Circulation. 2008;117:1247
doi: 10.1161/CIRCULATIONAHA.107.189181
(Circulation. 2008;117:1247.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Metabolic Syndrome and Risk of Development of Atrial Fibrillation: The Niigata Preventive Medicine Study
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The metabolic syndrome and atrial fibrillation (AF) are common
disorders, and the prevalence of both disorders is currently
increasing with a growing elderly population and changing lifestyle.
Because many of the components of the metabolic syndrome also
are risk factors for the development of AF, an association between
the metabolic syndrome and AF has been proposed. Furthermore,
inflammation and oxidative stress have been implicated in the
pathogenesis of both the metabolic syndrome and AF. Therefore,
we studied the association between the metabolic syndrome and
new-onset AF in the general population. In the present study,
subjects meeting the criteria for the metabolic syndrome were
at increased risk of development of AF. Among the components
of the metabolic syndrome, obesity, elevated blood pressure,
impaired glucose tolerance, and reduced high-density lipoprotein
cholesterol, but not elevated triglycerides, were associated
with AF. The risk of developing AF increased across a number
of the fulfilled metabolic syndrome components. Our data suggest
that the metabolic syndrome increases not only the risk of atherosclerotic
diseases but also the risk of AF. It is likely that an interaction
between the metabolic syndrome and deranged biochemical indexes
activates signaling pathways important in the pathogenesis of
AF. Modulation of the pathways may be of therapeutic value for
preventing AF. See p
1255.
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Cost-Effectiveness of Providing Full Drug Coverage to Increase Medication Adherence in Post–Myocardial Infarction Medicare Beneficiaries
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Effective therapies for the secondary prevention of coronary
heart disease–related events are significantly underused,
and attempts to improve adherence have often yielded disappointing
results. Elimination of patient out-of-pocket costs may be an
effective strategy to enhance medication use. We created a Markov
cost-effectiveness model to estimate the incremental cost-effectiveness
of providing Medicare beneficiaries with full coverage for combination
pharmacotherapy compared with current coverage under the Medicare
Part D program. We found that compared with current prescription
drug coverage, full coverage for post–myocardial infarction
secondary preventive therapies would result in greater functional
life expectancy (0.35 quality-adjusted life-year) and less resource
use ($2500). The elimination of patient cost sharing for medications
commonly prescribed to post–myocardial infarction patients
would therefore both improve health and save money from the
societal perspective. The magnitude of observed changes in health
outcomes is large and substantially greater than that observed
for other interventions widely used to improve post–myocardial
infarction outcomes. From the standpoint of Medicare, full drug
coverage was highly cost-effective ($7182/quality-adjusted life-year)
but not cost saving. Our results strongly support the hypothesis
that post–myocardial infarction Medicare beneficiaries
should receive statins, angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers, and β-blockers without
cost sharing and emphasize the urgent need for prospective clinical
studies to confirm the effectiveness of this approach. See p
1261.
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Biglycan Is Required for Adaptive Remodeling After Myocardial Infarction
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Known mechanisms leading to heart failure after myocardial infarction
include subsequent cardiac dilatation and infarct thinning,
also called infarct expansion, which may lead to the development
of aneurysm and left ventricle rupture. Therefore, adaptive
changes in cardiac remodeling are essential so that the ventricle
forms a stable scar rather than rupturing after myocardial infarction.
Collagenous networks elaborated by cardiac fibroblasts provide
the mechanical support for the scar tissue. It seems important
to consider that the stability and 3-dimensional arrangement
of cardiac collagen matrixes are controlled by accessory molecules
such as biglycan. Biglycan is a proteoglycan that binds to the
d bands of collagen type 1 fibrils and controls fibrillogenesis
and proteolysis of collagen by matrix metalloproteinases. The
present study reveals that after myocardial infarction, the
scar tissue of biglycan-deficient mice was characterized by
perturbed collagen fibril arrangement and that ventricular ruptures
occur more frequently compared with wild-type mice. Furthermore,
the surviving biglycan-deficient mice showed impaired hemodynamic
function with subsequent cardiac dilatation, suggesting that
in the absence of biglycan, adverse ventricular remodeling is
aggravated. Therefore, biglycan appears to play a critical role
in the formation of stable infarct scars and the preservation
of hemodynamic function after myocardial infarction. Because
biglycan accumulates in the scar tissue of human ischemic infarctions,
it is possible that the present findings extend to human postinfarct
remodeling. In the future, it will be of interest to determine
whether differences in cardiac biglycan expression may be modulated
by pharmacological treatment and whether this may change clinical
outcome. See p
1269.
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Catecholamines Regulate the Activity, Secretion, and Synthesis of Renalase
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The present work describes the renalase system, a previously
unrecognized mechanism for regulating catecholamines, cardiac
function, and blood pressure. In this pathway, the kidney secretes
prorenalase into the blood and is primarily responsible for
maintaining steady levels of the enzyme. Although prorenalase
has no detectable amine oxidase active in the basal state, it
is rapidly converted to renalase by increased catecholamines
and systolic blood pressure. Renalase in turn degrades catecholamines
and decreases blood pressure. Excess catecholamines not only
regulate the activation of prorenalase but also promote its
secretion and synthesis. Not surprisingly, abnormalities in
the renalase pathway occur in chronic kidney disease and end-stage
renal disease, as evidenced by decreased plasma levels in humans
and in rats subjected to subtotal nephrectomy. Unexpectedly,
however, renalase deficiency was documented not only in kidney
tissue but also in the heart of rats with chronic kidney disease.
Assuming that a similar reduction in cardiac renalase occurs
in patients with chronic kidney disease and end-stage renal
disease, we speculate that it could account for the increased
risk of ischemic and arrhythmic events described in this population.
It also has been reported that renalase deficiency occurs early
in the development of salt-dependent hypertension before significant
renal damage has occurred. Collectively, these data suggest
that renalase deficiency contributes importantly to the development
and maintenance of hypertension and is associated with an increased
risk for cardiovascular events. Therefore, renalase replacement
therapy may modify cardiovascular risks. See p
1277.
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Optimal Medical Therapy With or Without Percutaneous Coronary Intervention to Reduce Ischemic Burden: Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Nuclear Substudy
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Considerable controversy was generated by the main results from
the Clinical Outcomes Utilizing Revascularization and Aggressive
Drug Evaluation (COURAGE) trial, in which no difference in long-term
outcome was reported for stable patients with coronary disease
randomized to an initial strategy of percutaneous coronary intervention
(PCI) plus optimal medical therapy versus optimal medical therapy
alone. The COURAGE nuclear substudy published in this issue
of
Circulation was designed a priori to evaluate the near-term
effectiveness of treatment on ischemia as measured quantitatively
by myocardial perfusion imaging. The greater relative effectiveness
of PCI to reduce ischemia in patients with moderate to severe
baseline ischemia is consistent with the observation that patients
randomized to early PCI had better initial relief from angina.
The findings support the efficacy of PCI to reduce ischemia
and improve symptoms and set the stage for a future randomized
clinical trial using quantitative measures of ischemia. The
message from the COURAGE trial remains that PCI may be safely
deferred in stable patients but may be refined such that patients
with substantial residual ischemia on optimal medical therapy
should be considered for crossover PCI. These conclusions from
the COURAGE nuclear substudy should be greeted with cautious
enthusiasm because of its nonrandomized nature and small sample
size. See p
1283.
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CD137 Is Expressed in Human Atherosclerosis and Promotes Development of Plaque Inflammation in Hypercholesterolemic Mice
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Recruitment and activation of inflammatory cells in the vascular
wall are key events in the development of atherosclerosis. Intensified
inflammation is associated with clinical events such as myocardial
infarction. We identified CD137, a T-cell costimulatory molecule,
in human atherosclerotic lesions and found that its expression
correlated with the local levels of several agents associated
with plaque destabilization such as adhesion molecules, proinflammatory
cytokines, and matrix metalloproteinases. Activation of CD137
reduced proliferation of cultured smooth muscle cells and increased
surface levels of adhesion molecules in endothelial cells. In
a murine model of atherosclerosis, treatment with agonistic
CD137 antibodies caused significantly increased CD8
+ T-cell
infiltration and increased levels of murine major histocompatibility
complex class II proteins in atherosclerotic lesions, as well
as increased vascular levels of proinflammatory cytokines and
intercellular adhesion molecule-1. Taken together, these observations
suggest that CD137 activation in the vasculature may contribute
to the progression and increased vulnerability of atherosclerotic
lesions via augmented leukocyte recruitment, increased inflammation,
and development of a more disease-prone phenotype. See p
1292.
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Microsomal Prostaglandin E Synthase-1 Deletion Suppresses Oxidative Stress and Angiotensin II–Induced Abdominal Aortic Aneurysm Formation
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Abdominal aortic aneurysm is an inflammatory disorder characterized
by localized connective tissue degradation and smooth muscle
cell apoptosis, leading to aortic dilatation and rupture. Abdominal
aortic aneurysm represents a major cause of morbidity and mortality
in humans. Many cases are undiagnosed until they declare clinically
by leakage or rupture. Nonsurgical treatments that retard aneurysm
development or induce its regression remain to be identified.
Human aortic aneurysm biopsies stain strongly for cyclooxygenase-2
ex vivo, and some earlier studies provided evidence for the
potential efficacy of nonsteroidal antiinflammatory drugs, particularly
those selective for inhibition of cyclooxygenase-2. However,
cyclooxygenase-2–selective inhibitors themselves increase
the risk of myocardial infarction, heart failure, and stroke.
In the present study, we explored the potential utility of targeting
microsomal prostaglandin (PG) E
2 synthase-1 (mPGES-1), an antiinflammatory
drug target downstream of cyclooxygenase-2 and a major source
of PGE
2. We have shown previously that mPGES-1 retards atherogenesis;
here gene deletion retarded formation of abdominal aortic aneurysm
induced by an angiotensin II infusion in mice lacking low-density
lipoprotein receptor. This occurred concomitant with suppression
of aortic and systemic indices of oxidative stress, previously
implicated in the pathogenesis of abdominal aortic aneurysm.
Deletion of mPGES-1 inhibited production of PGE
2 but also resulted
in substrate rediversion to augment production of PGI
2 and PGD
2,
both of which upregulate antioxidant enzymes and restrain oxidant
stress. This study raises the possibility that inhibition of
mPGES-1 might have therapeutic potential in this potentially
fatal disease. See p
1302.
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Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase- Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes
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The role of inflammation in all stages of atherosclerotic cardiovascular
disease has become an active area of investigation. Various
inflammatory cells and immune mediators participate in processes
that begin with fatty streak development and culminate in cardiac
infarctions when the plaque is disrupted. The generation of
mice that lack phosphoinositide-3 kinase-
(PI3K
) showed an involvement
of this kinase in a wide variety of signaling pathways triggered
by the G-protein–coupled receptor. Interestingly, most
PI3K
functions are related to reactions to inflammation, because
a major role of PI3K
is to recruit inflammatory cells by acting
downstream of the chemokine receptor. Specific PI3K
inhibitors
have been developed and have shown immunomodulatory properties,
which makes PI3K
a good candidate for drug design for use in
autoimmune diseases. Using this pharmacological PI3K
inhibitor
and a hematopoietic PI3K
-deficient mouse model of atherosclerosis,
we demonstrated that PI3K
inhibition could alleviate the development
of atherosclerotic lesions by modulating inflammatory process.
Our results identify PI3K
as a new target in atherosclerosis
with the potential to modulate multiple stages of atherosclerotic
lesion formation, such as fatty streak constitution, cellular
composition, and final fibrous cap establishment. Our results,
as well as other data concerning the involvement of PI3K
in
cardiac pathologies, provide convincing arguments to advocate
the development of PI3K
inhibitor in cardioprotective therapy.
See p
1310.
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