Circulation. 2008;117:711-713
doi: 10.1161/CIRCULATIONAHA.107.188520
(Circulation. 2008;117:711-713.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Cell Therapy for Modification of the Myocardial Electrophysiological Substrate
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Cardiac arrhythmias account for significant worldwide morbidity
and mortality. Preventive antiarrhythmic therapies are aimed
at modifying the abnormal electrophysiological substrate by
either focal injury (surgery or radiofrequency catheter ablation)
or pharmacological therapy. Antiarrhythmic drug therapy has
been hampered by often low efficacy, global cardiac and systemic
actions that often lead to poorly tolerated systemic side effects,
and most important, life-threatening proarrhythmic effects.
In this study, we present a novel combined cell and gene therapy
approach for the modification of the myocardial electrophysiological
substrate. Using fibroblast cell grafts genetically engineered
to express specific potassium ionic channels, we aimed to perform
a targeted modification of local cardiac electrophysiological
properties. Detailed in vitro, in vivo, and computer modeling
studies demonstrated the feasibility of this approach by showing
that the engineered cells could couple with host cardiac cells
and that this modified their electrophysiological properties.
The cell grafts modulated important properties that are of interest
for future antiarrhythmic strategies. These include prolongation
of the local refractory period by a mechanism that does not
involve action potential prolongation (potentially reducing
the proarrhythmic risk associated with many antiarrhythmic agents
that prolong the QT interval) and reduction in local automaticity
(decreasing the spontaneous firing rate). See p
720.
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Angiotensin II Receptor Blockade Reduces Tachycardia-Induced Atrial Adhesion Molecule Expression
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Vascular thrombi develop in the presence of reduced blood velocities,
when the activity of the clotting system is increased, and in
the presence of endothelial alterations (Virchow’s triad).
Virchow’s triad also applies to atrial thrombus formation
during atrial fibrillation (AF). It is well known that AF causes
loss of regular atrial contractions, and AF thereby reduces
atrial blood flow velocities. Furthermore, AF is associated
with activation of the plasmatic clotting system and of thrombocytes.
However, the contribution of endothelial alterations to atrial
thrombogenesis has not been fully explored. Increased endocardial
expression of adhesion molecules (such as vascular cell adhesion
molecule) could be an important link between initiation of inflammatory
and prothrombogenic mechanisms responsible for thrombus development
at the atrial endocardium ("endocardial remodeling"). The present
study investigates the impact of AF on the expression of various
prothrombotic atrial proteins in a large cohort of patients.
The main finding of the study is an increased endocardial vascular
cell adhesion molecule-1 expression in patients with AF. Interestingly,
endocardial vascular cell adhesion molecule levels during AF
are further increased by well-known risk factors for thromboembolic
events such as diabetes mellitus and heart failure. We can show
that angiotensin II receptor blockers reduce tachycardia-induced
atrial vascular cell adhesion molecule-1 expression ex vivo
and in vivo, providing evidence that angiotensin II has a significant
pathophysiological role in the prothrombogenic process of endocardial
remodeling. Thus, the present study provides an important piece
of information to explain the impact of angiotensin II receptor
blockers on inflammatory and prothrombotic alterations at the
atrial endocardium during AF. See p
732.
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General Cardiovascular Risk Profile for Use in Primary Care: The Framingham Heart Study
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Cardiovascular disease (CVD) remains the leading cause of mortality
and morbidity. A plethora of effective drugs for the major risk
factors of CVD such as blood pressure, high cholesterol, and
diabetes control exists. Prevention strategies assessing the
risk of CVD and identifying the risk factors associated with
the risk have become major approaches for reducing CVD and its
unfavorable consequences. Presently, many of these strategies
involve focusing on a component of CVD such as hard coronary
disease consisting of myocardial infarction and coronary death,
assessing the risk by mathematical risk functions or scoring
functions, and designing treatment (behavioral and/or drug)
according to the level of risk. Our belief is that, especially
in the primary care setting, CVD risk should not be directed
only to a component of CVD such as coronary disease or stroke
but rather to all manifestation of CVD. In particular, individuals
with high overall CVD risk require aggressive risk factor modification.
In the present article, we present simple sex-specific risk
functions that assess the 10-year risk (probability) of developing
overall CVD. These functions involve inputs of blood pressure,
cholesterol levels, diabetes, and smoking. Thus, not only is
the overall risk quantified, but the source of the risk can
be identified for treatment. Simple scoring sheets are presented
that make the CVD functions immediately usable. Finally, straightforward
adjustments to the functions can be used also to assess the
risk for specific components of CVD. See p
743.
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Dietary Intake and the Development of the Metabolic Syndrome: The Atherosclerosis Risk in Communities Study
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Metabolic syndrome (MetSyn) is a cluster of cardiovascular disease
risk factor abnormalities associated with increased risk of
type 2 diabetes mellitus, cardiovascular disease, and all-cause
mortality. The role of diet in the development of MetSyn is
not well understood. In a prospective study of almost 15 000
middle-aged black and white adults, we observed a 13% to 18%
higher risk of incident MetSyn among those eating a "Western
diet" pattern, a diet characterized by high intakes of red and
processed meat, fried food, regular soda, and refined-grain
products and low intakes of fruit and vegetables, fish, and
whole-grain products. To support this result, we found that
eating 1 to 2 servings per day of meat was associated with 17%
to 26% higher risk of incident MetSyn compared with one-fourth
serving per day, and eating fried foods everyday also was associated
with higher risk. Risk of MetSyn was lower among adults consuming
>3 daily servings of dairy products compared with one-fourth
serving. Interestingly, adults who consumed 1 serving of diet
soda a day had a 34% higher risk of MetSyn compared with nonconsumers.
These prospective findings suggest that consumption of a Western
dietary pattern, meat, and fried foods promotes the incidence
of MetSyn, whereas dairy consumption provides some protection.
The diet soda association was not hypothesized and deserves
further study. See p
754.
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Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts
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A considerable body of evidence shows that the defective operation
of the sarcoplasmic reticulum Ca
2+ release channel, also known
as ryanodine receptor 2 (RyR2), is a major causative factor
of heart failure. Previously, we demonstrated that an interdomain
interaction within RyR2, which stabilizes the channel gating,
is defective in failing hearts, resulting in Ca
2+ leak and contractile
dysfunction. We have also shown that K201 (also known as JTV519)
reversed the mode of interdomain interaction from a defective
unzipped configuration to a normal zipped configuration and
stopped Ca
2+ leak. In this article, the mechanism by which K201
corrects the channel disorder of RyR2 is defined. The specific
binding site of K201 was found to reside in the central domain
of RyR2. The binding of K201 to this domain interferes with
an interdomain interaction between the RyR2 drug-binding domain
(2114 to 2149) and its partner domain. The specific interruption
of this interdomain interaction within RyR2 seems to play a
critical role in stabilizing the channel gating. These results
further support the notion that fixing the defective interdomain
interaction within RyR2 is a promising therapeutic strategy
for treatment of heart failure. See p
762.
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Adenosine Modulates Cardiovascular Functions Through Activation of Extracellular Signal-Regulated Kinases 1 and 2 and Endothelial Nitric Oxide Synthase in the Nucleus Tractus Solitarii of Rats
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The sympathetic nervous system has moved toward center stage
in cardiovascular medicine. Studies have demonstrated that sympathetic
overactivity characterizes the hypertensive state and participates
in the development, maintenance, and progression of elevated
blood pressure. The importance of sympathetic overactivity in
heart failure progression and mortality and in the generation
of ventricular arrhythmias is now well established, and a central
nervous system–mean arterial pressure (CNS-MAP) set-point
theory has recently been proposed. It has been hypothesized
that hypertension occurs as the result of a primary shift of
the CNS-MAP set point to a higher operating pressure, which
results in increased sympathetic nerve activity. The nucleus
tractus solitarius (NTS), located at the dorsal part of the
brainstem, was discovered to be an important sympathetic nervous
system integral center in the central nervous system. Adenosine,
a ubiquitously distributed neuromodulator, was found to participate
in sympathetic activity regulation in the NTS. In the present
study, we investigated the signaling mechanism of adenosine
with regard to cardiovascular modulation in the NTS and found
that the MEK-ERK (mitogen-activated protein kinase–extracellular
signal-regulated kinase) cascade, which was originally discovered
to be a critical regulator of cell division and differentiation,
participates in adenosine-mediated central cardiovascular control.
In addition, we also demonstrated that endothelial nitric oxide
synthase, which was originally identified in the vascular endothelium,
is present and participates in cardiovascular regulation in
the NTS. Further investigation of the molecular mechanisms involved
in sympathetic nervous activity modulation might elucidate the
pathogenesis of the CNS-MAP set-point shift and sympathetic
overactivity in essential hypertension. See p
773.
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Technetium 99m–Labeled Annexin V Scintigraphy of Platelet Activation in Vegetations of Experimental Endocarditis
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The mural thrombus, whatever its location (vascular, intracardiac,
or valvular), exhibits biological activity (proaggregant and
fibrinolytic) because of the maintenance of a dynamic interface
with the circulating blood. Experimental thrombotic endocarditis
is a model of mural thrombus, in which biological activity is
enhanced by bacterial colonization. Binding of bacteria to platelets
can induce their activation and aggregation, resulting in phosphatidylserine
exposure. Annexin V specifically binds with nanomolar affinity
to phosphatidylserines. This preclinical study shows the ability
of radiolabeled annexin V to provide in vivo functional imaging
of platelet activation in experimental endocarditis. Annexin
V uptake was predominant in the luminal layer of the vegetation,
at the interface with circulating blood, and its uptake was
enhanced by bacterial colonization of the vegetation. As suggested
by previous preclinical studies of atherothrombosis or abdominal
aortic aneurysm models, radiolabeled annexin V is able to provide
insight into platelet activation in various degenerative cardiovascular
diseases. Additionally, radiolabeled annexin V allowed the detection
of pulmonary emboli in right-sided endocarditis. The embolic
potential of vegetations is related to their fibrinolytic activity
and is a prognostic determinant in human endocarditis. Indeed,
the incidence of emboli was high when the infective pathogen
was
Staphylococcus aureus, a bacterium known to interact with
the plasminergic system of the host. In this regard, tracers
targeting fibrinolytic activity would be of interest. Finally,
the detection of phlebothrombosis associated with silicone rubber
catheters, close to human pacemaker leads, suggests a potential
role of radiolabeled annexin V in the diagnosis of implantable
cardiac device infection. See p
781.
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Saphenous Vein Graft Stenting and Major Adverse Cardiac Events: A Predictive Model Derived From a Pooled Analysis of 3958 Patients
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Saphenous vein graft percutaneous coronary intervention carries
with it a high risk of major adverse cardiac events, particularly
periprocedural myocardial infarction. The short-term risk approaches
20%, and before the introduction of embolic protection devices,
no adjunctive therapy had been shown to reduce this risk. Despite
accumulating evidence from randomized trials suggesting consistent
reductions in the rate of 30-day major adverse cardiac events
with the use of embolic protection devices by
40%, it is estimated
that these devices are used in only half of saphenous vein graft
interventions. Our analysis, which pooled 3958 patients enrolled
in 5 randomized, controlled trials and 1 registry of embolic
protection devices, identified 2 angiographic measures of plaque
burden, plaque volume and a graft degeneration score, as the
most important independent predictors of 30-day major adverse
cardiac events. Additional independent clinical risk factors
included increasing patient age and tobacco use. Saphenous vein
graft percutaneous coronary intervention consistently provided
embolic protection in reducing 30-day major adverse cardiac
events across the broad range of characteristics in patients
tested in randomized trials. The reliability of the model developed
across patients and trials suggests that new embolic protection
device safety and efficacy could be evaluated in the future
against risk-adjusted models of expected rates of adverse events.
This could facilitate evaluation of new embolic protection devices
and their adoption to prevent adverse events. See p
790.
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Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E–Deficient Mice
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The epidemic of obesity will promote morbidity and mortality
resulting from cardiovascular diseases in the next few decades.
Links between obesity and vascular risk remain to be elucidated;
however, several recent clinical studies have suggested that
visceral adiposity is largely responsible for obesity-associated
vascular risk. Whether visceral adipose tissue is a marker or
mediator of vascular risk is unclear. Experimental models of
obesity have demonstrated marked differences between visceral
and subcutaneous fat in terms of adipocytokine expression and
leukocyte infiltration. The multiple metabolic changes associated
with states of generalized obesity confound efforts to establish
a causal link between fat tissue and vascular end points. Here,
we used a model of fat transplantation, which is associated
with inflammation in the transplanted fat depot, to examine
the effect of inflammatory fat on atherosclerosis. In the absence
of generalized obesity or diabetes, we found that transplanted
visceral fat is capable of promoting atherosclerosis in mice.
This effect on atherosclerosis was not observed when subcutaneous
fat was transplanted, despite a similar degree of macrophage
infiltration into the transplanted fat depot. The specific factors
responsible for the effect of inflammatory visceral fat on atherosclerosis
remain to be identified, although plasma monocyte chemoattractant
protein-1 levels were higher in mice with visceral compared
with subcutaneous fat transplants. Treatment of mice with the
peroxisome proliferator–activated receptor-
ligand pioglitazone
reduced monocyte chemoattractant protein-1, fat inflammation,
and atherosclerosis induced by the visceral fat transplant.
Interventions that target inflammation within visceral fat may
be useful in reducing the vascular risk associated with central
obesity. See p
798.
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Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages
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Obesity is characterized by a systemic low-grade inflammatory
state that is thought to contribute to the genesis of obesity-associated
cardiovascular diseases and type 2 diabetes mellitus. However,
the cellular and molecular mechanisms underlying the link between
fat mass enlargement, inflammation, and obesity-associated pathologies
remain to be clearly defined. Adipose tissue (AT) itself produces
a wide range of adipokines with inflammatory properties, and
its excessive development has been associated in humans and
mice with accumulation of AT macrophages (ATMs). The present
study, performed in subcutaneous ATs from lean to overweight
individuals, showed that ATMs coexpressed proinflammatory and
antiinflammatory factors. Furthermore, ATMs specifically produced
and released the key matrix remodeling enzyme matrix metalloproteinase-9
compared with mature adipocytes and AT capillary endothelial
cells. Interestingly, the secretion of matrix metalloproteinase-9
from human AT in vivo, assessed by arteriovenous difference
measurement, was correlated with the body mass index of the
patients. An increase in body mass index also was found to be
associated in ATMs with lower expression levels of 2 proinflammatory
factors (ie, interleukin-8 and cyclooxygenase-2) and a higher
expression level of the remodeling marker lymphatic vessel endothelial
hyaluronan receptor-1. Finally, ATMs exerted marked in vitro
proangiogenic effects on AT-derived capillary endothelial and
progenitor cells. These overall results indicate that the human
ATMs that accumulate within the fat mass during its growth exhibit
a particular remodeling phenotype. ATMs may thus be active players
in AT development via their proangiogenic effects but also in
the genesis of obesity-associated cardiovascular pathologies
through their release of matrix metalloproteinase-9. See p
806.
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Oral Buflomedil in the Prevention of Cardiovascular Events in Patients With Peripheral Arterial Obstructive Disease: A Randomized, Placebo-Controlled, 4-Year Study
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Cardiovascular-related morbidity and mortality in patients with
peripheral arterial obstructive disease remain high. Buflomedil
is an
1-,
2-adrenolytic agent with vasoactive and hemorheologic
properties. An international, multicenter, randomized, double-blind,
placebo-controlled trial was performed to investigate whether
long-term administration of buflomedil would reduce the occurrence
of critical cardiovascular events and prevent the worsening
of clinical symptoms in patients >40 years of age with peripheral
arterial obstructive disease, intermittent claudication, and
an ankle-brachial index between 0.30 and 0.80. Aspirin was recommended
for all patients. The primary efficacy outcome was critical
cardiovascular events, defined as the composite of cardiovascular
death, nonfatal myocardial infarction, nonfatal stroke, symptomatic
deterioration of peripheral arterial obstructive disease, or
leg amputation. A total of 2078 patients were recruited. Mean
treatment duration was 33 months. The rate of the primary outcome
was significantly lower in buflomedil-randomized patients than
in placebo-randomized patients (9.1% versus 12.4%; hazard ratio,
0.742; 95% confidence interval, 0.603 to 0.915;
P=0.0163). Although
not significantly, the event rate of each of the components
of the primary efficacy outcome was reduced in buflomedil-randomized
patients. Concerning major clinical events, including total
death and surgical treatment of peripheral arterial obstructive
disease (amputation, vascular surgery, or angioplasty on the
lower limbs), the trend in favor of buflomedil was particularly
clear. Tolerance of buflomedil and placebo was comparable. Compared
with placebo, buflomedil administered for 3 years reduced the
occurrence of symptomatic cardiovascular events by 26%, the
main contributor to the difference in the composite outcome
being the reduction of symptomatic deterioration of peripheral
arterial disease. This amplitude of risk reduction was comparable
to that observed with other effective drugs classically administered
in this indication. Therefore, the use of buflomedil should
be considered in addition to an antiplatelet agent in patients
with peripheral arterial obstructive disease and intermittent
claudication. See p
816.
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Symptomatic Peripheral Arterial Disease in Women: Nontraditional Biomarkers of Elevated Risk
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Lower-extremity peripheral arterial disease (PAD) is an underrecognized
manifestation of atherosclerosis warranting greater attention
in both clinical research and clinical practice. Far less information
has been available about risk factors for PAD than for coronary
or cerebrovascular disease, especially among women. Although
established cardiovascular risk factors such as smoking, diabetes,
hypertension, and dyslipidemia also are clinical predictors
of PAD, few prospective studies have evaluated the role of novel
or emerging risk factors such as subclinical inflammation, thrombosis,
and endothelial dysfunction. This study is the first prospective
analysis of PAD in women to provide comparative data for a broad
range of more commonly evaluated novel biomarkers against each
other, markers of dysglycemia, renal dysfunction, and conventional
lipid levels. Biomarkers assessed included high-sensitivity
C-reactive protein, fibrinogen, soluble intercellular adhesion
molecule-1, homocysteine, lipoprotein(a), hemoglobin A
1c, creatinine,
creatinine clearance, and standard lipid parameters. In this
large population of initially healthy women
45 years of age
without prior vascular disease, only 4 factors, soluble intercellular
adhesion molecule-1, high-sensitivity C-reactive protein, high-density
lipoprotein, and ratio of total cholesterol to high-density
lipoprotein cholesterol, were associated with the incidence
of symptomatic PAD. The strongest association was noted for
soluble intercellular adhesion molecule-1 (adjusted hazard ratio
extreme tertiles, 4.0; 95% confidence interval, 1.9 to 8.6;
P for trend <0.001). Increased levels of this proinflammatory
cellular adhesion molecule reflect endothelial activation and
leukocyte recruitment. Interestingly, prior data from both this
cohort and other populations have shown only modest associations
of soluble intercellular adhesion molecule-1 with coronary or
cerebrovascular disease. The current results thus support the
concept that factors predisposing to plaque rupture as manifested
by acute coronary events differ from those causing more gradual
luminal obstruction as in the pathogenesis of PAD. See p
823.
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