Circulation. 2008;117:127
doi: 10.1161/CIRCULATIONAHA.107.188516
(Circulation. 2008;117:127.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Radiofrequency Ablation of Atrial Fibrillation: Is the Persistence of All Intraprocedural Targets Necessary for Long-Term Maintenance of Sinus Rhythm?
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Radiofrequency catheter ablation has emerged as an important
therapeutic option in patients with drug-resistant atrial fibrillation.
Different approaches have been tested, but specific intraprocedural
targets and end points remain controversial. Demonstration that
a particular procedural end point, such as conduction block
into a pulmonary vein (PV), is critical requires the demonstration
of persistence of that end point during follow-up. Recovery
of ablation lesions is well reported, so the demonstration of
persistence and relation of this to prevention of atrial fibrillation
requires repeat electrophysiological study in asymptomatic patients
after an effective ablation procedure. The aim of the present
study was to verify the long-term result of encircling PV ablation
with the end point of atrial potential abatement plus PV disconnection
confirmed with a multipolar catheter. Repeat electrophysiology
study was performed 2.5 years after successful ablation in a
series of patients in stable sinus rhythm after previously persistent
atrial fibrillation. These data were compared with those obtained
from redo ablation procedures because of atrial fibrillation
recurrences. In patients in stable sinus rhythm after ablation,
only 37.5% of the PVs remained disconnected, and 60% of the
PVs had recovered electrogram voltage within the ablation region.
No statistically significant differences were noted between
patients with and without recurrences after the initial ablation
procedure. This study suggests that common intraprocedural end
points such as voltage abatement and PV disconnection persist
only in a limited number of patients, even when the outcome
is favorable during follow-up. Further studies will be required
to confirm these data in larger populations and to determine
their implications for ablation strategies. See p
136.
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Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations
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Patients with glycogen-storage–associated cardiomyopathy
due to
PRKAG2 mutations generally have a poor prognosis because
of severe cardiac dysfunction, ventricular preexcitation, and
progressive conduction system disease. This study used a system
that allows regulation of the timing of expression of the
PRKAG2N488I mutation in mice during development. Altering the timing of
glycogen depletion in the heart prevents or reverses cardiac
hypertrophy, cardiac dysfunction, ventricular preexcitation,
and conduction system disease in
PRKAG2 glycogen-associated
cardiomyopathy. In the era of such advanced therapeutic approaches
as gene therapy and enzyme replacement, these data imply that
myocardial dysfunction and conduction system disease in glycogen-storage
cardiomyopathy could potentially be treated by modulation of
glycogen content in the heart and that early initiation of treatment
is critical to prevent the development of accessory pathways.
Lowering cardiac glycogen content significantly ameliorates
morbidity in
PRKAG2 cardiomyopathy and could eventually be a
viable alternative treatment option to device implantation and
heart transplantation for patients who have
PRKAG2 mutations
with glycogen-storage cardiomyopathy and arrhythmias. See p
144.
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Proarrhythmic Aspects of Atrial Fibrillation Surgery: Mechanisms of Postoperative Macroreentrant Tachycardias
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Surgical procedures to prevent atrial fibrillation are being
performed much more commonly with advances in surgical technologies
for lesion creation. As a result, more patients are likely to
experience proarrhythmic effects of these operations. Late macroreentrant
atrial tachycardias may occur in either atria and may be the
result of incomplete surgical lines (such as within the cavotricuspid
isthmus or adjacent to the mitral valve annulus). Macroreentry
also may occur at the site where surgical boundaries have not
been extended through all conducting atrial myocardium (such
as at the superior vena caval–right atrial junction).
Additional mechanisms may involve the creation of slowly conducting
zones of atrium based on the anisotropic conduction properties
of structures such as the crista terminalis or Bachmann’s
bundle. Although the precise mechanism of these functional central
obstacles has not been completely defined, such structures appear
to be the site of successful ablation for some arrhythmias in
the right atrial free wall and in the roof of the left atrium.
A critical aspect of any successful surgical program is close
collaboration between the cardiovascular surgeon who is performing
these operations and an experienced cardiac electrophysiologist
capable of mapping and ablating these arrhythmias. Patients
undergoing surgical ablation of atrial fibrillation require
close follow-up postoperatively. See p
155.
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Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease
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Red blood cell distribution width (RDW) is a numerical measure
of the variability in size of circulating erythrocytes and is
routinely reported as part of the complete blood count as an
aid in the differential diagnosis of anemia. A strong independent
association between RDW and the risk of adverse outcomes was
recently reported in patients with heart failure. However, whether
RDW is associated with adverse outcomes in other populations
is unknown. In this study, we found a graded, independent association
between baseline RDW level and the risk of all-cause death,
the development of new heart failure, and coronary events in
this population of individuals with previous myocardial infarction
who were free of clinically evident heart failure at baseline,
most of whom had RDW levels within the normal range. Adjustment
for multiple potential confounders attenuated but did not eliminate
the association between higher RDW levels and the adverse clinical
outcomes. In addition to reaching statistical significance,
the magnitude of the increased risk associated with higher levels
of RDW was clinically relevant. For example, the risk of all-cause
death in participants with RDW in the highest quartile was nearly
80% higher than those in the lowest quartile, similar to the
adjusted risk of a recurrent cardiovascular event among Cholesterol
and Recurrent Events study participants with C-reactive protein
in the highest quintile compared with the lowest. These findings
are notable given that RDW is widely available to clinicians
as part of the complete blood count and therefore incurs no
additional costs, in contrast to other novel markers of cardiovascular
risk. See p
163.
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Adherence to the Mediterranean Diet Is Inversely Associated With Circulating Interleukin-6 Among Middle-Aged Men: A Twin Study
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The Mediterranean diet is protective against cardiovascular
disease; a proposed mechanism is through reducing systemic inflammation.
Dietary habits are acquired while growing up and may be confounded
by other behavioral, environmental, or genetic factors shared
by family members. It is unknown to what extent the association
between the Mediterranean diet and inflammation is due to other
familial factors. We used data on identical and fraternal twins
raised together to answer this question because twins are naturally
matched for measured and unmeasured common environmental factors
while growing up. Monozygotic twin pairs are also 100% matched
for genetic factors, whereas fraternal pairs share on average
50% of their genes. We constructed a 10-unit diet score to measure
adherence to the Mediterranean diet; a higher score indicates
greater adherence to the Mediterranean diet. We found that a
1-unit increase in the Mediterranean diet score was associated
with a 5% decrease in systemic inflammation measured by means
of plasma interleukin-6 concentration. After further controlling
for shared familial and genetic factors by examining differences
between twins in a pair, we found that a twin with a 1-unit-higher
Mediterranean diet score than his twin brother had a 9% lower
interleukin-6 concentration. In contrast, shared familial and
genetic factors did not significantly contribute to the association
between MDS and inflammation. Our findings substantiate the
protective role of the Mediterranean diet on cardiovascular
risk and support the importance of consuming a healthier diet
to prevent cardiovascular disease. See p
169.
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Extreme Lipoprotein(a) Levels and Risk of Myocardial Infarction in the General Population: The Copenhagen City Heart Study
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In this study of the adult Danish general population, the Copenhagen
City Heart Study, which included 9330 men and women followed-up
for 10 years, we observed a stepwise increase in risk of myocardial
infarction with increasing levels of lipoprotein(a) in both
genders, with no evidence of a threshold effect. We found that
extreme lipoprotein(a) levels >95th percentile predict a
3- to 4-fold increase in risk of myocardial infarction and absolute
10-year risks of 20% and 35% in high-risk women and men. At
present, no acceptable means of lowering lipoprotein(a) levels
exist. However, lipoprotein(a) measurements among medium-risk
individuals will help to identify as yet unidentified high-risk
individuals who could benefit from other aggressive, prophylactic
measures, including statins directed at elevated cholesterol
levels. Indeed, the influence of lipoprotein(a) in causing myocardial
infarction and ischemic heart disease is muted with substantial
cholesterol reductions in hypercholesterolemic patients. In
particular, individuals with a strong family history of ischemic
heart disease would be candidates for lipoprotein(a) measurements
because lipoprotein(a) levels are predominantly genetically
determined and lipoprotein(a) is considered a quantitative genetic
trait. See p
176.
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Lack of Association Between the MEF2A Gene and Myocardial Infarction
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After the initial report of a 21-bp deletion in the
MEF2A gene
as the disease-causing genetic variant in a large family with
autosomal-dominant inheritance of coronary artery disease, case-control
studies on single genetic variants within the
MEF2A gene revealed
controversial results. In the present, and thus far the largest,
analysis, no evidence was found for a significant association
of the
MEF2A gene with myocardial infarction. We studied defined
genetic variants in 2 large study populations of patients with
familial and sporadic myocardial infarction and 2 control populations
and also analyzed single-nucleotide polymorphisms from a genome-wide
association study comprehensively covering the
MEF2A gene. Thus,
MEF2A is added to a growing list of candidate genes for complex
diseases in which no consistent association with a defined phenotype
across various populations could be observed. Therefore, results
from molecular genetic association studies have to be interpreted
with caution and should not yet be transferred or should be
transferred in only a very limited fashion to clinical practice
(eg, estimating the individual genetic risk for a complex disease).
However, genome-wide association studies analyzing hundreds
of thousands of single-nucleotide polymorphisms might offer
new opportunities in this regard. Recently, 4 genome-wide association
studies for myocardial infarction and coronary artery disease
revealed very promising results in that chromosomal regions
could be identified that displayed robust association with myocardial
infarction and coronary artery disease in various independent
populations. See p
185.
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Initial Aspirin Dose and Outcome Among ST-Elevation Myocardial Infarction Patients Treated With Fibrinolytic Therapy
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The International Study of Infarct Survival (ISIS-2) trial demonstrated
that treatment with 162.5 mg aspirin reduces morbidity and mortality
in ST-elevation myocardial infarction (STEMI). On the basis
of these data, the American College of Cardiology, American
Heart Association, and European Society of Cardiology gave a
class I level of evidence A to immediate use of 162 mg of aspirin.
Nevertheless, the most common initial dose of aspirin in the
immediate setting of STEMI is 325 mg (class I level of evidence
C). Given the uncertainty of immediate aspirin dose, we performed
a retrospective analysis of 2 large STEMI fibrinolytic trials
(Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries [GUSTO I] and Global
Use of Strategies to Open Occluded Coronary Arteries [GUSTO
III]) to assess the relationship between aspirin dose (162 versus
325 mg) and short-term outcomes after STEMI. We demonstrated
no significant association between initial aspirin dose (162
versus 325 mg) and risk of death, myocardial infarction, or
stroke. However, the initial dose of 325 mg was associated with
a significant increase in the risk of moderate or severe bleeding
compared with 162 mg. Although these data are nonrandomized,
they suggest that for the first dose of aspirin, 162 mg may
be as effective as and safer than 325 mg for the acute treatment
of STEMI. Until future randomized data are provided to support
the use of 325 mg in the setting of STEMI, it may be worthwhile
to use 162 mg, a dose previously established to lessen cardiovascular
morbidity and mortality in this setting. See p
192.
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Renal Vasodilatory Action of Dopamine in Patients With Heart Failure: Magnitude of Effect and Site of Action
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Decreased renal function is common in hospitalized patients
with heart failure, and attempts to improve it with a number
of vasoactive medications have not resulted in a consistent
favorable effect. A "renal dose" of dopamine has been used by
clinicians for many years to enhance renal function in critically
ill patients. The renal circulatory effect of dopamine, however,
has not been well studied in patients with heart failure. The
results of the present study demonstrated a significant vasodilatory
effect of dopamine in doses between 2 and 10 µg ·
kg
–1 · min
–1 on both resistance and conductance
renal arteries. This effect resulted in a significant reduction
in renal vascular resistance and a rise in renal blood flow.
In addition, intravenous dopamine resulted in a marked effect
on cardiac output. These beneficial effects of intravenous dopamine
both on the systemic and renal circulation are encouraging and
suggest that further research on the effect of dopamine on renal
function and outcome in hospitalized patients with heart failure
is warranted. See p
200.
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Platelet-Derived Stromal Cell–Derived Factor-1 Regulates Adhesion and Promotes Differentiation of Human CD34+ Cells to Endothelial Progenitor Cells
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The tissue-healing process in patients who have had a myocardial
infarction or any ischemic disease is based on recruitment and
subsequent differentiation of a small number of circulating
stem cells. Understanding the mechanisms that are responsible
for the local recruitment and differentiation of stem cells
may enable us to better understand the pathophysiology of tissue
remodeling and regeneration. This study investigated the role
of platelet-derived stromal cell–derived factor-1 (SDF-1)
in adhesion and subsequent differentiation of human CD34
+ cells
into endothelial progenitor cells. Adherent platelets express
substantial amounts of SDF-1 and recruit CD34
+ cells under high
arterial shear in vitro and after carotid ligation in mice in
vivo. Platelets that adhere to human arterial endothelial cells
enhance the adhesion of CD34
+ cells on endothelium under flow
conditions, a process that is inhibited by anti-SDF-1. During
intestinal ischemia/reperfusion in mice, anti-SDF-1 and anti-CXCR4,
but not isotype control antibodies, abolish the recruitment
of CD34
+ cells in microcirculation. Moreover, platelet-derived
SDF-1 binding to CXCR4 receptor promotes platelet-induced differentiation
of CD34
+ cells into endothelial progenitor cells, as verified
by colony-forming assays in vitro. These findings imply that
platelet-derived SDF-1 regulates adhesion of stem cells in vitro
and in vivo and promotes differentiation of CD34
+ cells to endothelial
progenitor cells. Because tissue regeneration depends on recruitment
of progenitor cells to peripheral vasculature and their subsequent
differentiation, platelet-derived SDF-1 may contribute to vascular
and myocardial regeneration. See p
206.
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Adiponectin Prevents Cerebral Ischemic Injury Through Endothelial Nitric Oxide Synthase–Dependent Mechanisms
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Obesity-linked diseases are linked to an increased risk for
ischemic stroke. Adiponectin is a fat-derived hormone that is
downregulated in obese subjects. In the present study, we examined
the causal role of adiponectin in ischemic stroke. Adiponectin
deficiency contributed to increased cerebral injury after ischemia-reperfusion.
Conversely, adiponectin supplementation reduced cerebral ischemia-reperfusion
injury. Adiponectin deficiency resulted in decreased cerebral
blood flow and reduced endothelial nitric oxide synthase signaling
during ischemia. The beneficial action of adiponectin was abolished
in endothelial nitric oxide synthase–deficient mice. Thus,
adiponectin protects the brain from acute ischemic injury through
an endothelial nitric oxide synthase–dependent mechanism.
Our data suggest that adiponectin represents a therapeutic target
molecule for the prevention of ischemic stroke. See p
216.
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High Absolute Risks and Predictors of Venous and Arterial Thromboembolic Events in Patients With Nephrotic Syndrome: Results From a Large Retrospective Cohort Study
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The association between the nephrotic syndrome and thromboembolic
events has been known for decades; however, no data are available
on the absolute risk of either venous (VTE) or arterial thromboembolism
(ATE). The reported risks of thromboembolism in patients with
nephrotic syndrome are based on case reports and small studies,
most with limited follow-up. Previous assessments of VTE risk
have been based largely on asymptomatic cases of renal vein
thrombosis, the clinical relevance of which is not clear. Moreover,
predictive factors of both VTE and ATE in these patients have
yet to be determined. In this study, the absolute risks of symptomatic
VTE and ATE were assessed. Thromboembolism was many times higher
than the estimated age- and sex-weighted absolute risks in the
general population. The risk of thromboembolism was excessively
high in the first 6 moths of observation. Whereas the risk of
VTE was related to the severity of nephrotic syndrome, the risk
of ATE was related to estimated glomerular filtration rate and
classic risk factors for atherosclerosis. These findings highlight
the need for prospective randomized trials to evaluate the effect
of current antiproteinuric treatment on the risk of thromboembolism
and the benefits of primary thromboprophylaxis. These findings
also suggest that primary thromboprophylaxis could be beneficial,
particularly during the first 6 months, for patients at highest
risk, and further studies are needed to demonstrate clinical
utility in this setting. See p
224.
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Radiofrequency Ablation of...
Reversibility of PRKAG2 Glycogen...