Circulation. 2008;117:3055-3056
doi: 10.1161/CIRCULATIONAHA.108.189731
(Circulation. 2008;117:3055-3056.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Obesity, Behavioral Lifestyle Factors, and Risk of Acute Coronary Events
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Obesity is an important modifiable risk factor for coronary
heart disease. However, it is clear that achieving weight loss
or preventing weight gain with aging is difficult for most individuals.
Whether the high cardiovascular risk associated with obesity
is alleviated by physical activity remains controversial; furthermore,
little is known about the cardiovascular risk associated with
obesity in the context of other behavioral lifestyle factors.
In our investigation of the associations of obesity in combination
with potentially modifiable behavioral lifestyle factors among
54 783 middle-aged men and women, we found that obesity was
strongly associated with the risk of acute coronary syndrome
among the physically active and inactive, in nonsmokers and
smokers, among those who adhered to a more or less heart-healthy
dietary pattern, and in participants with and without a moderate
alcohol intake. Body mass index also was associated with acute
coronary syndrome in subgroups of important clinical risk factors,
suggesting that prevention of obesity is important even in those
who adhere to an otherwise healthy lifestyle or who are free
of clinical symptoms. Our results further indicated that increasing
physical activity level, abstaining from smoking, consuming
a more heart-healthy diet, and having a moderate alcohol intake
likely result in a lower risk of acute coronary syndrome even
in obese individuals. See p
3062.
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Intracellular Protein Aggregation Is a Proximal Trigger of Cardiomyocyte Autophagy
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Chronic hemodynamic stress such as poorly controlled hypertension
induces hypertrophic growth of the heart. This pathological
growth response, with time, leads to ventricular dilation, systolic
dysfunction, and clinical heart failure, which is a leading
cause of morbidity and mortality in Western society. Whereas
numerous signaling pathways have been implicated in the stress
response of the myocardium, mechanisms governing the transition
from compensated hypertrophy to heart failure are poorly understood.
In this study, we report that pressure overload promotes accumulation
of ubiquitinated protein aggregates in left ventricular myocytes
that are processed into structures called aggresomes. We also
demonstrate that these protein aggregates activate an evolutionarily
conserved process of protein sequestration and removal called
autophagy. We go on to show that attenuation of autophagic activity
dramatically enhances both aggresome size and abundance, consistent
with a role for autophagic activity in protein aggregate clearance.
From these data, we conclude that pressure overload–induced
protein aggregation is a proximal trigger of cardiomyocyte autophagy
and that autophagic activity functions to attenuate aggregate/aggresome
formation in heart. Findings reported here are the first to
demonstrate that protein aggregation occurs in response to hemodynamic
stress, situating load-induced heart disease in the expanding
category of proteinopathic diseases. See p
3070.
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Critical Role of Bone Marrow Apoptosis-Associated Speck-Like Protein, an Inflammasome Adaptor Molecule, in Neointimal Formation After Vascular Injury in Mice
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Accumulating reports have demonstrated an important role of
the inflammation-induced adaptor complex, called the inflammasome,
in the fields of immunology and oncology. To date, there has
been no report describing the role of inflammasome in cardiovascular
diseases. Apoptosis-associated speck-like protein (ASC) containing
a caspase recruitment domain is an adaptor protein that forms
inflammasome and regulates caspase-1–dependent interleukin
(IL)-1β and IL-18 generation. Here, we show that ASC is
markedly expressed in the site of vascular injury in mice and
colocalized with macrophages or vascular smooth muscle cells.
Neointimal formation after vascular injury is significantly
attenuated in ASC-deficient mice compared with that in wild-type
mice. The expression of IL-1β and IL-18 was observed in
the neointimal lesion of wild-type mice but showed decreased
expression in the lesion of ASC-deficient mice. Additional studies
showed that ASC deficiency influences neointimal formation by
regulating the behavior of cells that are derived from bone
marrow. Our results show that bone marrow–derived ASC
is critical for neointimal formation after vascular injury and
identify ASC as a potential therapeutic target for atherosclerosis
and restenosis after percutaneous coronary intervention. See
p
3079.
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Cyclophilin A Mediates Vascular Remodeling by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation
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Decreased blood flow distal to a stenosis is associated with
accelerated atherosclerosis and occlusion, but the mechanisms
are not fully elucidated. Accumulating evidence indicates that
inflammation and vascular smooth muscle cell (VSMC) proliferation
contributes to vessel narrowing. It has become clear that an
increase in reactive oxygen species is a key pathogenic mechanism
for vascular disease. Cyclophilin A (CyPA) is a 20-kDa chaperone
protein secreted from VSMCs in response to reactive oxygen species
that stimulates VSMC proliferation and inflammatory cell migration
in vitro. Here, using genetically engineered mice to modulate
vascular CyPA expression, we show that decreasing CyPA has beneficial
effects on the inflammatory response and vascular intima formation
in low-flow vessels, as shown by significantly increased lumen
diameter and decreased intima/media ratio. The present study
may have important clinical implications, because it appears
that secreted CyPA mediates the growth and inflammatory effects.
This suggests that a receptor for CyPA may represent an attractive
therapeutic target for vascular diseases associated with oxidative
stress and inflammation. See p
3088.
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Follistatin-Like 1 Is an Akt-Regulated Cardioprotective Factor That Is Secreted by the Heart
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On injury, the heart secretes factors that influence its function.
It is widely recognized that the protein kinase Akt plays an
important role in regulating intracellular signaling pathways
that control cellular survival and physiological growth. To
identify novel factors involved in regulating cardiac function,
we sought to isolate and characterize proteins that are secreted
from murine heart in response to myocardial Akt activation.
The secreted protein follistatin-like 1 (Fstl1) is upregulated
in heart in response to transgenic Akt activation as well as
ischemia/reperfusion injury, pressure overload, and myocardial
infarction. Delivery of the
Fstl1 gene to mice protected the
heart from ischemia/reperfusion injury and reduced cardiac myocyte
death, whereas ablation of Fstl1 expression in myocytes led
to an increase in apoptotic cell death in vitro. Thus, Fstl1
functions as an endogenous cardiac myocyte survival factor that
is secreted by the heart in response to stress. As such, Fstl1
may serve a useful diagnostic or therapeutic function. See p
3099.
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Efficacy of In-Hospital Multidimensional Interventions of Secondary Prevention After Acute Coronary Syndrome: A Systematic Review and Meta-Analysis
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Secondary prevention programs for patients experiencing an acute
coronary syndrome have been shown to be effective in the outpatient
setting. Interest in the inpatient setting for secondary prevention
is heightened by the recognized potential of hospitalization
after an acute disease as a "teachable moment" for behavioral
change that may increase the benefit of counseling interventions
delivered to hospitalized patients. Early in-hospital initiation
of medications also might increase the likelihood of being adequately
treated. In recent years, multiple studies have assessed pragmatic
interventions targeting patient education and/or an increase
in prescription rates by physicians. The present work pools
the results of the existing studies to determine whether in-hospital,
patient-level interventions targeting multiple cardiovascular
risk factors reduce all-cause mortality after an acute coronary
syndrome. We included controlled clinical trials and before-after
studies and classified the interventions as patient-level interventions
(ie, education or counseling interventions) with or without
associated healthcare provider–level interventions (eg,
improving physician skills and effectiveness in counseling through
an educational program) and/or system-level interventions (eg,
facility outcome reporting). Overall, the studied interventions
seemed to reduce the risk of all-cause mortality at 1 year.
However, the apparent benefit depended on study design and the
level of intervention. Only interventions including a provider-
or system-level intervention suggested reduced mortality compared
with patient-level–only interventions. Because only before-after
studies suggest a significant reduction in mortality, the evidence
for in-hospital, patient-level interventions for secondary prevention
is promising but not definitive. Future research should formally
test which components of interventions provide the greatest
benefit. See p
3109.
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Bacteremia Associated With Toothbrushing and Dental Extraction
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There is ongoing debate concerning the health risks, cost-effectiveness,
and practicality of the routine use of prophylactic antibiotics
in the dental office setting. The relative risk for infective
endocarditis from bacteremia during invasive office procedures
such as dental extractions versus routine daily events such
as toothbrushing is unknown. Although toothbrushing does not
have the same incidence, duration, nature, or likely magnitude
of bacteremia as a dental extraction, we found a substantial
incidence of bacteremia (23%) of infective endocarditis–causing
species of bacteria from brushing. Therefore, given the far
greater frequency for oral hygiene than for dental office procedures,
toothbrushing appears to be a greater threat for individuals
at risk for infective endocarditis. Although amoxicillin has
a significant impact on bacteremia resulting from a dental extraction,
33% of patients undergoing extraction after prophylaxis showed
evidence of bacteremia, including infective endocarditis–related
species. The duration of bacteremia for some pathogenic species
persisted for at least 60 minutes after brushing and extraction
without antibiotic prophylaxis. The magnitude of bacteremia
for all 3 study groups was <10
4 colony-forming units per
milliliter of blood, which suggests that brushing and single-tooth
extraction are similar from the standpoint of magnitude. Given
the daily occurrence of bacteremia from toothbrushing and other
routine daily events and the lack of efficacy data for antibiotic
prophylaxis, the present study calls into question the appropriateness
of this practice and suggests that there should be a greater
focus on avoidance of dental disease in patients at risk for
endocarditis. See p
3118.
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Flow-Induced Arterial Remodeling Relates to Endothelial Function in the Human Forearm
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Chronic changes in arterial blood flow induce compensatory changes
in arterial size, a response known as remodeling. Arterial remodeling
occurs during normal growth and development and as a response
to exercise. As originally described, arterial remodeling is
a compensatory response that maintains the arterial lumen and
blood flow during the formation of atherosclerotic lesions.
The present study took advantage of a "natural experiment" to
study arterial remodeling in humans. When the radial artery
is harvested from the forearm for use as a bypass conduit during
coronary bypass surgery, the ulnar artery remains as the sole
supply of blood to the hand and is exposed to chronically increased
blood flow. We measured remodeling of the ulnar artery before
and after removal of the radial artery in 53 patients undergoing
coronary bypass surgery. We observed a chronic increase in ulnar
artery blood flow and outward remodeling of the artery. The
response was blunted in cigarette smokers but did not relate
to other risk factors. Remodeling was greatest in patients with
the largest increases in flow and correlated with the function
of the vascular endothelium. These findings are consistent with
the idea that the endothelium acts as the primary sensor to
changes in flow and coordinates the remodeling response. This
study provides new insights into the causes and predictors of
arterial remodeling in patients and is relevant to a variety
of clinical situations, including angiogenesis, collateral formation,
atherosclerosis, and restenosis after percutaneous intervention.
See p
3126.
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