Circulation. 2008;117:2041
doi: 10.1161/CIRCULATIONAHA.107.189187
(Circulation. 2008;117:2041.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction
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Heart failure with normal ejection fraction (HFNEF) is an increasing
problem; today,
50% of all heart failure patients have a normal
ejection fraction. The mortality rate seems to be similar to
that of patients with reduced ejection fraction, but our knowledge
about the underlying hemodynamic pathology is limited. We performed
a study investigating the diastolic function of patients with
HFNEF invasively using pressure-volume loops to obtain the diastolic
stiffness of the left ventricle. The highly increased diastolic
stiffness in the HFNEF group, the key finding of the present
study, shows that diastolic dysfunction can be demonstrated
in HFNEF patients. It may further explain their main clinical
symptomatology: exercise intolerance. Artificial pacing to mimic
tachycardia during exercise reduced the stroke volume resulting
from a leftward shift of the pressure-volume loops and therefore
blunted the increase in the cardiac output, which is needed
to comply with increased oxygen demand during exercise in patients
with HFNEF. This was associated with a limitation of workload
during exercise. Although it was shown recently that nondiastolic
abnormalities also occur in patients with HFNEF, we suggest
that diastolic stiffness is another important feature of HFNEF
that might trigger heart rate–dependent changes in the
global cardiac function and therefore contribute to heart failure
symptomatology. These data further suggest that destiffening
therapies might be a future goal for treating HFNEF. See p
2051.
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Noninvasive Detection and Localization of Vulnerable Plaque and Arterial Thrombosis With Computed Tomography Angiography/Positron Emission Tomography
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The identification of vulnerable plaque can add a new dimension
to the evaluation of cardiovascular atherosclerosis. Using an
atherosclerotic rabbit model of plaque disruption and thrombosis,
we demonstrated that positron emission tomography can localize
inflamed plaques with high macrophage density and quantify the
degree of inflammation in arteries comparable in size to human
coronary arteries. These inflamed arteries were significantly
more thrombotic. Currently, treatment decisions are based on
the degree of stenosis, but this approach frequently fails to
predict cardiac events. This was demonstrated recently by the
Clinical Outcomes Utilizing Revascularization and Aggressive
Drug Evaluation trial, the results of which were explained in
part by more interventions on severely stenotic but more stable
plaques instead of less stenotic but vulnerable plaques. Therefore,
localizing inflamed plaques and quantifying their degree of
inflammation can potentially enhance the accuracy of decisions
regarding therapy. The present study also has shown that computerized
tomography angiography can be used accurately to diagnose small
thrombi in atherosclerotic arteries similar in size to human
coronaries. However, the application of these findings to humans
still awaits solutions to multiple technical limitations. Nevertheless,
some of our findings can serve as the basis for future research
in noninvasive plaque characterization with computerized tomography
angiography/positron emission tomography technology. It is expected
that such research would be more easily performed in the carotid
rather than coronary arteries because of their larger size and
proximity to the skin. More investigations are needed to detect
vulnerable plaques and arterial thrombosis in humans using the
noninvasive computerized tomography angiography/positron emission
tomography technology. See p
2061.
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Comparison of Coronary Artery Stenting Outcomes in the Eras Before and After the Introduction of Drug-Eluting Stents
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Few studies have compared medium-term outcomes for drug-eluting
stents (DES) and bare metal stents, and most of those are relatively
small, randomized controlled trials. Furthermore, since the
introduction of DES, there has been increased use and duration
of use of clopidogrel, statins, and other evidence-based therapies.
The purpose of this study was to compare outcomes for patients
who underwent stenting in the eras before and after the introduction
of DES. In New York state, patients undergoing stenting in nonfederal
hospitals who had not undergone any previous revascularization
were studied. Risk factors that were significant predictors
of adverse outcomes were used to adjust adverse outcome rates.
The study included 11 436 patients who received stents between
October 1, 2002 and March 31, 2003 (the pre-DES era) and 12
926 patients who underwent stenting between October 1, 2003
and March 31, 2004 (the DES era). Mortality, the combined endpoint
mortality/myocardial infarction, target vessel revascularization,
and target lesion revascularization rates were compared at 2
years. Patients in the DES era had significantly better risk-adjusted
outcomes for mortality/myocardial infarction (adjusted hazard
ratio, 0.90; 95% confidence interval, 0.83 to 0.97), 9.9% versus
10.8%; target vessel revascularization (adjusted hazard ratio,
0.60; 95% confidence interval, 0.56 to 0.64), 11.2% versus 17.9%;
and target lesion revascularization (hazard ratio, 0.55; 95%
confidence interval, 0.51 to 0.59), 8.4% versus 14.7%. In conclusion,
patients in the DES era experienced lower mortality/myocardial
infarction, target vessel revascularization, and target lesion
revascularization rates, but there were no differences in mortality.
These improvements are likely to be a result of increased use
of clopidogrel, statins, and dual antiplatelet therapy in addition
to the introduction of DES. See p
2071.
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Long-Term Mortality After Percutaneous Coronary Intervention With Drug-Eluting Stent Implantation Versus Coronary Artery Bypass Surgery for the Treatment of Multivessel Coronary Artery Disease
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Several studies have compared the treatment effects of coronary
stenting and coronary artery bypass grafting (CABG) for multivessel
coronary artery disease, but little information exists since
the widespread availability of drug-eluting stents (DES). In
the present study, we evaluated 1547 patients with multivessel
disease who received DES and 1495 patients who underwent CABG.
The primary end point was all-cause mortality. Other outcomes
were repeat revascularization and the composite of death, Q-wave
myocardial infarction, or cerebrovascular events. After adjustment
for differences in baseline risk factors between patients receiving
DES and undergoing CABG, the long-term risks of death were similar
among all patients (hazard ratio, 0.85; 95% CI, 0.56 to 1.30;
P=0.45), diabetic patients (hazard ratio, 1.76; 95% CI, 0.82
to 3.78;
P=0.15), and patients with compromised ventricular
function (hazard ratio, 1.39; 95% CI, 0.41 to 4.65;
P=0.60)
during 3 years of follow-up. The adjusted risk of hard end points
(death, Q-wave myocardial infarction, or cerebrovascular events)
also was similar (hazard ratio, 0.84; 95% CI, 0.57 to 1.23;
P=0.36), whereas the risk of revascularization was significantly
higher in the DES than in the CABG group (hazard ratio, 2.81;
95% CI, 2.11 to 3.75;
P<0.001). Compared with CABG, coronary
stenting with DES showed equivalent long-term mortality and
serious composite outcomes but a higher rate of repeat revascularization
for patients with multivessel coronary artery disease. Our findings
need to be ascertained or refuted in ongoing, large randomized
clinical trials, which may provide the answer to treatment effects
between the 2 primary interventions. See p
2079.
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Genetic Components of the Circadian Clock Regulate Thrombogenesis In Vivo
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Clinical cardiovascular events such as myocardial infarction
and stroke undergo diurnal variation, but it has been unclear
whether this reflects a role for the molecular clock or temporal
variation in exposure to environmental triggers. Studies of
platelet aggregation ex vivo may be confounded by selection
of subpopulations because of platelet activation in vivo. Here
we describe diurnal variation in the time to thrombotic vascular
occlusion in vivo, subsequent to a photochemical vascular injury.
This pattern was disrupted or altered when circadian clock genes
(Bmal1, Clock, or Npas2) were either mutated or deleted, manipulations
that also affect blood pressure. Selective deletion of a single
circadian clock gene, Bmal1, from the endothelium alone was
sufficient to alter thrombogenesis in vivo. The impact of molecular
clock components on thrombogenesis and blood pressure may interact
with environmental variables to contribute to the diurnal variation
in cardiovascular events observed in humans. See p
2087.
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Local Delivery of Gene Vectors From Bare-Metal Stents by Use of a Biodegradable Synthetic Complex Inhibits In-Stent Restenosis in Rat Carotid Arteries
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Stent angioplasty for coronary disease has made a major impact
on improved therapeutic outcomes, and local delivery of highly
potent drugs, such as paclitaxel or sirolimus, with polymer-coated
drug-eluting stents is effective clinically for inhibiting the
development of in-stent restenosis; however, it is also apparent
that the current drug-eluting stents do not represent an ideal
approach. Nevertheless, recent clinical and experimental results
concerning drug-eluting stents indicate that local-delivery
therapeutic strategies for cardiovascular disease will become
increasingly important. The present study investigated local
delivery of gene therapy from stent surfaces by use of a novel
strategy of reversible chemical attachment of vectors to bare-metal
stents via a 3-component, hydrolyzable synthetic complex. Adenoviral
(Ad) vectors immobilized on the surfaces of stents with a packing
density up to 5
x10
9 adenovirus particles/cm
2 exhibited prolonged
(>1 month) release kinetics and demonstrated highly efficient
site-specific transduction of target cell types in vitro and
in vivo in rat carotid stent angioplasty studies. Moreover,
the tethering of adenovirus vectors to steel surfaces allowed
effective transduction in vitro in the presence of neutralizing
anti-Ad knob antibodies that otherwise completely blocked activity
of nonimmobilized vector. In rat carotid stent studies, the
deployment of stents configured with 10
9 adenovirus vectors
that were encoded for the inducible form of nitric oxide synthase
(Ad-iNOS) resulted in a significant reduction of in-stent restenosis
compared with bare-metal stents. These findings validate the
concept of gene-eluting stents and warrant further translational
investigations. See p
2096.
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Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials: The Cross Trial Safety Analysis
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Cyclooxygenase-2 inhibitors have been associated with increased
cardiovascular risk. We performed a patient-level pooled analysis
of 6 randomized controlled trials comparing 3 dose regimens
of celecoxib—400 mg QD, 200 mg BID, and 400 mg BID—with
placebo for conditions other than arthritis. We observed a dose
regimen–dependent increase in risk, with the 400-mg-QD
dose associated with the lowest risk (hazard ratio, 1.1; 95%
CI, 0.6 to 2.0), the 200-mg-BID dose associated with an intermediate
risk (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and the 400-mg-BID
dose associated with the highest risk (hazard ratio, 3.1; 95%
CI, 1.5 to 6.1). Moreover, we observed that patients with the
lowest baseline risk were at the lowest relative risk for celecoxib-related
events, with an interaction between baseline risk and celecoxib-related
risk. Although the doses tested in these trials were higher
than typical doses used in osteoarthritis patients, these data
suggest that celecoxib-related cardiovascular risk is related
to dose regimen and that twice-daily dosing may be associated
with greater risk than once-daily dosing. Moreover, patients
who are at higher a priori risk for atherosclerotic events appear
to be most vulnerable to celecoxib-related risk. These data
should help guide rational decision making for patients who
derive clinical benefit from cyclooxygenase-2 inhibitors. See
p
2104.
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Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells
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Pulmonary hypertension is a severe disease commonly associated
with chronic hypoxemia in disorders such as chronic obstructive
pulmonary disease and interstitial lung disease. It is characterized
by the development of pulmonary vascular remodeling, leading
to elevated pulmonary vascular resistance and ultimately progression
to right ventricular dysfunction and often death. Despite state-of-the-art
therapy, morbidity and mortality rates remain high as a result
of irreversible vascular remodeling. Cyclooxygenase-2 (COX-2)
is upregulated in pulmonary artery smooth muscle cells during
hypoxia and may play a protective role in the vascular response
of the lung to hypoxia. In the present study, we investigated
the role of COX-2 in a mouse model of hypoxia-induced pulmonary
hypertension. The absence of COX-2 or pharmacological inhibition
of COX-2 led to severe pulmonary hypertension after hypoxia
with exaggerated elevation of right ventricular systolic pressure,
significant right ventricular hypertrophy, and striking vascular
remodeling. Vascular remodeling was characterized by pulmonary
artery smooth muscle cell hypertrophy and significant upregulation
of the endothelin-1 (ET
A) receptor in the lung during hypoxia.
Our findings also demonstrate that COX-2–deficient pulmonary
artery smooth muscle cells have enhanced contractility after
exposure to hypoxia that can be rescued by COX-2–derived
prostaglandin E
2 or prostaglandin I
2. The results of our study
suggest that COX-2 plays an important protective role in the
lung under hypoxic conditions and that selective COX-2 inhibition
may have detrimental pulmonary vascular consequences in patients
with hypoxemic lung diseases or preexisting pulmonary hypertension.
These findings have significant clinical implications and raise
the possibility that selective COX-2 inhibitors might worsen
symptoms in patients with pulmonary hypertension. See p
2114.
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Increased High-Density Lipoprotein Cholesterol Predicts the Pioglitazone-Mediated Reduction of Carotid Intima-Media Thickness Progression in Patients With Type 2 Diabetes Mellitus
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As the prevalence of type 2 diabetes mellitus increases in the
United States and worldwide, it remains important to evaluate
new ways of addressing the accelerated rates of atherosclerosis
and cardiovascular disease (CVD) seen in these patients. Even
in the statin era, residual incremental CVD risk compared with
patients without diabetes remains. One notable accompaniment
of type 2 diabetes mellitus is a low level of high-density lipoprotein
(HDL) cholesterol. Cross-sectional and observational studies,
as well as observations in atherosclerosis-prone animals, indicate
that raising HDL cholesterol should be a powerful tool for reducing
atherosclerosis and CVD risk in patients with diabetes. We have
previously demonstrated that treating type 2 diabetic subjects
with pioglitazone reduced progression of carotid intima-media
thickness, a measure of carotid atherosclerosis and marker of
CVD risk, compared with treatment with glimepiride. In the present
analysis, we examined changes in individual cardiovascular risk
factors after 24 weeks of treatment for their relationship to
carotid intima-media thickness change at 72 weeks. Although
treatment with pioglitazone led to improvement in multiple CVD
risk parameters, only the increased HDL cholesterol and reduced
insulin levels appeared to explain the treatment benefit. Of
these, the HDL effect was larger and more consistent. Quartiles
of HDL cholesterol change were progressively associated with
more carotid intima-media thickness benefit, with an increment
of 5% to 16% sufficient to produce a significant benefit for
carotid intima-media thickness. These results demonstrate an
important relationship between increases in HDL cholesterol
produced by pioglitazone treatment and reduced progression of
atherosclerosis in subjects with type 2 diabetes mellitus. They
also underscore the potential of raising HDL cholesterol as
a high-value therapeutic target for reducing atherosclerosis
and CVD risk in patients with diabetes. See p
2123.
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Role of Left Ventricular...
Noninvasive Detection and...