Circulation. 2008;118:1-2
doi: 10.1161/CIRCULATIONAHA.108.189733
(Circulation. 2008;118:1-2.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Role of Conduction Velocity Restitution and Short-Term Memory in the Development of Action Potential Duration Alternans in Isolated Rabbit Hearts
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T-wave alternans often are a precursor to ventricular fibrillation
and thus sudden cardiac death. It has been suggested that spatially
discordant alternans (SDA) of action potential duration may
lead to T-wave alternans, but the underlying mechanisms of SDA
development are not clear. Previous studies have proposed preexisting
action potential duration heterogeneities and steep dependence
of conduction velocity in the myocardium on the preceding diastolic
interval as possible causes of SDA. Our experiments demonstrate
that a new mechanism associated with pacing history, ie, short-term
memory, might also underlie SDA formation in the heart. In addition,
we show that the heterogeneity of action potential duration
does not necessarily correlate with the onset of alternans.
Our findings have significant clinical relevance because they
suggest that new dynamic factors such as the rate at which the
heart muscle is paced also may play a role in the development
of SDA and subsequently ventricular fibrillation. This suggests
that cardiac memory needs to be considered an additional factor
that can contribute to arrhythmia initiation. Ultimately, our
findings can be used to define a new paradigm in the clinic
for testing arrhythmia inducibility and need to be considered
in the design of antiarrhythmic drugs. See p
17.
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Gender and Outcome in Adult Congenital Heart Disease
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Gender differences in prognosis have frequently been reported
in cardiovascular disease but less so in adult congenital heart
disease. In the CONgenital CORvitia (CONCOR) national registry
of adults with congenital heart disease (n=7414), we found that
women had a 33% higher risk of pulmonary hypertension, a 33%
lower risk of aortic outcomes, a 47% lower risk of endocarditis,
and a 55% lower risk of an implantable cardioverter-defibrillator
implant. These findings should stimulate basic and clinical
research to advance the knowledge on gender-specific issues
in adult congenital heart disease. See p
26.
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Association of Insulin Resistance and Inflammation With Peripheral Arterial Disease: The National Health and Nutrition Examination Survey, 1999 to 2004
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Peripheral arterial disease (PAD) is an important manifestation
of systemic atherosclerosis. Systemic inflammation and insulin
resistance are closely linked pathological states, and each
contributes to the development of atherosclerosis. However,
the specific association of insulin resistance with PAD and
the influence of insulin resistance on the relationship between
inflammation and PAD have not been established. Using data from
the National Health and Nutrition Examination Survey 1999 to
2004, we found that insulin resistance, as measured by the homeostasis
model of insulin resistance, is strongly associated with PAD
independently of known cardiovascular risk factors. Furthermore,
we found that the presence of insulin resistance blunts the
association between inflammation, as measured by C-reactive
protein, and PAD. These findings suggest a direct link between
PAD and insulin resistance along its entire spectrum and highlight
the complex interplay of insulin resistance and inflammation
in atherosclerosis. See p
33.
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Effect of Doxazosin Gastrointestinal Therapeutic System as Third-Line Antihypertensive Therapy on Blood Pressure and Lipids in the Anglo-Scandinavian Cardiac Outcomes Trial
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The use of doxazosin in the management of hypertension has declined
after publication of the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT) because of
concerns about its safety, particularly with regard to heart
failure. In view of this, investigators from the Anglo-Scandinavian
Cardiac Outcomes Study–Blood Pressure Lowering Arm (ASCOT-BPLA)
conducted an observational analysis of the blood pressure–lowering
efficacy and safety of modified-release doxazosin used as a
common third-line agent in study participants whose blood pressure
was uncontrolled despite their other randomized study drugs
(either amlodipine and perindopril or atenolol and bendroflumethiazide).
Among 10 069 participants who received doxazosin for a median
of 12 months of uninterrupted treatment, blood pressure fell
by an average of almost 12/7 mm Hg. This was associated with
modest reductions in total and LDL cholesterol but a small rise
in fasting plasma glucose concentrations. Doxazosin was generally
well tolerated; 7.5% of recipients discontinued the drug because
of adverse events, most commonly dizziness, fatigue, headache,
and edema. There was no apparent excess of heart failure (a
rigorously defined and validated secondary end point in ASCOT)
among those who received doxazosin, despite the fact that they
had more severe hypertensive disease (higher systolic blood
pressure and more left ventricular hypertrophy at baseline)
than those who did not receive the drug. The authors acknowledge
the limitations of the uncontrolled, observational data while
concluding that they provide evidence to support the efficacy
and safety of modified-release doxazosin used as third-line
therapy in the treatment of hypertension. See p
42.
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Intracoronary Compared With Intravenous Bolus Abciximab Application in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: The Randomized Leipzig Immediate Percutaneous Coronary Intervention Abciximab IV Versus IC in ST-Elevation Myocardial Infarction Trial
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Abciximab reduces major adverse cardiac events in patients with
ST-elevation myocardial infarction undergoing primary percutaneous
coronary intervention. Intracoronary abciximab bolus application
results in high local drug concentrations and consequently might
be more effective than a standard intravenous bolus. In the
present randomized, controlled trial, intracoronary abciximab
bolus application with subsequent 12-hour continuous intravenous
infusion showed reduced no reflow and infarct size as assessed
by contrast-enhanced magnetic resonance imaging. Furthermore,
myocardial perfusion measured by early ST-segment resolution
was significantly better in patients treated by intracoronary
abciximab application, and there was a trend toward improved
angiographic perfusion. On the other hand, there was no increased
risk from this direct application. If the infarct size and no-reflow
reduction and the improvement in perfusion can be translated
into an improved clinical outcome, a larger trial powered to
detect differences in outcome will be warranted. See p
49.
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Results of a Double-Blind, Placebo-Controlled Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia
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Critical limb ischemia continues to be associated with a high
incidence of limb loss and mortality. Patients frequently have
multiple associated comorbidities that place them at high risk
for open surgical bypass. Endovascular approaches are often
not an option because of the extent of disease, and they have
limited durability. There is no effective medical therapy for
critical limb ischemia. Therapeutic angiogenesis through gene
or stem cell delivery to the ischemic limb is a developing technology
that attempts to improve perfusion to the ischemic limb. Concerns
exist about the potential for gene therapy–mediated therapeutic
angiogenesis to promote tumor growth or the progression of proliferative
diabetic retinopathy. The present study demonstrates that hepatocyte
growth factor plasmid gene therapy is safe and well tolerated.
In addition, there is a potential indication of efficacy. Given
the results of this phase I/II study, future studies are warranted
to determine the efficacy of this agent on the more clinically
relevant end points of wound healing, major amputation, and
patient survival. See p
58.
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Mechanical Inhibition of Angiogenesis at the Saphenofemoral Junction in the Surgical Treatment of Varicose Veins: Early Results of a Blinded Randomized Controlled Trial
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The major frustration in the treatment of varicose veins is
recurrence. After surgery, this occurs in 40% to 60% after 5
to 10 years and even earlier after sclerotherapy. Although there
are a number of contributing factors, neovascularization with
regeneration of venous channels is most common, as shown by
ultrasound imaging and measurement of reflux. Prevention of
neovascular venous reconnection by placing a mechanical obstacle
to this process at the site of surgery has been suggested. This
study tested this in a sizable surgical randomized controlled
trial with 398 limbs, in which the active treatment group had
a patch of polytetrafluoroethylene placed over the site of ligation
of the saphenofemoral junction. Follow-up after 3 years showed
the ultrasound-detectable recurrence at the saphenofemoral junction
to be consistently reduced by 50% whether the surgery was for
severe venous disease or for previous recurrence. However, not
all neovascular reconnection was prevented. Ultrasound imaging
in these instances demonstrated the newly formed vessels to
skirt around the patch. Histological examination of the excised
polytetrafluoroethylene patch, as shown in this study, confirmed
the ability of neovascular vessels to track around the patch
and reconnect to the superficial venous system. Whether these
more circuitous neovascularizations will become clinically significant
is not clear yet, but the potential clinical benefit of the
reduced neovascularization is evident from the lower Venous
Clinical Severity Score in the patch group after 3 years. However,
the more reliable establishment of the clinical utility of the
patch will require the 5-year assessment to be completed. See
p
66.
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Impact of Plasma Oxidized Low-Density Lipoprotein Removal on Atherosclerosis
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A consensus has been reached that lowering plasma low-density
lipoprotein (LDL) inhibits atherosclerosis progression. However,
whether lowering plasma oxidized LDL (oxLDL) alone contributes
to preventing atherosclerosis remains uncertain. The antiatherogenic
effects of antioxidant therapy that may inhibit oxLDL formation
are controversial because most clinical trials yielded negative
results. Here, it has been shown that removal of oxLDL from
the circulation has a very strong effect against atherosclerosis.
In this study, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL
receptor, was expressed ectopically in the livers of apolipoprotein
E–deficient mice (LOX-1 mice), using adenoviral gene transfer,
to remove oxLDL from the circulation. Intriguingly, a transient
decrease in plasma oxLDL, without affecting non-oxLDL cholesterol
levels, completely inhibited atherosclerotic progression. Systemic
oxidative stress was shown to be decreased in LOX-1 mice. Thus,
oxLDL plays very important roles in atherosclerosis formation,
and the underlying mechanisms may involve both direct (foam
cell formation) and indirect (increased oxidative stress) effects.
In addition, smooth muscle cells in the surface areas of atherosclerotic
plaques were increased in LOX-1 mice, suggesting that oxLDL
makes plaques vulnerable, possibly leading to plaque ruptures.
Thus, the results of this study provide potential therapeutic
targets for atherosclerosis, ie, treatments that would potently
lower plasma oxLDL, including inhibition of oxLDL formation
and removal of oxLDL from the circulation. These promising strategies
may contribute to the prevention of not only atherosclerosis
formation but also the development of acute coronary syndrome.
See p
75.
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