Circulation. 2008;117:1499
doi: 10.1161/CIRCULATIONAHA.107.189183
(Circulation. 2008;117:1499.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Epicardium-Derived Cells in Development of Annulus Fibrosis and Persistence of Accessory Pathways
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Atrioventricular reentrant tachycardia is a common arrhythmia
in both children and adults; however, the causal mechanisms
underlying the appearance of accessory pathways remain a subject
of debate. During cardiogenesis, initial slow conduction over
the circumferential myocardial AV continuity, which results
in sequential activation of the preseptated heart, is replaced
by apex-to-base conduction through the specialized AV node/His-Purkinje
system in the septated heart. Concurrently, incorporation of
the AV junctional myocardium in the lower atrial rim by fusion
of the endocardial AV cushions and epicardial AV sulcus results
in formation of the isolating annulus fibrosis. Migration of
multipotent epicardium-derived cells (EPDCs) through the continuous
AV junctional myocardium, ultimately reaching the endocardium-derived
AV cushions, spatiotemporally correlates with annulus fibrosis
formation. The AV junction has been postulated to be subject
to physiological perinatal remodeling, which temporarily leaves
functional small accessory pathways as anatomic substrates for
spontaneously resolving neonatal AV reentrant tachycardias.
Dyssynchrony in the delicate interplay between EPDCs and AV
junctional cells, as shown in the EPDC-inhibited quail model
in the present study, may result in marked defects in the isolating
annulus fibrosis, with the persistence of large accessory pathways
functionally resulting in ventricular preexcitation. We speculate
that absence of EPDCs or a delay in EPDC migration results in
the persistence of pathological substrates for postnatally persistent
accessory pathways and AV reentrant tachycardias into childhood
or adult life. See p
1508.
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Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3, Randomized, Placebo-Controlled Trial
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Pharmacological cardioversion often is used to restore sinus
rhythm in patients with hemodynamically stable and recent-onset
atrial fibrillation. However, currently available antiarrhythmic
agents have modest efficacy, and the risk of proarrhythmia is
of concern. Vernakalant is a new and relatively atrium-selective
antiarrhythmic agent undergoing investigation for the conversion
of atrial fibrillation to sinus rhythm. The results of this
placebo-controlled trial demonstrate the efficacy of intravenous
vernakalant in terminating recent-onset atrial fibrillation.
Moreover, conversion was rapid and not associated with ventricular
proarrhythmia. The clinical implication is that intravenous
vernakalant may represent a valuable new antiarrhythmic drug
for the acute conversion of atrial fibrillation to sinus rhythm,
and it may be particularly useful in patients with recent-onset
atrial fibrillation in the emergency room setting. See p
1518.
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Prevalence of Angina in Women Versus Men: A Systematic Review and Meta-Analysis of International Variations Across 31 Countries
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Is male sex a risk factor for stable angina pectoris in the
same way that it is for acute coronary syndromes? In this meta-analysis
based on almost 25 000 angina cases in women and men from 31
countries, we found that women had a slightly higher prevalence
of stable angina pectoris than men. This study adds to current
understanding by demonstrating for the first time that the female
excess of angina is remarkably consistent across countries with
widely differing myocardial infarction mortality rates, spanning
4 decades of study period and 4 decades of participant age.
Such generalizability may suggest an inherent biological basis
rather than artifactual explanations. The sex ratio of angina
contrasts with the ubiquitous male excess of myocardial infarction,
is unexplained, and warrants further study. The observation
of a female excess of angina, independent of diagnostic and
treatment practices, has clinical implications for understanding
the quality of care in women. See p
1526.
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Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment
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Statins reduce low-density lipoprotein (LDL) cholesterol by
inhibiting hydroxymethyl glutaryl coenzyme A reductase (HMGCR),
a rate-limiting enzyme of cholesterol synthesis. Although statins
are highly efficacious for most patients, there is a wide range
of response among individuals, and there is evidence that genetic
factors can contribute to this variation in response. In the
present study, we identified common single nucleotide polymorphisms
in the gene encoding HMGCR and tested the associations of 11
of these single nucleotide polymorphisms (all noncoding) with
the magnitude of change of LDL cholesterol and other lipids
and lipoproteins in response to simvastatin (40 mg/d for 6 weeks)
in 596 whites and 326 blacks with a wide range of LDL cholesterol
levels. We found that carriers of 2 interrelated HMGCR single
nucleotide polymorphism clusters (haplotypes) manifested both
lower plasma levels of LDL cholesterol (3.27±0.05 versus
3.48±0.03 mmol/L) and a smaller magnitude of LDL cholesterol
change in response to statin (–1.28±0.03 versus
–1.45±0.02 mmol/L) than did noncarriers. Notably,
these effects were observed only in blacks, in whom the prevalence
of one of the haplotypes was substantially greater than in whites.
Although the absolute magnitudes of these genetic effects are
not large enough to warrant their analysis in clinical practice,
the findings point to the possibility that other genetic markers
may be discovered that may collectively improve prediction of
statin efficacy and toxicity and hence may be useful in guiding
optimal therapy. Furthermore, these findings point to the need
for considering racial and ethnic differences in studies aimed
at identifying genetic factors affecting drug treatment response.
See p
1537.
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Hemodynamic Effects of Volume Expansion in Patients With Cardiac Tamponade
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Cardiac tamponade may be a life-threatening syndrome that requires
urgent therapy. The optimal treatment is pericardial drainage,
either by needle pericardiocentesis or by a surgical procedure;
however, these procedures may not be readily available, and
alternative methods can be considered as interim therapy. Intravascular
fluid expansion has been proposed as a potentially useful procedure
for this purpose, but the scientific evidence for its clinical
effectiveness is very poor. The present report is based on 49
patients with large pericardial effusion and medical tamponade
who underwent combined pericardiocentesis and cardiac catheterization
and were submitted to fluid overload with administration of
500 mL of intravenous normal saline over a 10-minute period.
At baseline, all patients met hemodynamic criteria of tamponade
(equalization of intrapericardial and intracavitary pressures).
Volume expansion caused a significant increase in mean arterial
pressure and cardiac index, but only half of the patients had
an increase in cardiac index >10%. The only predictor of
this favorable response was low systolic blood pressure (<100
mm Hg). Volume expansion caused a significant increase in intrapericardial,
right atrial, and left ventricular end-diastolic pressures.
Remarkably, cardiac index decreased in 30% of patients, although
no patient developed clinical complications. In conclusion,
volume expansion should not be considered for all patients with
cardiac tamponade on a systematic basis, but it can help to
stabilize hypotensive patients while they are being prepared
for pericardiocentesis. This beneficial effect should be put
against a consistent increase in left ventricular end-diastolic
pressure. See p
1545.
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Restrictive Left Ventricular Filling Pattern Does Not Result From Increased Left Atrial Pressure Alone
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Diastolic function has been evaluated noninvasively from the
dynamics of left ventricular filling, reflected in the pattern
of mitral valve flow velocity measured by Doppler echocardiography
and by tissue Doppler assessment of mitral annular velocity.
A restrictive filling pattern with a high peak early diastolic
peak filling velocity (E), short E deceleration time, and reduced
and delayed peak early diastolic mitral annular velocity (E')
has been thought to indicate severe diastolic dysfunction. However,
because the restrictive filling pattern occurs in patients with
elevated left atrial pressure, it may be merely a manifestation
of an overfilled ventricle, not diastolic dysfunction. We tested
this hypothesis by evaluating left ventricular filling in chronically
instrumented animals in 2 situations with similar elevations
of left atrial pressure: normal animals after acute volume loading
and animals with severe heart failure with restrictive filling.
We found that the restrictive filling pattern is differentiated
from overfilling of a normal ventricle by a decreased and delayed
E' reflecting slow relaxation and a short E deceleration time
resulting from increased left ventricular operating stiffness.
Thus, restrictive filling indicates the presence of diastolic
dysfunction and is not due to elevated left atrial pressure
alone. See p
1550.
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Magnetic Resonance Imaging Overestimates Ferumoxide-Labeled Stem Cell Survival After Transplantation in the Heart
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Iron labeling of stem cells has been touted as a reliable method
to assess engraftment and migration after cell transplantation
by magnetic resonance imaging (MRI). Cardiac-derived stem cells
or mesenchymal stem cells labeled with iron oxide were injected
intramyocardially into rats to investigate the relationship
between iron-dependent MRI signals and cell survival. Comparing
in vivo images with histological results in the same hearts,
we found that intense MRI signals, generated by iron in tissue
macrophages, persisted for 3 to 5 weeks after rapid loss of
viable transplanted cells, as in the case of xenogenic transplantation.
The iron-derived MRI signals were similar whether they arose
from macrophages or viable or dead stem cells. Importantly,
the results were not cell (cardiac-derived or mesenchymal stem
cells) or substrate (normal versus infarcted myocardium) specific.
Iron oxide labeling and MRI may be appropriate for localization
of cell injection sites, but these methods are not reliable
for in vivo tracking of viable cells in the heart. See p
1555.
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Human Apolipoprotein A-I Gene Transfer Reduces the Development of Experimental Diabetic Cardiomyopathy
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The present study reports that an increase in high-density lipoprotein
(HDL) via human apolipoprotein A-I gene transfer reduces the
development of experimental diabetic cardiomyopathy. Besides
the demonstration of cardiac antiinflammatory, antioxidative,
and antiapoptotic features of HDL, the present study describes
new cardioprotective effects of HDL. It shows for the first
time that fibrosis and glycogen accumulation are reduced after
human apolipoprotein A-I transfer in an experimental model of
diabetic cardiomyopathy. This study, performed in an animal
model characterized by severe hyperglycemia, oxidative stress,
and a ratio of HDL cholesterol to low-density lipoprotein cholesterol
of 1, strongly suggests that HDL has direct cardioprotective
effects, which is strengthened by the finding that HDL directly
improves impaired cardiomyocyte contractility ex vivo. Our findings
underscore the cardioprotective effects of HDL; however, the
relevance of the use of HDL-raising therapies for the cotreatment
of diabetic cardiomyopathy should be examined in future studies
investigating the effect of increasing HDL on established diabetic
cardiomyopathy. Moreover, it has to taken into account that
the current HDL-elevating drugs only moderately increase HDL
compared with apolipoprotein A-I gene transfer. Furthermore,
the way that these drugs interfere with HDL metabolism differs,
which might contribute to important differences in success and
tolerability. See p
1563.
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Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice
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Matrix metalloproteinase (MMP)-9 is expressed in the myocardium
during cardiac injury. It has been postulated that the presence
of this MMP is detrimental to cardiac repair after infectious
and ischemic heart injury. Potential treatments have even been
devised that suppress the expression of MMPs during infectious
myocarditis. We show that the absence of MMP-9 in a knockout
(KO) mouse model enhances susceptibility to cardiac infection
by coxsackievirus. There was a lower viral load in the pancreas
in wild-type (WT) mice than in KO mice, and importantly, there
was limited infection of the WT myocardium. The MMP-9 KO mice
had significantly more pancreatic and myocardial infection (cross-sectional
myocardial foci count of 102 versus 19 in WT mice) and significantly
decreased cardiac output. Immune infiltration was increased
in MMP-9 KO mice compared with WT mice (15.2% versus. 2.0%,
respectively). Our study is consistent with other evidence of
the suppression of bacterial infection by MMP-9, but a similar
effect has never been shown in a viral model of infection. This
study suggests that MMP-9 plays a role in suppressing viremia
to the point of protecting the heart from infection, while mediating
an appropriate immune response. Therefore, treatments meant
to prevent the onset of infectious myocarditis by coxsackievirus
would be best to preserve MMP-9 function. See p
1574.
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Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number
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Cardiomyocyte death leading to loss of contractile units has
been implicated in the pathogenesis of all forms of heart failure.
Although the exact stimuli, mechanisms, and rate of apoptosis
in the adult human heart are unknown, a dynamic balance exists
between cardiomyocyte loss and replacement during life and disease.
We found that the small antiapoptotic molecule survivin controls
both cell death and cell division during cardiac development;
its deletion in a cardiomyocyte-specific fashion in mice led
to progressive heart failure resulting from a profound reduction
in total cardiomyocyte numbers per heart. By systematically
counting total cardiomyocytes, we were able to determine the
minimal cardiomyocyte number sufficient for normal lifelong
cardiac function. Survivin overexpression in cultured cardiomyocytes
inhibited apoptosis, induced DNA synthesis, and promoted cell
cycle progression. In the failing human heart, survivin was
potently induced and decreased again after hemodynamic relief
through a mechanical left ventricular assist device. We observed
that the long-known existence of polyploidy of cardiomyocytes
in the failing human heart was remarkably decreased after hemodynamic
support and correlated with the level of survivin expression
at any time. Thus, survivin may be a marker of DNA synthesis,
polyploidy, or possibly even cell cycle traverse in the failing
human heart, making it a bona fide target for myocardial regeneration
therapies. We suggest that the individual number of "cardiomyocyte
working units" that are under the control of survivin may be
an independent factor in the susceptibility to cardiac diseases
independently of their cause. See p
1583.
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