Circulation. 2008;117:2169
doi: 10.1161/CIRCULATIONAHA.107.189188
(Circulation. 2008;117:2169.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Risk Factors for Aborted Cardiac Arrest and Sudden Cardiac Death in Children With the Congenital Long-QT Syndrome
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The congenital long-QT syndrome (LQTS) is an important cause
of sudden cardiac death in young individuals without structural
heart disease. However, data on risk factors for life-threatening
cardiac events in children with this genetic disorder are limited.
The present study assessed the risk of aborted cardiac arrest
or sudden cardiac death in a population of 3015 LQTS children
1 through 12 years of age who were enrolled in the International
LQTS Registry. Using time-dependent multivariable analysis,
we identified male gender, QTc duration, and a history of prior
syncope as risk factors for life-threatening cardiac events
in LQTS children. Furthermore, we demonstrate that significant
interactions exist among these 3 clinical risk factors that
may be used to identify risk subsets in this population. Notably,
β-blocker therapy is shown to be associated with a significant
reduction in the risk of life-threatening cardiac events during
childhood, with a more pronounced benefit (73% risk reduction)
in high-risk children who experience recent syncope. However,
the rate of life-threatening cardiac events in high-risk children
who are treated with this mode of medical therapy is still considerable,
with an average annual event rate of 2% while on medical therapy.
These findings suggest that careful follow-up is warranted in
LQTS children because risk factors for life-threatening cardiac
events in this population are time dependent and age specific,
resulting in a substantial variability in the phenotypic expression
of LQTS during long-term follow-up. See p
2184.
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Long-QT Syndrome After Age 40
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The congenital long-QT syndrome (LQTS) is associated with increased
risk for ventricular tachyarrhythmias and sudden cardiac death
in young individuals without structural heart disease. It is
not known whether this inherited cardiac disorder is associated
with increased risk in older patients, in whom comorbidities
may dominate mortality risk. The present study is the first
to report on the clinical course of LQTS patients after the
age of 40 years. We demonstrate that affected LQTS patients
have a >2.5-fold increase in the risk of aborted cardiac
arrest or death compared with their unaffected counterparts.
Risk factors for aborted cardiac arrest or death after age 40
in LQTS patients include female gender and time-dependent syncope,
whereas among unaffected individuals in this age group, men
are shown to have a higher risk of life-threatening cardiac
events. Importantly, we show that the presence of the LQT3 genotype
is a powerful risk factor in this age group and is associated
with nearly a 5-fold increase in the risk of aborted cardiac
arrest or death, whereas the rate of life-threatening cardiac
events among individuals with the LQT1 genotype is similar to
that of genotype-negative patients. The results of this study
demonstrate that LQTS continues to confer increased risk after
age 40 and further stress the importance of identifying age-specific
genetic and clinical risk factors in patients who are affected
with this genetic disorder. See p
2192.
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Effects of Off-Pump Versus On-Pump Coronary Artery Bypass Grafting on Early and Late Right Ventricular Function
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Although right ventricular (RV) function is an important determinant
of outcome after cardiac surgery, it has been studied infrequently
compared with left ventricular function. Those studies of RV
function conducted with cardiopulmonary bypass have traditionally
attributed postoperative RV dysfunction to a combination of
cardiopulmonary bypass and deflation of the lungs allied to
myocardial injury associated with a period of obligate ischemia
and cardioplegic arrest. Controversy exists in general about
the postulated benefits of off-pump coronary artery bypass grafting,
and specifically, no robust investigation has been conducted
into the impact of this technique on RV function. In the present
study of patients with normal RV function preoperatively, 30
patients were randomized to off-pump coronary artery bypass
grafting and 30 to conventional on-pump coronary artery bypass
grafting. RV function was assessed with cardiac magnetic resonance
imaging preoperatively, at 6 days after surgery, and finally
at 6 months after surgery. No difference was observed in RV
function between on-pump and off-pump coronary artery bypass
grafting, which suggests that cardiopulmonary bypass and cardioplegic
arrest are not the major determinants of RV function. Rather,
diastolic dysfunction and impaired RV filling related to fluid
status and heart rate, as well as myocardial contusion and collection
of pericardial fluid, may play a role. See p
2202.
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Spontaneous Myocardial Infarction in Mice Lacking All Nitric Oxide Synthase Isoforms
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Although it is well established that endothelial nitric oxide
synthase (eNOS) exerts powerful antiarteriosclerotic effects,
eNOS-deficient mice do not spontaneously develop arteriosclerosis.
This inconsistency may be due to a compensatory mechanism by
other nitric oxide synthases (NOS) that are not genetically
disrupted. Thus, it remains to be fully elucidated whether or
not nitric oxide derived from the NOS system indeed plays a
pathogenetic role in arteriosclerotic/atherosclerotic cardiovascular
diseases. To address this issue, we have recently developed
mice in which the NOS system is completely deleted (triply n/i/eNOS
–/– mice). Here, we show that the triply deficient mice exhibit
markedly reduced survival due to spontaneous myocardial infarction
accompanied by severe coronary arteriosclerotic lesions. Furthermore,
the triply NOS-deficient mice manifested metabolic syndrome,
including visceral obesity, hypertension, hypertriglyceridemia,
and glucose intolerance. These results provide the first direct
evidence that genetic disruption of the entire NOS system causes
spontaneous myocardial infarction associated with multiple cardiovascular
risk factors in vivo, which demonstrates the critical role of
the endogenous NO/NOS system in maintaining cardiovascular homeostasis.
Importantly, activation of the renin-angiotensin system was
noted in the triply NOS-deficient mice, and long-term oral treatment
with an angiotensin II type 1 receptor blocker significantly
suppressed both coronary arteriosclerotic lesion formation and
the occurrence of spontaneous myocardial infarction and improved
the prognosis of those mice, along with ameliorating the metabolic
syndrome. These findings indicate that activation of the renin-angiotensin
system plays a pivotal role in the pathogenesis of myocardial
infarction in conditions of defective NO production, which suggests
the therapeutic importance of renin-angiotensin system inhibitors
to prevent myocardial infarction in humans. See p
2211.
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Stromal Cell–Derived Factor-1 Is Cardioprotective After Myocardial Infarction
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The majority of acquired heart disease is due to coronary artery
disease, in which blood flow to an area of the heart is reduced
or eliminated, resulting in death of myocardium and replacement
with nonfunctional scar tissue. Efficient methods to limit initial
loss of myocardium and subsequent expansion of the infarct in
the acute period could be of significant value. We investigated
the potential of the secreted protein stromal cell–derived
factor-1
(SDF-1
) to improve cardiac function and damage in murine
hearts immediately after coronary occlusion. We found that SDF-1
protected cardiomyocytes from cell death within the first 72
hours after hypoxic insult and also resulted in increased angiogenesis
in the area of risk within 72 hours. SDF-1
induced Akt phosphorylation
and upregulated vascular endothelial growth factor protein after
coronary occlusion in vivo. In vitro, SDF-1 activated Akt in
cardiomyocytes and endothelial cells and upregulated vascular
endothelial growth factor only in endothelial cells. These findings
indicate that SDF-1
may affect multiple cell types in vivo to
protect and repair the heart. Future studies will address the
intracellular changes that SDF-1
may be inducing in cardiomyocytes
and whether these changes mirror the known metabolic and energy
usage adaptations typical of hibernating myocardium. See p
2224.
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Thymosin β4 Is an Essential Paracrine Factor of Embryonic Endothelial Progenitor Cell–Mediated Cardioprotection
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Myocardial organ detriment and dysfunction are common during
a prolonged period of ischemia, although subsequent reperfusion
as standard therapy is established. Among the pleiotropic causes
of ischemia-reperfusion injury, loss of cardiomyocytes, microcirculatory
disturbances preventing perfusion, and an overwhelming inflammatory
reaction have been observed frequently. Novel therapeutic approaches,
including application of progenitor cells, have provided new
avenues to this decade-old problem. In the present study, we
provide preclinical evidence that a particular source of embryonic
endothelial progenitor cells is capable of cardioprotection
against acute ischemia-reperfusion injury (24 hours). Moreover,
we were able to confine the paracrine effect of the progenitor
cell population to a single, highly expressed protein, thymosin
β4. Depriving the progenitor cell population of thymosin
β4 abolished cardioprotection, whereas regional application
of thymosin β4 peptide provided cardioprotection similar
to the embryonic endothelial progenitor cells. Mechanistically,
thymosin β4 supports cardiomyocyte cell survival, prevents
endothelial apoptosis, and limits postischemic inflammation.
Because no side effects were observed, thymosin β4 might
represent a novel therapeutic agonist in the scenario of clinical
ischemia-reperfusion injury. See p
2232.
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Noncanonical Wnt11 Signaling Is Sufficient to Induce Cardiomyogenic Differentiation in Unfractionated Bone Marrow Mononuclear Cells
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The premise that adult stem and progenitor cells from a variety
of tissues possess the capacity for cardiomyocytic lineage commitment
has led to the emergence of a new and rapidly evolving field
of cardiac regenerative medicine and to the development of innovative
cell-based therapeutic modalities focused on reconstituting
the damaged human heart. Indeed, the use of autologous adult
bone marrow–derived mononuclear cells as cell-based myocardial
reparative therapies has already proved to be clinically safe
and modestly efficacious. Thus, if such cell types are able
to modify the injured myocardial substrate, then, ostensibly,
the in vivo cardiac reparative capabilities of these cells would
be greatly enhanced by augmenting their cardiomyogenic potential
before myocardial transplantation. To this end, we sought to
create a novel physiological in vitro method that would allow
us to preprogram bone marrow–derived mononuclear cells
toward commitment to a cardiomyocytic fate. Studies performed
here demonstrate the feasibility of this approach by showing
that Wnt11, a morphogen that is indispensable for cardiac development
during embryogenesis, is sufficient to predetermine bone marrow–derived
mononuclear cell fate. The cardiomyogenic transformation of
these cells was confirmed via combinatorial assessment of gene/protein
expression and phenotypic characterization of their cardiomyocytic
properties. We believe that these data will contribute to the
formulation of a new enterprise in cardiac regenerative medicine
focused on enhancing the tissue-specific regenerative potential
of stem cell therapies, perhaps through preprogramming, before
their myocardial transplantation for cardiac repair. See p
2241.
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Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, Peroxisome Proliferator-Activated Receptor- , and Proinflammatory Adipokines
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Adipose tissue inflammation, increased expression of proinflammatory
adipokines, and decreased expression of insulin-sensitizing
adipokines are associated with an increased risk of insulin
resistance and cardiovascular disease in obesity. These studies
in the
db/
db mouse model of obesity and diabetes mellitus demonstrated
increased aldosterone in obese versus lean mice, consistent
with reports of increased aldosterone production in human obesity.
Treatment of
db/
db mice with the mineralocorticoid receptor
antagonist eplerenone reduced adipose tissue inflammation; reduced
adipose tissue expression of monocyte chemoattractant protein-1,
plasminogen activator inhibitor type 1, and tumor necrosis factor-
;
and increased adipose tissue expression of insulin-sensitizing
factors peroxisome proliferator-activated receptor-
and adiponectin.
In cultured preadipocytes, aldosterone increased expression
of tumor necrosis factor-
, monocyte chemoattractant protein-1,
and interleukin-6 and reduced expression of adiponectin and
peroxisome proliferator-activated receptor-
, lending further
support to the concept that aldosterone has detrimental effects
on adipokine expression. These studies suggest that excess mineralocorticoid
receptor activation is present in obesity, contributing to changes
in adipose tissue that promote low-grade inflammation, insulin
resistance, and ultimately cardiovascular injury. Future studies
are needed to determine whether mineralocorticoid receptor antagonists
will have a beneficial effect on these outcomes in human obesity.
See p
2253.
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Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis
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Patients with rheumatoid arthritis demonstrate a >2-fold
increase in cardiovascular morbidity and mortality, even though
traditional cardiovascular risks often are absent. An increasing
body of evidence suggests that the systemic inflammation associated
with rheumatoid arthritis also contributes to accelerated atherosclerosis
in rheumatoid arthritis patients. In view of the still-persisting
uncertainty about how to handle and reduce the risk of future
cardiovascular disease in patients with rheumatoid arthritis,
aggressive control of traditional risk factors and vessel wall
inflammation is needed. Whether and to what degree the intriguing
effects of angiotensin-converting enzyme inhibition with ramipril
in improving endothelial function, which although clinically
well established remains a surrogate measure of outcome, may
translate into clinical benefits for our patients with rheumatological
diseases who are at particularly high cardiovascular risk need
to be tested in large-scale clinical trials. See p
2262.
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Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea
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Alterations in multiple vascular endothelial pathways promote
the development of hypertension, ischemic stroke, and myocardial
ischemia. However, reduced nitric oxide availability, as indirectly
assessed by flow-mediated dilatation, is for practical purposes
the only endothelial pathway considered in patients with vascular
conditions. Quantification of proteins regulating nitric oxide
production and activity, inflammation, and oxidative stress
in freshly harvested venous endothelial cells shows that, in
addition to reducing nitric oxide production and activity, repetitive
episodes of hypoxia/reoxygenation associated with transient
cessation of breathing are responsible for vascular inflammation
and oxidative stress buildup in patients with obstructive sleep
apnea (OSA) free of overt cardiovascular diseases. Similar to
what has been reported in patients with coronary disease, impaired
endothelial repair capacity, as evidenced by reduced endothelial
progenitor cell count, accompanies vascular endothelial dysfunction
in patients with OSA. Adherence to continuous positive airway
pressure therapy substantially enhances nitric oxide production
and activity and completely reverses endothelial inflammation
and oxidative stress buildup while normalizing endothelial repair
capacity in patients with OSA. The reversal of endothelial dysfunction
with continuous positive airway pressure therapy emphasizes
the importance of early recognition and treatment of OSA. The
present findings account for the well-documented increased risk
for hypertension, ischemic stroke, and myocardial ischemia in
OSA. See p
2270.
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