Circulation. 2008;117:857-859
doi: 10.1161/CIRCULATIONAHA.107.188521
(Circulation. 2008;117:857-859.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Deficient Zebrafish Ether-à-Go-Go–Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants
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Various genetic defects, primarily in cardiac ion channels,
are known to cause human cardiac repolarization disorders such
as long- and short-QT syndrome; however, suitable genetic animal
models to study disease mechanisms and evaluate new treatment
strategies are largely lacking. In search of suitable arrhythmia
models, we isolated the zebrafish mutation
reggae (
reg), which
displays clinical features of the malignant human short-QT syndrome
such as accelerated cardiac repolarization accompanied by cardiac
fibrillation. By positional cloning, we identified the
reg mutation
that resides within the voltage sensor of the zebrafish
ether-à-go-go–related
gene (zERG) potassium channel. The mutation causes premature
zERG channel activation and defective inactivation, which results
in shortened action potential duration and accelerated cardiac
repolarization. Consequently, QT intervals in ECGs from heterozygous
and homozygous
reg mutant adult zebrafish are considerably shorter
than in wild-type zebrafish. Hence, with its molecular and pathophysiological
concordance to the human arrhythmia syndrome, zebrafish
reg represents the first animal model for human short-QT syndrome
and may help to further dissect disease mechanisms and to identify
new pharmacological treatment options in high-throughput screens.
See p
866.
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Clinical Characteristics and In-Hospital Outcomes of Patients With Cardiogenic Shock Undergoing Coronary Artery Bypass Surgery: Insights From the Society of Thoracic Surgeons National Cardiac Database
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Because few patients with cardiogenic shock (CS) undergo coronary
artery bypass grafting (CABG), the contemporary clinical features
and outcomes or risk factors for operative mortality in these
patients are not well known. Our study of 708 593 patients with
and without CS undergoing CABG enrolled in the Society of Thoracic
Surgeons National Cardiac Database (2002–2005) found that
patients with preoperative CS constituted 14 956 (2.1%) of patients
undergoing CABG yet accounted for 16% of all CABG deaths. Operative
mortality in CS patients was high and surgery specific, rising
from 20% for isolated CABG to 33% for CABG plus valve surgery
and 58% for CABG plus ventricular septal repair. Although overall
CABG mortality improved during the 4-year study period, that
for CS patients undergoing CABG did not. Finally, we identified
factors associated with higher death risk for CS patients undergoing
CABG using multivariable analysis and summarized these into
a simple bedside risk score (c statistic=0.74) that accurately
stratified those with low (<10%) to very high (>60%) mortality
risk. We believe that estimation of patient-specific risk of
mortality is feasible with the simplified additive risk tool
developed in our study with the use of routinely available preprocedural
data and that physicians will find this tool applicable and
useful in routine clinical practice. See p
876.
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Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction
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KAI-9803, a
-protein kinase C inhibitor, reduced infarct size,
enhanced early recovery of regional left ventricular contractility,
and improved microvascular function in animal models of acute
myocardial infarction. The safety, tolerability, and activity
of escalating intracoronary doses of KAI-9803 were evaluated
among patients with acute ST-segment elevation myocardial infarction
undergoing primary percutaneous coronary intervention in the
"first-in-human" Direct Inhibition of
-Protein Kinase C Enzyme
to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA
MI) trial. A total of 154 patients who had an occluded left
anterior descending infarct artery on angiography were randomized
in a 2:1 fashion and received 1 of 4 doses of KAI-9803 (cohort
1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0
mg) versus blinded concurrent placebo delivered in 2 divided
doses via intracoronary injection before and after reestablishment
of antegrade epicardial flow with percutaneous coronary intervention.
The incidence of serious adverse events and other safety end
points was similar between patients treated with KAI-9803 versus
placebo. Although the study was not powered to demonstrate efficacy
with the biomarker end points assessed, signs of drug activity
with KAI-9803 were suggested by trends for consistent, nonsignificant
reductions in cardiac marker elevations, ST-segment recovery,
and
99mtechnetium sestamibi infarct size values across dosing
cohorts with KAI-9803. Thus, KAI-9803 had an acceptable safety
and tolerability profile when delivered via intracoronary injection
during primary percutaneous coronary intervention for ST-segment
elevation myocardial infarction, and signs of potential drug
activity were demonstrated with biomarker end points in this
small, exploratory study. See p
886.
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Measurement of Walking Distance and Speed in Patients With Peripheral Arterial Disease: A Novel Method Using a Global Positioning System
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Treadmill testing is the "gold standard" in the evaluation of
maximal walking capacity in patients with Fontaine stage 2 claudication,
although treadmills are not readily accessible to all physicians.
Furthermore, walking on a treadmill imperfectly reflects unconstrained
outdoor walking. In 24 patients with peripheral arterial disease,
we compared the maximal walking distance measured on a treadmill
with the maximal walking distance observed during a 1-hour community-based
outdoor walk while the patient’s position was monitored
with a global positioning system (GPS). Our data support the
evidence that global positioning system–determined maximal
walking distance is correlated with the maximal walking distance
observed on a treadmill. To the best of our knowledge, this
is the first report on the use of a global positioning system
in vascular patients. Ultimately, we believe that the use of
a global positioning system might lead to new insights in the
evaluation of walking capacity in arterial claudication and
specifically to approaches for measurement of new dimensions
in the evaluation of these patients, such as walking speed,
fatigue, and walking gait. See p
897.
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Trends and Cardiovascular Mortality Effects of State-Level Blood Pressure and Uncontrolled Hypertension in the United States
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High blood pressure is one the most important risk factors for
cardiovascular disease. Information on blood pressure and uncontrolled
hypertension is needed for priority setting and for interventions.
In the United States, national data on blood pressure are obtained
by measurement, but at the state level, the data are limited
to self-reported hypertension diagnosis. Such self-reported
data may be biased for several reasons, including undiagnosed
hypertension among people who may not have had health system
contact and reduced risk among those with diagnosis who have
effectively controlled their hypertension status. This analysis
uses self-reported hypertension diagnosis and a number of other
indicators such as insurance status, history of contact with
a doctor, body mass index, age, and other sociodemographic factors
to estimate true blood pressure and hypertension status. The
results show that uncontrolled hypertension was highest in the
District of Columbia, Mississippi, Louisiana, Alabama, Texas,
Georgia, and South Carolina (18% to 21% of men and 24% to 26%
of women in these states had uncontrolled hypertension after
accounting for differences in age in these states). Uncontrolled
hypertension was lowest in Vermont, Minnesota, Connecticut,
New Hampshire, Iowa, and Colorado, ranging from 15% to 16% for
men and
21% for women. In the 1990s, uncontrolled hypertension
increased among women, especially those
60 years of age, in
every state. As a result, early in the 2000s, women had a higher
prevalence of uncontrolled hypertension than men in every state
by 4 to 7 percentage points. Lifestyle and pharmacological interventions
for lowering blood pressure are particularly needed in the South
and Appalachia, with emphasis on control among women. See p
905.
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Monitoring of the Biological Response to Murine Hindlimb Ischemia With 64Cu-Labeled Vascular Endothelial Growth Factor-121 Positron Emission Tomography
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Angiogenesis, the recruitment of new vessels, is part of the
adaptive processes in ischemia and involves the interaction
of various angiogenic factors. One of the major regulators of
angiogenesis is vascular endothelial growth factor (VEGF) receptor
type 2 (VEGFR2). VEGFR2 is an endothelium-specific receptor
tyrosine kinase that is overexpressed in ischemic tissues and
that triggers multiple signaling networks that result in endothelial
cell survival, mitogenesis, migration, differentiation, and
vascular permeability. By radiolabeling the natural ligand of
VEGFR2, the isoform VEGF
121, using copper-64 (
64Cu), we found
that temporal and spatial expression levels of VEGFR2 can be
tracked by positron emission tomography (PET) in a chronic hindlimb
ischemia model in mice. In mice that underwent treadmill exercise
training over several weeks, VEGFR2 expression levels were increased
compared with nonexercised mice and could be monitored noninvasively
by
64Cu-labeled VEGF
121 PET imaging in vivo. With PET imaging
being increasingly used for cardiovascular applications in clinics,
our proof-of-concept study suggests that molecular imaging with
PET-based approaches may be valuable for noninvasive monitoring
of angiogenesis in patients with peripheral arterial disease.
In particular, in patients with peripheral arterial disease
and refractory symptoms who are undergoing novel therapeutic
approaches such as gene- and cell-based therapies, quantitative
PET imaging may be helpful in patient stratification and decision
making in future clinical studies. See p
915.
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Two-Year Clinical Outcomes With Drug-Eluting Stents for Diabetic Patients With De Novo Coronary Lesions: Results From a Real-World Multicenter Registry
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In most centers, treatment with drug-eluting stents (DES) provides
the current standard of care for diabetic patients undergoing
percutaneous coronary interventions. The rationale for this
choice is derived more from knowledge that diabetic patients
are at high risk of restenosis after bare metal stent implantation
than robust clinical evidence; indeed, diabetes mellitus is
currently an "off-label" indication for DES. This article reports
the 2-year results of a prospective multicenter registry subanalysis
of 1648 diabetic patients treated by bare metal stent (n=1089)
or DES (n=559) implantation. Selection of patients for treatment
with DES was left to the physician’s discretion. After
adjustment for known confounders, use of DES was associated
with a moderate reduction (11.6% versus 15%;
P=0.04) in the
need for new revascularizations (no benefit was detected in
insulin-dependent diabetics). No difference was detected in
adjusted 2-year rates of mortality, mortality or reinfarction,
or major adverse events. Although no statistically significant
difference could be observed in 2-year rates of angiographic
stent thrombosis (1.5% for DES versus 0.7% for bare metal stents;
P=0.17), it is noteworthy that very late stent thrombosis episodes
occurred only in the DES group. In this large real-world diabetic
population, use of DES was associated with a modest reduction
in the 2-year risk of target vessel revascularization, a benefit
that was limited to non–insulin-dependent diabetic patients.
Larger long-term studies are needed to clarify the long-term
effectiveness and safety of DES in diabetic patients. See p
923.
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Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques
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Many data support the concept that the collagen content of the
fibrous cap of an atherosclerotic plaque governs its propensity
to rupture and causes thrombotic complications. The mechanisms
that regulate the plaque collagen content thus have considerable
clinical interest. Members of the matrix metalloproteinase (MMP)
family possess interstitial collagenase activity capable of
breaking down this critical component of the plaque structure.
Previous work has highlighted a role for MMP-13, a secreted
interstitial collagenase, in collagen breakdown in mouse atherosclerotic
plaques. The present study tested the role of a membrane-bound
MMP (MMP-14) present in plaques in regulating the interstitial
collagen content of atheromatous lesions. Animals that lack
MMP-14 do not survive to adulthood, so these experiments used
animals with bone marrow cells lacking MMP-14 to test the hypothesis
that this enzyme contributes to collagen catabolism in mouse
atheromata. After 16 weeks of an atherogenic diet, low-density
lipoprotein receptor–deficient mice engrafted with MMP-14–deficient
bone marrow contain significantly more interstitial collagen
compared with those receiving wild-type bone marrow. The effect
of MMP-14 on collagen metabolism may be indirect through activation
of the latent zymogen form of MMP-13 as shown by biochemical
experiments. Thus, MMP-14 from bone marrow–derived cells
can influence the collagen content of atheromata, a critical
component of plaque stability. See p
931.
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Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo
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In industrialized societies, virtually all young adults have
atherosclerosis. Most of these lesions are asymptomatic and
will remain so for the rest of the person’s life. However,
a small percentage will progress to a dangerous stage involving
plaque breakdown, acute luminal thrombosis, and acute vascular
events like myocardial infarction and sudden cardiac death.
Thus, a major goal is to elucidate the cellular-molecular events
involved in benign-to-vulnerable plaque progression. A key feature
of vulnerable plaques is necrotic cores, which likely promote
plaque breakdown and acute thrombosis. Necrotic cores are "graveyards
of dead macrophages," a prominent cell type in atherosclerosis.
This study used a cell-culture model of macrophage death to
explore death-promoting molecules that may be relevant to advanced
atherosclerosis. These experiments revealed an important role
for a calcium-signaling pathway involving 2 molecules, calcium/calmodulin-dependent
protein kinase II and signal transducer and activator of transcription-1
(STAT-1). Both mouse and human advanced atheromata have activated
STAT-1. Most important, when macrophages were made deficient
in STAT-1 in a mouse model of advanced atherosclerosis, macrophage
death and plaque necrosis were diminished. Two important caveats
of this study need to be mentioned. First, the processes of
macrophage death and plaque necrosis are complex, so the calcium/calmodulin-dependent
protein kinase II–STAT1 pathway represents only 1 piece
of the puzzle. Second, the mouse is a poor model of plaque disruption
and acute thrombosis. Thus, additional studies are needed to
explore other pathways involved in advanced lesional macrophage
death, and improved mouse models are required to prove the hypothesis
that macrophage death and plaque necrosis promote plaque disruption
and acute thrombosis. Nonetheless, this study provides important
new molecular-cellular information related to the progression
of advanced atherosclerotic lesions—information that someday
may be translated into therapy designed to block benign-to-vulnerable
plaque transformation. See p
940.
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Phosphorylation of LKB1 at Serine 428 by Protein Kinase C- Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells
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Metformin is one of most commonly used drugs for the treatment
of type II diabetes mellitus. Unlike traditionally used glucose-lowering
reagents, such as sulfonylureas or insulin, metformin improves
cardiovascular functions and reduces cardiovascular risks in
diabetes. Earlier studies from us and others found that clinically
relevant concentrations of metformin activated the AMP-activated
protein kinase (AMPK); these studies ascribed the beneficial
effects of metformin on vascular function to AMPK activation.
The present study was designed to elucidate the mechanism by
which metformin activates AMPK. Exposure of cultured endothelial
cells to metformin significantly increased the phosphorylation
of both AMPK at Thr172 and LKB1 at Ser428, an AMPK kinase, which
was paralleled by increased activation of protein kinase C (PKC)-
,
as evidenced by increased activity, phosphorylation, and nuclear
translocation of PKC-
. Consistently, either pharmacological
or genetic inhibition of PKC-
ablated metformin-enhanced phosphorylation
of both AMPK at Thr172 and LKB1 at Ser428. Our data suggest
that the Ser428 phosphorylation of LKB1 by PKC-
is required
for metformin-triggered AMPK activation. See p
952.
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Deficient Zebrafish Ether-a-Go...
Clinical Characteristics and In...