Circulation. 2008;117:1769
doi: 10.1161/CIRCULATIONAHA.107.189185
(Circulation. 2008;117:1769.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Conditional FKBP12.6 Overexpression in Mouse Cardiac Myocytes Prevents Triggered Ventricular Tachycardia Through Specific Alterations in Excitation-Contraction Coupling
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Ventricular arrhythmias are a frequent fatal outcome during
chronic heart failure. As is the case in catecholaminergic ventricular
tachycardia, they seem to result from a leak out of the sarcoplasmic
reticulum (SR) during diastole, itself favored by stress. The
ryanodine receptor (RyR2) is the SR channel through which calcium
normally comes out of the SR during systole to trigger contraction
and leaks out of the SR during diastole. It has been suggested
that RyR2 leakage may be favored by the unbinding from RyR2
of the small regulatory protein FKBP12.6, also known as calstabin
2. In the present study, we show in a mouse model that increasing
the expression level of FKBP12.6 in cardiac myocytes results
in increased FKBP12.6 binding to RyR2, even when the latter
is hyperphosphorylated, a feature associated with a decreased
rate of ventricular tachycardia triggered by burst pacing in
stress conditions, and a reduced SR calcium leak in isolated
myocytes. Our results firmly support the hypothesis that the
FKBP12.6-RyR2 complex is an important candidate target for pharmacological
prevention of ventricular tachycardia. Other studies are now
needed to determine precisely how FKBP12.6 binding to a hyperphosphorylated
RyR2 exerts this beneficial effect and to identify new molecules
that may favor this binding. See p
1778.
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Impact of Ethnicity and Gender Differences on Angiographic Coronary Artery Disease Prevalence and In-Hospital Mortality in the American College of Cardiology–National Cardiovascular Data Registry
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Dramatic population shifts have made the United States ever
more ethnically diverse. Its healthcare centers reflect this
ethnic "melting pot," yet our understanding of diverse healthcare
needs and differences in disease prevalence and outcomes between
male and female ethnic subsets remains poor. The American College
of Cardiology’s National Cardiovascular Data Registry
(NCDR) for cardiac catheterization, with data collection in
>600 US hospitals, is well suited to track national patterns
of disease prevalence and clinical outcomes. The present report
focused on patients referred for diagnostic coronary angiography
and revealed significant gender and ethnic differences in coronary
disease prevalence and in-hospital mortality rates. Our results
reveal higher risk-adjusted in-hospital mortality for white,
non-Hispanic women referred for evaluation of stable and unstable
chest pain syndromes. One driver for higher in-hospital mortality
for white, non-Hispanic women was their advanced age at presentation.
An additional risk driver could relate to lower use of elective
coronary revascularization procedures and lower glycoprotein
IIb/IIIa inhibitor use. Moreover, in this registry, black women
had a consistently lower prevalence of obstructive coronary
disease than other patient subsets. A key finding was higher
disease prevalence, similar to that of men, in higher-risk black
women, including those who were older, diabetic, or hyperlipidemic
or who had lung disease. We believe the NCDR data can be invaluable
as an aid in the development of clinical practice guidelines
tailored to gender subsets of the population to improve the
efficient use of angiographic laboratories and to target at-risk
populations of women and men. See p
1787.
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Cardiac Autonomic Dysfunction: Effects From Particulate Air Pollution and Protection by Dietary Methyl Nutrients and Metabolic Polymorphisms
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Reductions in heart rate variability (HRV), a noninvasive measure
of cardiac autonomic dysfunction that independently predicts
cardiovascular mortality, have been related to short-term exposure
to particulate air pollution (PM), particularly to fine-particulate
air pollution of <2.5 µmol/L in aerodynamic diameter
(PM
2.5). This relation has frequently been investigated to clarify
mechanisms underlying the increased risk of cardiovascular disease
associated with PM
2.5 exposure. In a repeated-measures study
of 549 elderly individuals from eastern Massachusetts, we evaluated
HRV in relation to genetic polymorphisms (C677T methylenetetrahydrofolate
reductase [
MTHFR] and C1420T cytoplasmic serine hydroxymethyltransferase
[
cSHMT]) and dietary intakes of methyl nutrients that participate
in the methionine cycle and contribute to biological processes
such as methyl group transfers, homocysteine synthesis, and
redox states that are potentially affected by PM exposure. Results
from this investigation indicate that genetic and nutritional
variations conducive to lower methionine cycle function affect
HRV either independently or by enhancing the negative effects
of PM. In particular, carriers of [CT/TT]
MTHFR genotypes exhibited
lower HRV, which was decreased further in the presence of higher
ambient PM
2.5 in the 48 hours before the examination. PM
2.5 exposure was associated with lower HRV in individuals with [CC]
but not in those with [CT/TT]
cSHMT genotypes. In addition,
the negative effects of PM
2.5 on HRV were abrogated in subjects
with higher intakes (above the median) of vitamin B
6, vitamin
B
12, or methionine. These findings provide novel hypotheses
to investigate the mechanisms of action of air particles and
ultimately to identify measures to reduce the effects of air
pollution in human populations. See p
1802.
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High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury
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Cardiac dysfunction/infarction from coronary heart disease is
a leading cause of morbidity and mortality. A critical reduction
in coronary flow lowers the high-energy supply, and heart function
declines as mitochondrial damage and oxidative stress develop.
These factors can further amplify damage on coronary reperfusion.
Many efforts have been made to ameliorate the consequences of
ischemia and reperfusion injury. Here, we report that high-dose
folic acid (FA) treatment does both. FA is required for purine
biosynthesis and thus formation of high-energy phosphates, is
itself an antioxidant, and helps to preserve nitric oxide synthase
function. Rats pretreated with FA (10 mg/300 g body weight per
day) for 1 week were subjected to 30 minutes of left anterior
descending coronary artery occlusion followed by 90 minutes
of reperfusion. During the occlusion, FA-treated animals had
better global and regional function coupled with enhanced ATP
and ADP in the anterior wall. Postreperfusion function was enhanced
and myocardial necrosis/apoptosis was reduced by FA treatment,
accompanied by reduced oxidant stress (during ischemia and postreperfusion)
and preserved nitric oxide synthase function. Reduced necrosis
occurred even when FA was administered shortly after the onset
of coronary occlusion. FA treatment alone enhanced purine biosynthesis
(eg, increased inosine monophosphate and its catabolites), suggesting
that by mass action FA may help to maintain high-energy phosphates
despite reduced flow and blunt development of irreversible tissue
damage coupled to oxidant stress. Clinical translation of these
results might pave the way for a novel and inexpensive approach
to treat acute coronary syndromes and to potentially reduce
postinfarction morbidity and mortality. See p
1810.
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Severe Heart Failure and Early Mortality in a Double-Mutation Mouse Model of Familial Hypertrophic Cardiomyopathy
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The well-accepted paradigm in autosomal-dominant monogenic medical
diseases is that 1 gene mutation in a single gene is the direct
cause of disease. This is seen in a number of medical genetic
disorders spanning all subspecialties, including neurological
disorders, familial cancer syndromes, and thalassemia. Until
recently, cardiac genetic disorders have been thought to involve
only single-gene defects; however, several groups have recently
reported families with familial hypertrophic cardiomyopathy
in which 2 disease-causing gene defects have been identified.
These clinically affected patients with 2 mutations develop
more severe disease, including earlier age of onset, more severe
cardiac hypertrophy, and a greater number of sudden cardiac
death events. The present study combined 2 separate animal models
of single-mutation familial hypertrophic cardiomyopathy to produce
a unique double-mutation model of familial hypertrophic cardiomyopathy,
characterized by rapid development of a dilated cardiomyopathy,
severe heart failure, and premature death. These mice also demonstrated
alterations in both calcium handling and STAT3 signaling. This
model provides evidence that the number of disease-causing mutations
identified in a patient may explain, at least in part, the clinical
heterogeneity observed in human familial hypertrophic cardiomyopathy,
particularly in the small subgroup of familial hypertrophic
cardiomyopathy patients who develop a burnt-out end-stage heart
failure phenotype. Elucidation of how multiple mutations lead
to diverse clinical outcomes, using appropriate animal models
as presented in this study, will likely affect a range of clinical
considerations, including genetic diagnosis and improved risk
stratification, and therefore will provide the opportunity to
initiate earlier treatment and prevention strategies. See p
1820.
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Effects of Left Bundle-Branch Block on Cardiac Structure, Function, Perfusion, and Perfusion Reserve: Implications for Myocardial Contrast Echocardiography Versus Radionuclide Perfusion Imaging for the Detection of Coronary Artery Disease
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The present study is the first to simultaneously assess cardiac
structure, function, perfusion, and perfusion reserve using
quantitative myocardial contrast echocardiography in patients
with symptomatic left bundle-branch block who predominantly
had left ventricular dysfunction. In these patients, regardless
of coronary artery disease (CAD), there were asymmetrical reductions
in septal wall thickness and function compared with the posterior
wall; however, resting myocardial blood volume and flow were
homogeneously preserved. Single-photon emission computed tomography
(SPECT) is widely used for the detection and risk stratification
of CAD. However, we demonstrated that because of asymmetrical
reductions in septal thickness and function, SPECT has a significantly
higher incidence of false-positive perfusion defects resulting
from partial volume effects as a consequence of its poorer spatial
and temporal resolution compared with myocardial contrast echocardiography.
Despite no difference in sensitivity between the 2 techniques
for the detection of CAD, because of partial volume effects,
reversible defects (suggesting myocardial ischemia) occurred
in only 57% of CAD patients with SPECT imaging compared with
92% with myocardial contrast echocardiography. This finding
has both cost and safety implications in that patients would
be inappropriately referred for coronary arteriography after
SPECT and a significant proportion of patients undergoing SPECT
would inadvertently be denied revascularization. Compared with
other imaging techniques such as multislice computed tomography,
SPECT, or stress echocardiography, myocardial contrast echocardiography
has the advantage of providing an accurate comprehensive assessment
of cardiac structure and function and denoting the presence
or absence of flow-limiting CAD and the status of myocardial
viability in a single examination in patients presenting with
symptomatic left bundle-branch block. See p
1832.
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Matrix-Array 3-Dimensional Echocardiographic Assessment of Volumes, Mass, and Ejection Fraction in Young Pediatric Patients With a Functional Single Ventricle: A Comparison Study With Cardiac Magnetic Resonance
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Quantitative measurement of chamber volumes is a cornerstone
of clinical cardiac assessment. Ejection fraction, despite its
limitations, is a nearly universal measurement of and surrogate
for ventricular contractility. Although ejection fraction can
be determined with a wide range of techniques, each method has
its own set of advantages and shortcomings. Calculations by
2-dimensional echocardiography require geometric assumptions
that cannot be applied to complex-shaped single ventricles or
morphological right ventricles. Radionuclide ventriculography
can provide accurate right or left ventricular measurements
but requires intravenous access and ionizing radiation. Cardiac
magnetic resonance avoids radiation exposure for both patient
and healthcare worker but requires patient cooperation to the
extent that toddlers and infants are imaged reliably only under
sedation. Matrix-array 3-dimensional echocardiography imaging
is rapid, can be performed at the bedside, and obviates the
need for geometric assumptions. With the results of the present
study, we are able to introduce the perspective that 3-dimensional
echocardiography has the potential to be applied in patients
with functional single ventricles. The present study represents
the first series that documents matrix-array 3-dimensional echocardiography
ventricular volume measurements in patients with single-ventricle
physiology. However, challenges remain. Matrix-array 3-dimensional
echocardiography requires additional equipment and training
and needs further study in unsedated patients. In addition,
a significant amount of postprocessing time is needed to manually
trace endocardial borders. Despite these limitations, matrix-array
3-dimensional echocardiography is an exciting technique that
provides the clinician with an additional tool to help evaluate
ventricular volumes and ejection fractions. See p
1842.
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Phospholemman-Mediated Activation of Na/K-ATPase Limits [Na]i and Inotropic State During β-Adrenergic Stimulation in Mouse Ventricular Myocytes
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During activation of the sympathetic nervous system, cardiac
performance is increased as part of the fight-or-flight stress
response. The increase in contractility with sympathetic stimulation
is an orchestrated combination of intrinsic inotropic, lusitropic,
and chronotropic effects mediated in part by activation of β-adrenergic
receptors and protein kinase A. This activation causes phosphorylation
of several Ca cycling proteins in cardiac myocytes (increasing
Ca entry via L-type Ca channels, sarcoplasmic reticulum Ca pumping,
and the dissociation rate of Ca from the myofilaments). Here,
we demonstrate how Na/K-pump stimulation, mediated by phospholemman
phosphorylation, is an additional important player in the sympathetic
fight-or-flight response. Enhancement of Na/K-ATPase activity
limits the rise in intracellular Na caused by the higher level
of Na influx and, by doing so, limits the rise in cellular and
sarcoplasmic reticulum Ca load. Mutations that would prevent
phospholemman phosphorylation and thus make Na/K-ATPase insensitive
to sympathetic stimulation could lead to excessive elevation
of intracellular Na during stress. Although this could enhance
inotropy (like Na/K-ATPase inhibition by cardiac glycosides),
it also could contribute to arrhythmogenesis (again, like glycosides)
during stress or exercise when sympathetic tone is elevated.
See p
1849.
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Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E–Deficient Mice
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It is well established that atherosclerotic lesions in the arteries
are localized in some areas where endothelial dysfunction could
be crucial in determining lesion development, but less is known
about endothelial death and regeneration. In the present study,
we provided quantitative data on endothelial turnover in whole
aorta and mapped the location of high-turnover areas of endothelial
cells, which are colocalized with endothelial dysfunction and
lesion location. We also demonstrated that stem cells contribute
to the repair of severely damaged endothelial cells in high-turnover
areas, which have not been shown to exhibit the full function
of mature endothelial cells. Clinically, one of the conventional
treatments for vascular diseases involves lowering blood cholesterol
levels, which may have a role in endothelial protection of the
vessel wall. Our findings in animal models may illustrate a
new strategy for therapy, that is, promoting endothelial repair
by stem cells that exist in circulating blood. If more detailed
mechanisms of stem cell differentiation into endothelial cells
are elucidated, we may be able to design new drugs to enhance
stem cell differentiation into mature endothelial cells. Thus,
atherosclerotic lesions may be retarded or prevented in the
early stage of the disease. See p
1856.
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Left Ventricular Systolic Function and Outcome After In-Hospital Cardiac Arrest
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In-hospital cardiac arrest is a major public health problem.
In 2005, >20 000 in-hospital cardiac arrests were reported
in the American Heart Association’s National Registry
of Cardiopulmonary Resuscitation, representing
10% of the hospitals
in the United States. Only 18% of these adults with in-hospital
arrests survived to hospital discharge. Importantly, postarrest
myocardial dysfunction occurs commonly after successful resuscitation
and is a major contributor to poor outcome. Although pre-event
left ventricular ejection fraction (LVEF) is well established
as a major prognostic factor in many cardiac conditions, the
effect of prearrest LVEF on outcome after cardiac arrest has
not been previously evaluated. In the present study of 613 in-hospital
cardiac arrest patients with recent prearrest echocardiograms
from the Heart Institute in Sao Paulo, the patients with a prearrest
LVEF <45% (ie, moderate or severe dysfunction) were substantially
less likely to survive to hospital discharge than patients with
prearrest LVEF
45% (8% versus 19% survival rate). Among patients
who had postarrest echocardiograms within 72 hours, LVEF decreased
by 25% in both groups. Therefore, the mean postarrest LVEF was
23% in the patients with prearrest LVEF <45%. This resultant
severe postarrest left ventricular dysfunction among patients
with prearrest LVEF <45% presumably contributed to the lower
rate of survival to discharge in that group. Importantly, 84%
of the hospital deaths after initially successful resuscitations
were due to postresuscitation refractory shock with or without
multiple organ failure. Prearrest LVEF appears to be an important
contributor to outcome after in-hospital cardiac arrest. See
p
1864.
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Conditional FKBP12.6...
Impact of Ethnicity and...