Circulation. 2008;117:331-332
doi: 10.1161/CIRCULATIONAHA.107.188517
(Circulation. 2008;117:331-332.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts: Implication for the Therapeutic Effect of Statin in Atrial Structural Remodeling
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The renin-angiotensin-aldosterone system plays a pivotal role
in various cardiovascular diseases. Clinical use of angiontensin-converting
enzyme inhibitors or angiotensin blockers is helpful in preventing
the progression of many cardiovascular diseases. Basic investigations
of the angiotensin II receptor pathways in the heart have focused
primarily on ventricular cells. In the present study, we investigated
the downstream pathways of the angiotensin II receptor in atrial
cells in an attempt to understand the pathogenesis of atrial
structural remodeling. An important angiotensin II signaling
pathway, the Janus kinase/signal transducers and activators
of transcription (STAT) pathway, which has rarely been characterized
in the atrium, was found to mediate angiotensin II–induced
atrial structural remodeling. Angiotensin II activates signal
transducer and activator of transcription 3 through a Rac1-dependent
mechanism, which is inhibited by losartan (an angiotensin II
type 1 receptor blocker) and a cholesterol-lowering agent, simvastatin,
which inhibits Rac1 translocation. Our investigation not only
reappraised the beneficial effects of blockade of the renin-angiotensin-aldosterone
system in atrial fibrillation but also further elucidated the
downstream pathways of the angiotensin II receptor involved
in atrial structural remodeling. We also provide a rationale
for the use of statins to prevent angiotensin II–related
atrial structural remodeling. The clinical effects of statins
in the treatment of atrial fibrillation merit further investigation.
See p
344.
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Mayo Clinic Risk Score for Percutaneous Coronary Intervention Predicts In-Hospital Mortality in Patients Undergoing Coronary Artery Bypass Graft Surgery
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This study established that the new Mayo Clinic Risk Score,
originally derived to predict outcomes after percutaneous coronary
intervention with preprocedure variables, can also predict in-hospital
mortality after coronary artery bypass graft surgery. This is
the first risk score to demonstrate good discriminatory ability
in both patients undergoing percutaneous coronary intervention
and those undergoing coronary artery bypass grafting. Favoring
its widespread deployment is that it is simple, easy to use,
and derived from preprocedural variables without reliance on
subjective variables. Using the Society of Thoracic Surgeons
database, we found overall acceptable discriminatory ability
of the Mayo Clinic Risk Score, with an increase in the observed
in-hospital mortality rate with higher Mayo Clinic Risk Scores.
Moreover, the model was robust across most low- and high-risk
subgroups. See p
356.
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Implantable Cardioverter-Defibrillators in Tetralogy of Fallot
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Tetralogy of Fallot represents the most common form of congenital
heart disease in implantable cardioverter-defibrillator (ICD)
recipients; however, little is known about the utility of ICDs
in this patient population. We conducted a multicenter cohort
study in high-risk patients with tetralogy of Fallot to assess
this therapy. In particular, we sought to quantify rates of
appropriate and inappropriate ICD shocks, identify risk factors,
and characterize ICD-related complications. Overall, 121 patients
from 11 sites were included and followed up for a median of
3.7 years. ICD placement was indicated for primary (56%) or
secondary (44%) prevention; major indications for primary prevention
included palpitations, syncope, or ventricular tachycardia.
A high rate of appropriate shocks was present in both primary
(7.7%/year) and secondary (9.8%/year) prevention groups, and
ICDs were highly effective in interrupting ventricular tachyarrhythmias.
In patients with primary prevention indications, the risk of
appropriate shocks was modulated by a combination of surgical,
hemodynamic, ECG, and electrophysiological factors. Overall,
these results suggest that ICDs are effective in primary and
secondary prevention against sudden death in this patient population;
however, major drawbacks include a high rate of inappropriate
shocks (5.8% per year) and late lead-related complications (21%).
See p
363.
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Electronic Alerts Versus On-Demand Decision Support to Improve Dyslipidemia Treatment: A Cluster Randomized Controlled Trial
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Clinical decision support systems have been demonstrated to
improve the implementation of evidence-based guidelines by influencing
physicians’ behavior. Some systems require the physician
to ask for support (that is, the system only provides support
when the physician demands that support). Other systems generate
alerts to the physician independent of a request by the physician
for those alerts. Indirect evidence suggests that alerting users
is more effective in changing physician behavior than on-demand
systems. However, randomized trials comparing these methods
in a clinical setting were lacking. We constructed a clinical
decision support system for screening and treatment decisions
in the area of dyslipidemia in primary care. The system was
integrated into the electronic health record of general practitioners
and could function in either an alerting mode or on demand.
The system was based on the 1999 guidelines of the Dutch College
of General Practitioners. In a clustered randomized trial design,
we studied the effect of both alerting and on-demand decision
support with respect to screening and treatment of dyslipidemia.
In the 38 Dutch practices, with 87 886 eligible patients, we
demonstrated that a clinical decision support system alerting
users to dyslipidemia-based screening and treatment actions
changed physician behavior more than on-demand decision support.
In efforts to improve care by using evidence-based guidelines,
decision support systems that alert physicians should be considered
as an implementation strategy. See p
371.
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Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis
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Phagocytic cells in inflammatory atherosclerotic lesions are
a key histological component. They actively secrete enzymes
involved in plaque progression and rupture and thus have been
used as biomarkers for lesion severity. Here, we show that dextran-coated
nanoparticles labeled with
64Cu can be used for positron emission
tomography imaging of these phagocytes. Combined with computed
tomography imaging for anatomic coregistration, the developed
approach was highly accurate for detection of inflamed plaques
in murine arteries and at tracer concentration. Compared with
conventional
18F-fluoro-2-deoxyglucose positron emission tomography
imaging,
64Cu-TNP yielded higher target-to-background ratio,
presumably as a result of specific targeting to the phagocytic
compartment. The approach may have important clinical applications
in surveying lesion severity among different vascular beds and
as a surrogate for therapeutic efficacy. See p
379.
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Noninvasive In Vivo Imaging of Monocyte Trafficking to Atherosclerotic Lesions
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Inflammation drives many aspects of atherogenesis and lesion
progression and complication. Monocytes, the most numerous inflammatory
cells in plaques, function as major effectors of this inflammatory
response. Traditional imaging techniques generally visualize
the structure of atherosclerotic lesions but do not report the
cellular events that critically control the clinical consequences
of the disease. The present study describes a technique that
enables noninvasive in vivo imaging of monocyte trafficking
to atheromata, with the use of Food and Drug Administration–approved
components. Its application could provide novel biological insights,
aid the evaluation of antiatherogenic drugs, and sharpen the
risk stratification of selected patients. See p
388.
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Nix-Mediated Apoptosis Links Myocardial Fibrosis, Cardiac Remodeling, and Hypertrophy Decompensation
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Left ventricular hypertrophy after hemodynamic overload tends
inexorably to functionally decompensate through the process
of ventricular remodeling. Ventricular dilation and diminished
ejection performance in remodeled ventricles have been associated
with histological changes reflecting "dropout" of cardiac myocytes
and their replacement with fibrous tissue. An unanswered question
is whether genetically programmed cardiomyocyte death in the
form of apoptosis, which is observed in pressure overloaded
hearts, contributes mechanistically to progressive remodeling
and functional decompensation in cardiac hypertrophy. We previously
observed stimulated expression of specific apoptosis genes in
hearts undergoing physiological stress and recently found that
ablation of the ischemia-regulated proapoptotic gene Bnip3 prevented
postinfarction left ventricular remodeling in gene-targeted
mice (
J Clin Invest. 2007;117:2825–2833). Here, we show
that a related proapoptotic factor, Nix, which is strikingly
induced in pathological cardiac hypertrophy, contributes to
adverse remodeling of pressure overload and genetic cardiac
hypertrophies. Using mouse models in which the
Nix gene was
ablated in either the whole animal or specifically in cardiac
myocytes, we show that absence of Nix in the heart prevents
50% of apoptotic cardiomyocyte cell death in response to pressure
overload or genetically stimulated hypertrophy, restrains left
ventricular dilation, and preserves contractile function, thereby
preventing development of heart failure. These studies demonstrate
feasibility for a general therapeutic strategy of "myocardial
regeneration in reverse" by targeting specific stress-induced
proapoptotic factors. In the case of pressure overload hypertrophy,
functional decompensation can be prevented by minimizing apoptotic
myocardial loss and the adverse remodeling that it causes by
targeting hypertrophy-inducible Nix. See p
396.
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Perinatal Risk Factors for Ischemic Heart Disease: Disentangling the Roles of Birth Weight and Preterm Birth
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Several studies have reported an increased risk for ischemic
heart disease in adult life among people with a low birth weight.
At present, however, it remains unclear whether the association
between low birth weight and ischemic heart disease is mediated
through poor fetal growth and/or short gestational duration.
To study the associations between poor fetal growth and short
gestational duration and risk of ischemic heart disease with
greater precision than previous studies, we examined all birth
records at 4 major delivery units in Sweden for the period of
1925 through 1949 and assembled a cohort of
3000 born preterm
and/or with a low birth weight. For comparison, an equal number
of subjects with no history of low birth weight or short gestational
duration were identified within the same source population.
We obtained information on ischemic heart disease through the
nationwide Hospital Discharge and Cause of Death Registries
for the period of 1987 through 2002. The cohort included >600
cases of ischemic heart disease, and we found that compared
with subjects with a normal fetal growth, those born small for
gestational age (birth weight
–2 SD below the mean) had
a statistically significant increase in risk of ischemic heart
disease of 64%. The negative association between fetal growth
and risk of ischemic heart disease was independent of gestational
duration. Our study suggests that the association between low
birth weight and adult risk of ischemic heart disease is mediated
entirely by poor fetal growth. See p
405.
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Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr(–/–) Mice
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Several observational studies show that serum osteoprotegerin
levels correlate positively with the severity and progression
of coronary artery disease, atherosclerosis, and vascular calcification
in patients. However, animal studies suggest that osteoprotegerin
may protect against vascular calcification (eg, mice deficient
in osteoprotegerin develop aortic calcification). To address
this paradox, atherosclerotic
ldlr(–/–) mice were
fed an atherogenic diet and treated with osteoprotegerin or
vehicle. Although serum osteoprotegerin levels increased with
initiation of the atherogenic diet (before treatment), exogenous
recombinant osteoprotegerin treatment significantly reduced
the calcified lesion area and level of the osteogenic marker
osteocalcin in the aorta without a significant change in atherosclerosis
or cholesterol level. These data support a role for osteoprotegerin
in the vasculature as an inhibitor of calcification and a marker,
rather than a mediator, of atherosclerosis. See p
411.
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Dietary  -Lipoic Acid Supplementation Inhibits Atherosclerotic Lesion Development in Apolipoprotein E–Deficient and Apolipoprotein E/Low-Density Lipoprotein Receptor–Deficient Mice
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The recognition that inflammation is a key mechanism in the
pathogenesis of atherosclerosis and its clinical manifestations
(eg, angina pectoris, myocardial infarction, and stroke) has
significant implications for cardiovascular disease prevention,
treatment, and research at the basic, clinical, and population
levels. It is now clear that chronic inflammatory processes
and immune mechanisms contribute to the development of atherosclerosis
at all stages of the disease. Obesity and hyperlipidemia, as
risk factors for atherosclerosis, also are strongly linked to
increased vascular inflammation. The present study provides
several important new findings: Dietary
-lipoic acid supplementation
inhibits atherosclerotic lesion formation in apolipoprotein
E– and apolipoprotein E/low-density lipoprotein receptor–deficient
mice, 2 widely accepted animal models of human atherosclerosis;
and the inhibition of atherosclerosis by
-lipoic acid was associated
with reduced weight gain, decreased plasma triglycerides, and
decreased vascular inflammation. Although our results obtained
in animal models cannot be directly extrapolated to humans,
they strongly suggest that
-lipoic acid supplementation may
be useful as an inexpensive but effective intervention strategy
that targets inflammation, obesity, and hypertriglyceridemia,
thereby reducing known risk factors for the development of atherosclerosis
and other inflammatory vascular diseases in humans. See p
421.
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