Circulation. 2009;119:1691-1693
doi: 10.1161/CIRCULATIONAHA.109.192180
(Circulation. 2009;119:1691-1693.)
© 2009 American Heart Association, Inc.
Clinical Summaries
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Syncope and Risk of Sudden Death in Hypertrophic Cardiomyopathy
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In patients with hypertrophic cardiomyopathy, syncope can be
neurally mediated or a warning of dangerous arrhythmias or hemodynamic
impairment, but its prognostic significance is not clearly established.
We assessed the relationship between syncope and sudden death
in 1511 consecutive hypertrophic cardiomyopathy patients; 205
(14%) had a history of unexplained or neurally mediated syncope.
Over a 5.6-year mean follow-up, 74 patients died suddenly. Unexplained
syncope but not neurally mediated syncope was associated with
an increased risk of sudden death (hazard ratio 1.78,
P=0.08
compared with patients without syncope). Temporal proximity
of unexplained syncope to initial patient evaluation was important.
Patients with recent unexplained syncope (
6 months before initial
evaluation) showed a 5-fold increase in risk compared with patients
without syncope, a relationship that was maintained throughout
all age groups. In adolescents, unexplained syncope was associated
with a 60% cumulative risk at 5 years. Older patients (
40 years)
with remote syncope (>5 years before initial evaluation)
showed no increased sudden death risk. Thus, unexplained syncope
is a marker for increased risk in hypertrophic cardiomyopathy,
particularly when it occurs in close temporal proximity to patient
evaluation. Remote syncopal events are not a marker of increased
risk in older patients. See p
1703.
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Relationship of Oxidized Phospholipids on Apolipoprotein B-100 Particles to Race/Ethnicity, Apolipoprotein(a) Isoform Size, and Cardiovascular Risk Factors: Results From the Dallas Heart Study
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Oxidized phospholipids (OxPLs) play a central role in mediating
a variety of immune, proinflammatory, and plaque-destabilizing
processes that further amplify inflammatory responses. We have
found that OxPLs circulate on apolipoprotein B-100 (apoB) particles
primarily on lipoprotein(a) [Lp(a)]. OxPL/apoB levels are elevated
in patients with coronary, carotid, and femoral artery disease;
with acute coronary syndromes; and after percutaneous coronary
intervention and independently predict new cardiovascular events.
OxPL/apoB levels were measured in 1831 black, 1047 white, and
603 Hispanic subjects in the Dallas Heart Study. OxPL/apoB levels
were highest in blacks, followed by whites and Hispanics, and
did not correlate with any traditional risk factors except Lp(a).
The highest correlation between OxPL/apoB and Lp(a) was present
in blacks, followed by whites and Hispanics; was dependent on
apolipoprotein(a) [apo(a)] isoform size; and became progressively
weaker with larger isoforms. The size of the major apo(a) isoform
(number of kringle type IV repeats) was negatively associated
with OxPL/apoB regardless of racial/ethnicity group. This study
demonstrates that elevated OxPL/apoB levels are associated with
both small apo(a) isoforms and high Lp(a), which explains the
differences in racial groups, which have genetic differences
in both apo(a) and Lp(a) levels. The association of OxPL with
small apo(a) isoforms, in which a similar relationship is present
among all racial subgroups despite differences in Lp(a) levels,
may be a key determinant of cardiovascular risk. See p
1711.
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Associations of Gestational Weight Gain With Offspring Body Mass Index and Blood Pressure at 21 Years of Age: Evidence From a Birth Cohort Study
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Routine measurement of maternal weight during pregnancy is controversial.
The practice was abandoned in many countries in the late 1990s
because it was found to be a poor indicator of intrauterine
growth retardation. However, this position is now being reconsidered
as emerging evidence suggests that greater weight gain in pregnancy
might indicate those women who are at increased risk of future
cardiovascular and metabolic disease and may be a risk factor
for future offspring health. In this study, we examined the
association of maternal weight gain in pregnancy with offspring
body mass index and blood pressure at 21 years of age. We found
that greater weight gain during pregnancy was independently
associated with greater risk for offspring body mass index and
obesity. We also found some evidence that this association with
greater body mass index might result in greater offspring systolic
blood pressure. This study supports other evidence suggesting
that excessive pregnancy weight gain should be avoided for the
health of both mother and offspring. Further large studies are
required to confirm these findings and to determine what should
be considered healthy weight gain for the short- and long-term
health of both mother and offspring. Ultimately, trials are
required to explore whether routine monitoring of weight gain
in pregnancy and provision of advice about healthy weight gain
are effective at reducing obesity-related outcomes in mothers
and offspring in the long term. See p
1720.
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Trends in All-Cause and Cardiovascular Disease Mortality Among Women and Men With and Without Diabetes Mellitus in the Framingham Heart Study, 1950 to 2005
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Over the past several decades, a marked decline has occurred
in mortality from cardiovascular disease. Despite this decline,
diabetes mellitus remains a key risk factor for cardiovascular
disease and is associated with a 2- to 4-fold higher risk of
cardiovascular disease, as well as an increased risk of mortality
by up to 3-fold. Declines in mortality rates over time have
been observed in people with and without diabetes mellitus.
However, a recent analysis of national trends data from the
National Health and Nutrition Examination Survey suggested that
declines in all-cause mortality have occurred among men with
diabetes mellitus but not women. In this study, we assessed
time-period trends in all-cause mortality among women and men
with and without diabetes mellitus in the Framingham Heart Study,
in which diabetes status has been routinely screened for and
all deaths have been adjudicated. The analysis included participants
who attended examinations during an "earlier" (1950 to 1975)
and a "later" (1976 to 2001) time period. Our results showed
a decline in all-cause and cardiovascular disease mortality
rates among both men and women with and without diabetes mellitus
over the period of 1950 to 2005. Additionally, both men and
women with diabetes mellitus continue to remain at a higher
risk of all-cause and cardiovascular disease mortality than
those without diabetes mellitus. In summary, reductions in all-cause
mortality among both women and men with diabetes mellitus have
occurred over time. See p
1728.
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Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion
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Metabolic responses to surgical cardioplegic arrest have been
incompletely characterized in humans. We applied targeted mass
spectrometry-based "metabolomics" analysis to arterial and venous
blood samples taken before and after ischemia/reperfusion in
patients undergoing cardiac surgery. We observed significant
alterations in myocardial fuel substrate uptake at baseline
among patients with coronary artery disease and after ischemia/reperfusion
among those with preexisting left ventricular dysfunction relative
to subjects presenting with neither left ventricular dysfunction
nor coronary artery disease. Additionally, net release of acylcarnitine
species and lactate by the myocardium after ischemia/reperfusion
is suggestive of severe impairment of oxidative metabolism.
The ability to maintain oxidative metabolism in the immediate
postischemic phase was diverse in the study cohort and associated
with improved periprocedural hemodynamics. We conclude that
myocardial metabolism is severely altered after surgically induced
global ischemia, with the dysfunctional ventricle being particularly
susceptible to this insult. Furthermore, metabolic profiling
in the perioperative period has the potential to predict the
postoperative hemodynamic course, highlight pathways most severely
dysregulated by ischemia/reperfusion, and target future cardioprotective
strategies. See p
1736.
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Stress Doppler Echocardiography in Relatives of Patients With Idiopathic and Familial Pulmonary Arterial Hypertension: Results of a Multicenter European Analysis of Pulmonary Artery Pressure Response to Exercise and Hypoxia
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This is the first prospective multicenter study with Doppler
stress echocardiography devoted to screening for exercise- and
hypoxia-induced pulmonary hypertension in relatives of idiopathic
or familial pulmonary arterial hypertension patients and to
investigate the threshold of normal pulmonary artery pressures
during exercise in a large collective of healthy control subjects.
One main finding of this study is that relatives of patients
with idiopathic or familial pulmonary arterial hypertension
have a significantly higher frequency of a hypertensive tricuspid
regurgitation velocity response to exercise and to prolonged
hypoxia than control subjects. The highest proportion of subjects
with hypertensive tricuspid regurgitation velocity response
was found in relatives who shared a
BMPR2 mutation with the
index patients. The data in this study suggest that a hypertensive
pulmonary artery pressure response to exercise and hypoxia is
genetically determined with familial clustering. The clinical
significance of hypertensive pulmonary artery pressure response
to exercise and hypoxia, however, is currently unsettled. It
may reflect a normal variation in pulmonary artery pressures
without clinical significance, or it may be related to some
limitation in exercise capability that is relevant only under
stress conditions. However, it may also reflect a genetic trait
associated with increased risk for the development of pulmonary
hypertension or high-altitude pulmonary edema. Although great
effort was necessary to standardize the echocardiographic examination
and to obtain high-quality tricuspid regurgitation velocity
profiles, the study showed that this screening approach is applicable
in clinical settings. Follow-up assessments in relatives of
idiopathic or familial pulmonary arterial hypertension patients
may provide a basis to decide whether stress echocardiography
is an appropriate tool for early diagnosis of pulmonary arterial
hypertension. See p
1747.
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Detection and Quantification of Left Atrial Structural Remodeling With Delayed-Enhancement Magnetic Resonance Imaging in Patients With Atrial Fibrillation
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Catheter ablation has become an increasingly popular and acceptable
treatment option for the atrial fibrillation patient. Nevertheless,
many questions remain about preprocedural predictors of ablation
failure. Here, we describe a novel delayed-enhancement magnetic
resonance imaging-based method to detect and quantify preexistent
left atrial structural remodeling in patients undergoing ablation
of atrial fibrillation. We found that patients with extensive
preablation left atrial enhancement were more likely to suffer
atrial fibrillation recurrence after ablation than those with
minimal or moderate degrees of enhancement. This noninvasive
modality would allow patients to be selectively screened before
ablation to determine whether they are appropriate candidates
for the procedure. The ability to properly select ablation patients
will reduce the unnecessary risks and costs to those patients
who stand to benefit little from the procedure. See p
1758.
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Molecular Magnetic Resonance Imaging of Myocardial Perfusion With EP-3600, a Collagen-Specific Contrast Agent: Initial Feasibility Study in a Swine Model
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Cardiac magnetic resonance (MR) perfusion imaging during the
first pass after intravenous administration of extracellular
contrast agents is hampered by the spatial and temporal resolution
achievable and by the artifacts seen in ultrafast MR imaging.
Furthermore, time-consuming quantitative data analysis is often
needed. The use of molecular MR imaging with a target-specific
contrast agent with perfusion-dependent binding to myocardium
may enable prolonged visualization of perfusion defects and
thus may help to overcome limitations of currently used first-pass
extracellular MR imaging. EP-3600 is a new gadolinium-containing
small-peptide molecular contrast agent that binds reversibly
to myocardial collagen. EP-3600 was investigated for myocardial
perfusion imaging in a large-animal (swine) model of nonocclusive
coronary stenosis. Molecular MR imaging was performed on a clinically
used 1.5-T whole-body scanner with a sequence that can be used
in humans during daily routine. It could be shown that remote
myocardium demonstrates a significant signal increase over the
entire examination time (60 minutes), whereas the perfusion
defect was visible as a hypointense area for at least 20 minutes
after intravenous contrast administration. Thus, EP-3600 enables
prolonged, high-contrast, high-spatial-resolution visualization
of myocardial perfusion defects in a human-size animal model
and may lead to a paradigm shift in clinical cardiac perfusion
MR imaging. This new approach could also enable the use of exercise
stress outside the MR room instead of currently used drug-induced
hyperemia inside the MR gantry. See p
1768.
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Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction
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Clinical trials of vascular endothelial growth factor (VEGF)
gene therapy have proven that VEGF has beneficial effects on
ischemic heart disease; however, potential problems associated
with the prolonged and excessive production of VEGF cannot be
ignored. Clinical studies of VEGF protein revealed evidence
of a dose-dependent effect (ie, high-dose VEGF protein resulted
in a better therapeutic effect). Given the side effects of high-level
VEGF in the circulation, an increase in the local VEGF level
may represent a reasonable treatment for ischemic heart disease.
In the present study, we investigated the angiogenic effect
of a fusion protein composed of VEGF and a collagen-binding
domain (CBD-VEGF) and its therapeutic effects in a rat acute
myocardial infarction model. The results demonstrated that CBD-VEGF
induced much more blood vessel formation than native VEGF in
collagen membranes implanted subcutaneously. Compared with native
VEGF, CBD-VEGF maintained a higher level in extracellular matrix
and a lower level in circulation, and it preserved heart function,
reduced scar size, and increased capillary vessels after injection
into the border zone of acute myocardial infarction in rats.
Although the latent side effects and precise role of CBD-VEGF
during healing must be investigated further, our results may
suggest a novel therapeutic approach for patients with ischemic
heart disease. See p
1776.
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Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease
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Aging societies face a growing burden of vascular and valvular
calcification. Half of all individuals with chronic renal disease
succumb to cardiovascular complications. Despite its vast clinical
significance, the mechanisms of accelerated cardiovascular calcification,
particularly in chronic renal disease, remain obscure, and we
currently lack therapies to prevent its progression. Recent
clinical trials showed no benefit of statin therapy on progression
of calcific aortic valve stenosis, a growing clinical challenge
without alternatives to costly invasive treatments. Hence, the
need to discover new pathways that contribute to cardiovascular
calcification and to develop new therapeutic strategies to prevent
or reverse calcification has driven our recent research investigations.
The present study provides support for the hypothesis that elastin
breakdown products produced by cathepsin S, a proteinase regulated
by inflammation and overexpressed in diseased arteries and valves,
can trigger osteogenesis. These results indicate that antiinflammatory
therapies and preservation of elastin integrity might prevent
cardiovascular calcification and its complications when introduced
early. Therapeutic interventions in calcification-prone patients
with chronic renal disease may target inflammation and phosphate
balance. New therapeutic options may also include inhibition
of elastolytic cathepsins, particularly cathepsin S. Although
calcification in atherosclerosis typically occurs in the intima,
chronic renal disease calcification primarily involves the media.
Therefore, development of high-resolution imaging of calcification
in different arterial layers may distinguish the cause of calcification
and provide a powerful tool in personalized medicine. More importantly,
identification of high-risk patients requires new imaging modalities
to detect calcifying atherosclerotic plaques and aortic valve
lesions at stages during which the disease remains silent or
reversible. See p
1785.
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Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage
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Acute ischemic syndromes are related primarily to rupture of
unstable plaques, leading to thrombus formation and occlusive
complications. Unstable plaques are typically constituted of
the most prominent cell types in atherosclerosis: macrophages
and macrophage-derived foam cells. Most of these macrophages
are postapoptotic and form a graveyard of dead collapsed cells
that might contribute to constitution of the necrotic core.
Genetic manipulations of apoptotic genes have been shown to
differentially alter atherosclerotic lesion size in murine models
of atherosclerosis; however, the potential beneficial or detrimental
role of apoptotic macrophage death in plaque development remains
controversial. To address this question, we created transgenic
mice in which both the lifespan of macrophages was increased
in response to elevated resistance to apoptosis (CD68-hBcl2)
and targeted induction of lesional macrophage apoptosis (CD11c-DTR)
could be achieved. These data provide the first in vivo evidence
that macrophage apoptosis is atheroprotective in fatty streak
lesions; in contrast, however, defective clearance of apoptotic
debris in advanced lesions favors arterial wall inflammation
and enhanced recruitment of monocytes, thereby leading to enhanced
atherogenesis. Considered together, these findings suggest that
attenuating macrophage apoptosis in advanced plaques represents
a promising therapeutic strategy. See p
1795.
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Complement-Dependent Neutrophil Recruitment Is Critical for the Development of Elastase-Induced Abdominal Aortic Aneurysm
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Abdominal aortic aneurysm (AAA) is a disease characterized by
chronic inflammation and remodeling of aortic wall tissue. Studies
using "end-stage" human AAA tissues procured at surgery have
identified a number of candidate molecules; however, these may
or may not contribute to the initiation and progression of AAA.
To better understand the mechanisms that promote AAA, we turned
to an elastase-induced mouse model that recapitulates many features
of human AAA. In this model, neutrophils are identified as critical
mediators of AAA development. Neutrophil depletion or impaired
neutrophil recruitment protects against AAA development; however,
the signal that initiates the influx of neutrophils to the aortic
wall remains undefined. We hypothesized that complement participates
in the development of elastase-induced AAA, possibly by providing
the chemotactic signal that recruits neutrophils to the aortic
wall. In the present experiments, we showed that complement
depletion abrogated AAA development. We also demonstrated that
the alternative pathway of the complement system plays a major
role in this process by generating the potent anaphylatoxins
C3a and C5a, which recruit neutrophils to the aortic wall. Ruptured
AAA is the cause of death in 1% to 3% of men over the age of
65 years. Although elective surgical repair is usually definitive,
this operation is reserved for large aneurysms. At present,
no therapies are available that alter the progressive growth
of small aneurysms. The identification of the involvement of
the complement system in the pathophysiology of AAA provides
a new target for therapeutic intervention in this common disease.
See p
1805.
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Syncope and Risk of...
Relationship of Oxidized...