Circulation. 2008;117:1621
doi: 10.1161/CIRCULATIONAHA.107.189184
(Circulation. 2008;117:1621.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Differential Behaviors of Atrial Versus Ventricular Fibroblasts: A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
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Cardiac tissue fibrosis is important in the progression of heart
disease and plays an important role in cardiac arrhythmogenesis,
particularly for atrial fibrillation. In a variety of cardiac
disease models, atrial fibrosis is much more prominent than
fibrosis in the ventricles, even when the profibrotic stimulus
appears to be operating comparably at both the atrial and ventricular
levels. This study examined the hypothesis that differences
between atrial and ventricular fibroblast properties contribute
to the predominant atrial fibrotic phenotype. To assess this
possibility, we compared morphological, secretory, and proliferative
responses of canine atrial versus ventricular fibroblasts. Atrial
fibroblasts showed in vitro and in vivo behaviors indicating
a greater tendency to activated myofibroblast dedifferentiation.
Atrial fibroblast proliferation responses were consistently
greater than ventricular responses for a variety of growth factors,
including fetal bovine serum, platelet-derived growth factor,
basic fibroblast growth factor, angiotensin II, endothelin-1,
and transforming growth factor-β
1. Atrial tissue showed
larger myofibroblast density than ventricular tissue, particularly
in the presence of congestive heart failure. Congestive heart
failure atria had more active fibroblast division rates and
enhanced gene expression of fibroblast-selective markers compared
with ventricles. Gene microarrays revealed 225 differentially
expressed transcript probe sets between paired atrial and ventricular
fibroblast samples, including extracellular matrix, cell signaling,
and metabolism genes, and identified platelet-derived growth
factor as a potential contributor to atrial-ventricular fibroblast
differences. Platelet-derived growth factor inhibition eliminated
atrial-ventricular fibroblast proliferative response differences.
Our results suggest that important differences exist in properties
of atrial versus ventricular fibroblasts, that these differences
contribute to atrium-selective fibrosis, and that platelet-derived
growth factor signaling may be an interesting therapeutic target
for the prevention of arrhythmogenic atrial structural remodeling.
See p
1630.
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Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2–/– Mice: Evidence for Independent Chemokine Functions in Atherogenesis
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The past decade has witnessed a dramatic increase in our understanding
of the importance of inflammation in all stages of atherosclerotic
heart disease. Subendothelial foam cells, the hallmark of early
lesions, are derived from circulating blood monocytes, and recent
evidence indicates that chemokines play important roles in directing
monocyte migration from the blood to the vessel wall. Genetic
deletions of monocyte chemoattractant protein-1 (MCP-1, CCL2),
fractalkine (CX3CL1), or their cognate receptors, CCR2 and CX3CR1,
have been shown to markedly reduce monocyte recruitment and
atherosclerotic lesion size in murine models of atherosclerosis;
however, whether these 2 chemokine systems were redundant or
made independent contributions was unknown. To address this
question, we created double knockouts of fractalkine and CCR2
(on the apolipoprotein E–null background) and performed
a 4-arm atherosclerosis study. The results demonstrate that
deletion of CCR2 affords significantly more protection than
deletion of fractalkine. Significantly, deletion of fractalkine
in CCR2-null mice further reduced monocyte recruitment and atherosclerotic
lesion size, which indicates that both chemokines make independent
and significant contributions to atherogenesis. These data provide
the first in vivo evidence for independent roles for CCR2 and
CX3CL1 in monocyte recruitment and atherosclerotic lesion formation
and suggest that successful therapeutic strategies for atherosclerosis
or other classic inflammatory diseases such as rheumatoid arthritis
or multiple sclerosis may need to target multiple chemokines
or chemokine receptors. See p
1642.
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Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6Chi and Ly6Clo Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice
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Monocytes are critical mediators of atherogenesis and are recruited
into atherosclerotic arteries in response to chemokine/chemokine
receptor signaling. Evidence that particular chemokine pathways
may cooperate to promote monocyte accumulation into inflamed
tissues, particularly atherosclerotic arteries, is still lacking.
Here, we show that combined inhibition of CCL2, CX3CR1, and
CCR5 in apolipoprotein E–deficient mice almost abolishes
lesion formation, indicating that these pathways play independent
and additive roles in atherosclerosis. Another important finding
is that the major role of chemokines and chemokine receptors
in atherosclerosis may relate to their role in the modulation
of monocyte number in both the bone marrow and circulating blood.
Our results clearly show that inhibition of CCL2, CX3CR1, and
CCR5 abolishes hypercholesterolemia-associated blood monocytosis,
identifying a critical role for chemokine signaling in this
process. It is remarkable that the reduction in lesion size
in mice with defective CCL2, CX3CR1, and/or CCR5 signaling strongly
correlated with the reduction in circulating monocyte number,
particularly the CD11b
+ Ly6G
– 7/4
lo subset. Thus, in addition
to their roles in leukocyte recruitment from the blood into
the vessel wall, which is the prevailing paradigm to explain
the proatherogenic effects of several chemokine/chemokine receptor
pathways, signals mediated through CCL2, CX3CR1, and CCR5 critically
determine the frequency of circulating monocyte subsets and
cooperate to promote full macrophage accumulation within atherosclerotic
vessels. It will be important to examine in future studies whether
particular blood monocyte subsets are associated with the extent
of atherosclerosis in humans. See p
1649.
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Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality: Sixteen Years of Follow-Up in US Women
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In parallel with the increase in overall body adiposity in the
US population, the prevalence of abdominal obesity increased
substantially during the past decades. Evidence is growing that
abdominal obesity is particularly detrimental to health. Greater
abdominal adiposity is strongly related to an increased risk
for cardiovascular disease and some other diseases independently
of overall adiposity. In this study, we investigated several
measures of abdominal adiposity, including waist circumference,
waist-to-hip ratio, and waist-to-height ratio in relation to
all-cause, cardiovascular disease, and cancer mortality during
16 years of follow-up in the Nurses’ Health Study. With
>600 000 person-years of follow-up and 3507 deaths, ours
is one of the largest studies with the longest follow-up on
abdominal adiposity and mortality. Our data indicate that anthropometric
measures of abdominal adiposity were strongly and positively
associated with all-cause, cardiovascular disease, and cancer
mortality independently of body mass index. Elevated waist circumference
and waist-to-hip ratio were associated with significantly increased
cardiovascular disease mortality even among normal-weight women
(body mass index, 18.5 to <25 kg/m
2). Although maintaining
a healthy weight should continue to be a cornerstone in the
prevention of chronic diseases and premature death, it is equally
important to maintain a healthy waist size and to prevent abdominal
obesity. See p
1658.
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Age-Dependent Associations Between Chronic Periodontitis/Edentulism and Risk of Coronary Heart Disease
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Chronic periodontitis is a highly prevalent inflammatory disease
of the periodontium and an important cause of tooth loss. More
recently, periodontitis has been implicated as a putative cardiovascular
risk factor. We studied the association between periodontitis/edentulism
and incident coronary heart disease (CHD) in the VA Normative
Aging/Dental Longitudinal Study, an ongoing long-term closed-cohort
study of men in the greater Boston (Massachusetts) area that
performed comprehensive medical and dental examinations triennially.
A total of 1203 men free of CHD at baseline were followed up
for up to 35 years (median 24 years). Of these, a total of 364
men were diagnosed with CHD (either fatal or nonfatal), and
109 men died of CHD. We found a dose-dependent association between
chronic periodontitis and incidence of CHD among men <60
years of age. Compared with men with no or minimal periodontal
bone loss, men with severe periodontal bone loss had more than
twice the risk of developing CHD (hazard ratio 2.12, 95% confidence
interval 1.26 to 3.60). No association was found among men >60
years of age. Edentulous men
60 years of age tended to be more
likely to develop any CHD and were significantly more likely
to develop fatal CHD than dentate and periodontally healthy
men. In summary, chronic periodontitis is associated with incident
CHD among younger men. See p
1668.
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Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
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Recent studies exploring the entire genome identified the chromosomal
locus 9p21.3 as being associated with the risk of coronary artery
disease and myocardial infarction. To use this information for
clinical risk prediction, the present study investigated close
to 10 000 individuals. The findings consistently replicated
the significant association between the 9p21.3 locus and coronary
artery disease in 7 case-control studies. The chromosomal locus
was further investigated by genotyping of 31 additional single-nucleotide
polymorphisms and detailed haplotypes that further characterized
the genomic structure of the chromosomal locus and its association
with coronary artery disease. Moreover, the present study revealed
that an autosomal-additive mode of inheritance best explained
the underlying association. This information is essential for
appropriate incorporation of the genotypic information into
algorithms for risk prediction. Indeed, the present study can
be considered an important step for using genomic information
to better predict risk of coronary artery disease. See p
1675.
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N-Terminal Prohormone Brain Natriuretic Peptide as a Predictor of Cardiovascular Disease and Mortality in Blacks With Hypertensive Kidney Disease: The African American Study of Kidney Disease and Hypertension (AASK)
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Individuals with chronic kidney disease are at an elevated risk
of adverse cardiovascular outcomes. This study found that among
hypertensive blacks with a glomerular filtration rate of 20
to 65 mL · min
–1 · 1.73 m
–2 and no
other identified cause of kidney disease, higher levels of N-terminal
prohormone brain-type natriuretic peptide strongly predicted
the occurrence of coronary artery disease, heart failure, and
cardiovascular death. These results extend previous findings
demonstrating that N-terminal prohormone brain-type natriuretic
peptide was a cardiovascular risk marker for blacks and for
individuals with chronic kidney disease in whom it had been
suggested that N-terminal prohormone brain-type natriuretic
peptide may not be predictive of future events because of confounding
by reduced renal clearance. Higher N-terminal prohormone brain-type
natriuretic peptide levels did not predict progression of renal
disease. See p
1685.
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Interrelation of Coronary Calcification, Myocardial Ischemia, and Outcomes in Patients With Intermediate Likelihood of Coronary Artery Disease: A Combined Positron Emission Tomography/Computed Tomography Study
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The measurement of coronary artery calcification (CAC) by computed
tomography (CT) has received considerable attention for diagnosis
and risk stratification of patients with suspected coronary
artery disease. The decision of whether and when myocardial
perfusion imaging should be coupled with CAC scoring is becoming
increasingly relevant because hybrid single-photon emission
computed tomography/CT and positron-emission tomography/CT scanners
are becoming more widely available. The goals of the present
study were to assess the relationship between CAC scoring and
stress-induced myocardial ischemia, as assessed by combined
positron-emission tomography CT, and to define the incremental
prognostic information added by the integration of CAC scoring
and myocardial perfusion imaging in patients with intermediate
likelihood of coronary artery disease. The frequency of ischemia
among patients with a CAC score
400 was high (48%), and multivariable
analysis supported the concept of a threshold CAC score
400
governing this relationship. Conversely, the absence of CAC
only afforded a negative predictive value of 84% to rule out
ischemia. Survival analysis demonstrated a stepwise increase
in event rates (death and myocardial infarction) with increasing
CAC scores. Among patients with normal myocardial perfusion,
the annualized event rate in patients with no CAC was lower
than in those with a CAC score
1000 (2.6% versus 12.3%). Similar
differences were observed in patients with inducible ischemia.
The study suggests that imaging approaches that combine quantitative
information on the anatomic burden of coronary artery disease
with its physiological consequences offer improved risk stratification
over conventional approaches that use myocardial perfusion alone.
If confirmed in larger prospective studies, it is possible that
the use of combined imaging technologies may offer improved
risk assessment and a more rational risk-based approach to management.
See p
1693.
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Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction
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Pharmacological inhibition of microsomal prostaglandin E
2 synthase-1
(mPGES-1) has been proposed as an alternative to inhibition
of cyclooxygenase-2 in the management of patients with pain
and inflammatory diseases. Here, we examined the role of prostaglandin
E
2 (PGE
2) in postinfarction cardiac remodeling by taking advantage
of homozygote mPGES-1 knockout mice, which have low basal and
induced PGE
2 synthesis. Contrary to our original hypothesis,
we found that deletion of mPGES-1 did not affect the size of
the infarct after coronary ligation. However, the mPGES-1 knockout
animals had worse left ventricular systolic and left ventricular
diastolic function, more ventricular dilation, and markedly
attenuated cardiomyocyte hypertrophy in the region remote from
the infarction compared with wild-type mice. Coupled with the
observation that the bulk of PGE
2 biosynthesis in the infarct
was carried out by inflammatory cells, these findings suggest
that diffusion of PGE
2 from the infarct and peri-infarct regions
influences the hypertrophy of cardiomyocytes remote from the
infarction. These data imply that hypertrophy in the region
remote from the infarct is not regulated purely by mechanical
forces but also by inflammatory mediators such as PGE
2. The
potential clinical importance of these observations is significant
because the millions of patients who previously took cyclooxygenase-2
inhibitors are potential candidates to take pharmacological
inhibitors of mPGES-1, which are currently in development. Our
findings emphasize the importance of carefully evaluating cardiac
function in patients at risk for myocardial infarction who are
treated with agents that selectively block PGE
2 biosynthesis,
which have been proposed to have less cardiovascular toxicity
than inhibitors of cyclooxygenase-2. See p
1701.
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Clinical Predictors for Fatal Pulmonary Embolism in 15 520 Patients With Venous Thromboembolism: Findings From the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry
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Pulmonary embolism (PE) remains a potentially fatal disease
in patients with venous thromboembolism. Its incidence varies
widely in the literature, from <1% to 7%. Identifying patients
at increased risk of fatal PE is therefore important for optimally
adapting treatment to the level of risk. This is all the more
important because the use of generally recommended treatments
in high-risk patients, such as administration of fibrinolytic
drugs or placement of vena cava filters, may be complicated
by severe adverse events. Using data from the international
prospective Registro Informatizado de la Enfermedad TromboEmbolica
venosa (RIETE) registry about 15 520 patients with objectively
confirmed symptomatic acute venous thromboembolism, we determined
independent predictive factors for fatal PE. Symptomatic nonmassive
PE was observed in 40.4%, and massive PE in 1.6%. At 3 months,
the cumulative rate of fatal PE was 1.68%. On multivariable
analysis, compared to patients with deep-vein thrombosis at
presentation, the risk of fatal PE was multiplied by 5.42 in
patients with symptomatic nonmassive PE and by 17.5 in patients
presenting a symptomatic massive PE. Other clinical factors
independently associated with an increased risk of fatal PE
were immobilisation for neurological disease (4.90-fold higher),
age >75 years (2.54-fold higher), and cancer (2.04-fold higher).
The clinical factors predicting a fatal PE identified in this
study can be routinely identified and could therefore easily
be included in a risk stratification scheme for daily practice.
These results may help to improve the management of patients
with PE and therefore increase survival rates. See p
1711.
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Differential Behaviors of Atrial...
Fractalkine Deficiency Markedly...