is attributable to
cardiac causes, risk-stratification methods in this group of
patients have been less well described. In this study, we examine
the impact of renal function on death rates and highlight the
important role of single-photon emission CT (SPECT) imaging
in the risk stratification of patients with varying degrees
of renal dysfunction. In this study population of 1652 predominately
male patients, patients with CKD had higher death rates than
those without CKD, and the same trend was seen for patients
with an abnormal myocardial perfusion SPECT. Cardiac death was
low in patients with normal scans and no CKD (0.8% per year).
It rose more than 3-fold to 2.7% per year in CKD patients with
no perfusion defects on myocardial perfusion SPECT and was substantially
higher (9.5% per year) in patients with CKD and perfusion defects
on myocardial perfusion SPECT. An abnormal myocardial perfusion
SPECT and CKD in synergy predicted death more accurately than
either one alone. Additionally, across the entire spectrum of
renal function, myocardial perfusion abnormalities on SPECT
were powerful predictors of cardiac death and all-cause mortality.
The presence of ischemia, in particular, was independently associated
with cardiac death, nonfatal myocardial infarction, and all-cause
mortality. A CKD patient with an abnormal myocardial perfusion
SPECT is in the highest risk group. The best route of management
(invasive versus medical therapy) in this group of patients
remains to be defined. Even in the presence of a normal SPECT,
CKD confers risk that requires special attention to risk factor
modification. See p
2540.
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Gasping During Cardiac Arrest in Humans Is Frequent and Associated With Improved Survival
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The incidence and significance of gasping after primary cardiac
arrest are controversial. This study confirms that gasping is
common in the early minutes after cardiac arrest, but in untreated
patients its incidence decreases rapidly with time. Gasping
was present in 33% of patients who arrested after emergency
medical system arrival, in 20% when emergency medical system
arrival was <7 minutes, in 14% when arrival time was 7 to
9 minutes, and in 7% when arrival time was >9 minutes. Among
the patients who received bystander cardiopulmonary resuscitation,
survival to hospital discharge occurred among 39% of patients
who gasped versus only 9% who did not gasp. Thus, resuscitation
efforts are most effective in patients who gasp. Gasping often
delays the recognition of cardiac arrest in patients with witness
collapse and thereby may delay prompt initiation of bystander
resuscitation efforts. During resuscitation efforts, the return
of gasping may be interpreted as a sign of recovery, so resuscitation
efforts are often interrupted. Gasping is not a sign of recovery
but a sign that resuscitation efforts are effective and should
be continued because the chance of survival in such patients
is greater. When gasping is present, assisted ventilation during
resuscitation efforts might not be necessary. Recognition of
gasping and its significance in patients with primary cardiac
arrest is important to successful resuscitation efforts. See
p
2550.
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Plasma Fetuin-A Levels and the Risk of Myocardial Infarction and Ischemic Stroke
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Fetuin-A is a protein almost exclusively secreted by the liver.
Studies in humans have demonstrated that circulating fetuin-A
levels are positively associated with fat accumulation in the
liver, insulin resistance, the metabolic syndrome, and diabetes
mellitus, conditions that are associated with increased risk
of cardiovascular disease. Whether fetuin-A is associated with
cardiovascular diseases in the general population is unknown.
We evaluated the association of plasma fetuin-A concentrations
with myocardial infarction and ischemic stroke on the basis
of 395 subjects with myocardial infarction and stroke and 2198
individuals who remained free of cardiovascular events during
follow-up. We observed that fetuin-A concentrations are strongly
associated with risk of myocardial infarction and ischemic stroke
independently of standard risk factors. Of note, some previous
studies investigating the role of fetuin-A in cardiovascular
diseases have yielded conflicting results. Low fetuin-A levels
were associated with increased cardiovascular mortality in patients
with end-stage renal disease. Because circulating fetuin-A is
an inhibitor of calcification, increased vascular calcification
in patients with renal disease (who display low fetuin-A levels)
may be the mechanism underlying the observed association with
increased mortality in this group of patients. Overall, these
data and the present study indicate that the role of fetuin-A
in cardiovascular diseases may be complex. Our data provide
the first evidence for a link between high plasma fetuin-A levels
and an increased risk of myocardial infarction and ischemic
stroke. Additional research is warranted to elucidate the mechanisms
by which fetuin-A influences the risk of cardiovascular disease.
See p
2555.
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Degradation and Healing Characteristics of Small-Diameter Poly( -Caprolactone) Vascular Grafts in the Rat Systemic Arterial Circulation
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Finding better shelf-ready small-diameter grafts has been on
the agenda of many researchers and clinicians for decades. Currently
available expanded polytetrafluoroethylene and Dacron grafts
have a very limited use under 6 mm of internal diameter in cardiac
and vascular surgery, mainly because of early thrombosis and
late intimal hyperplasia. Biodegradable polymers have recently
been investigated to serve as vascular scaffolds. After optimization
studies, we produced biodegradable small-diameter scaffolds
made of poly(
-caprolactone) nanofibers using electrospinning
and implanted 15 poly(
-caprolactone) and 15 expanded polytetrafluoroethylene
grafts (2-mm diameter, 13-mm length) with a follow-up of up
to 6 months. Our results showed that these poly(
-caprolactone)
grafts have significantly better healing characteristics such
as faster endothelial coverage, better cellular infiltration
accompanied by neoangiogenesis, and stable and homogeneous neointima
formation compared with expanded polytetrafluoroethylene grafts.
Rapid coverage of luminal surface by a confluent endothelium
may prevent early graft thrombosis. In contrast to the expanded
polytetrafluoroethylene grafts, which show increasing neointima
formation and stenotic lesions over time, poly(
-caprolactone)
grafts showed a more homogeneous neointimal layer covered by
confluent endothelium. This may prevent late graft occlusions
resulting from intimal hyperplasia. However, this hypothesis
has to be tested by studies that have long-term follow-up in
the arterial circulation of animals. Using biodegradable scaffolds,
this study adds data to the fields of vascular prostheses and
tissue engineering. Our promising results are a step toward
the shelf-ready coronary bypass grafts of the future. See p
2563.
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