Circulation. 2008;118:697-698
doi: 10.1161/CIRCULATIONAHA.108.190521
(Circulation. 2008;118:697-698.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Routine Use of Bilateral Skeletonized Internal Thoracic Artery Grafting: Long-Term Results
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Recent studies have shown survival benefit and freedom from
reintervention with the use of 2 internal thoracic arteries
(ITAs) compared with a single ITA. However, in most of these
studies, bilateral ITA (BITA) grafting is offered to only a
selected group of nonurgent, nondiabetic young patients. Unlike
those reports, our study describes long-term results of BITA
grafting in nonselected patients. The study includes many elderly,
emergency, and diabetic patients who would not otherwise be
referred for BITA grafting. In most centers, the ITA is isolated
from the chest wall as a pedicle, together with the vein, muscle,
fat, and accompanying endothoracic fascia. This technique damages
blood supply to the sternum, which in turn impedes sternal healing
and exposes the sternum to the risks of early dehiscence and
infection in operations involving both ITAs. The risk of sternal
infection is particularly high in patients with preoperatively
limited sternal blood supply such as the elderly and those with
diabetes mellitus. Harvesting the ITA as a skeletonized artery
preserves sternal collateral blood supply, thus enabling more
rapid healing and lower risk of infection. We have found that
skeletonized BITA grafting is associated with low morbidity
and good long-term results. Use of skeletonized BITA was found
to be an appropriate technique for the elderly and most patients
with diabetes mellitus. However, in patients with chronic lung
disease, in repeat operations, and in obese and female diabetic
patients, the risk of sternal infection is still unacceptably
high; for these patients, we advocate operations incorporating
only a single ITA. See p
705.
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Heterogeneity of Left Ventricular Wall Thickening Mechanisms
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Left ventricular (LV) wall thickening is a significant contributor
to stroke volume. Although myocardial fiber contraction provides
the cellular basis for regional myocardial wall thickening,
15% fiber shortening leads to only an 8% increase in myocyte
diameter, which cannot explain the observed >40% radial LV
wall thickening and >60% ejection fraction. Myocardial fibers
have been shown to be grouped into laminar "sheets" 3 to 4 cells
thick that are interconnected by an extensive extracellular
matrix. This study demonstrates fundamentally different regional
contributions of laminar mechanisms for amplifying fiber shortening
to systolic wall thickening. Systolic fiber shortening was identical
at each transmural depth in both the anterior and lateral LV
sites, but systolic wall thickening of the anterior site was
much greater than that of the lateral site. This implies that
sheet geometry and dynamics and the exact nature of their coupling
by the extracellular matrix are of great importance to systolic
wall thickening. The complexity of this mechanism of wall thickening
suggests that abnormalities in either the contractile unit (fiber
and sheet) or the infrastructure (extracellular matrix) can
dramatically affect wall thickening. The characterization of
the baseline 3-dimensional myocardial architecture and dynamics
is important because collagen degradation can be brought about
by disease states, and altered baseline myocyte infrastructure
may be a key mechanism in ventricular dysfunction. Enhanced
understanding of myocardial fibrous and laminar architecture
coupling to transmural LV strains and LV wall mechanics could
contribute significantly to the design of better surgical remodeling
procedures to restore normal ventricular strain patterns in
patients with cardiomyopathy. Furthermore, attempts to implant
healthy contractile cells or tissue-engineered constructs into
diseased hearts or to surgically manipulate cardiac geometry
must take into account not only the contraction of cardiac cells
but, of equal importance, their orientation and transmural coupling,
which may be specific to each ventricular region and transmural
depth. See p
713.
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Genetic Ablation of the Bmpr2 Gene in Pulmonary Endothelium Is Sufficient to Predispose to Pulmonary Arterial Hypertension
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Pulmonary hypertension (PH) is a lung disease of diverse origins.
Pulmonary hypertension is classified into arterial, venous,
hypoxic, thromboembolic, and miscellaneous varieties. Of these
varieties, pulmonary arterial hypertension (PAH) typically carries
the worst prognosis. PAH is promoted by the imbalance of hormones,
growth factors, neurotransmitters, or environmental stresses,
which leads to pulmonary vascular constriction, cell proliferation,
or remodeling. Bone morphogenetic protein receptor type II (BMPR2)
signaling plays a critical role in PAH pathogenesis because
germline mutations of
BMPR2 are associated with
25% to 30% of
all PAH cases. PAH pathogenesis involves multiple vascular and
nonvascular cell types. We show that mice with the genetic ablation
of
Bmpr2 in pulmonary endothelial cells exhibited an elevation
of right ventricular systolic pressure, right ventricular hypertrophy,
and histopathological features reminiscent of human PAH lungs,
demonstrating for the first time in vivo that
Bmpr2 mutation
in endothelium is sufficient to predispose to PAH. Our data
suggest that impaired BMPR2 signaling in pulmonary endothelial
cells may increase the risk of pulmonary endothelial cells to
damage that renders the pulmonary vessels more susceptible to
dysregulated remodeling. One of the major impediments for PAH
studies is limited access to biological samples because pathological
samples are available only from lung explants and autopsy specimens
at the very late stage of the disease. Animal models that reproduce
key features of PAH provide relevant pathological samples from
early to late stages of PAH. If we are able to detect pulmonary
hypertension from these mutant mice at an early phase with noninvasive
monitoring systems, it will facilitate the usefulness of this
animal model for various PAH studies. See p
722.
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Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction
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Endothelial dysfunction contributes to cardiovascular diseases,
including hypertension, atherosclerosis, and coronary artery
disease. It is characterized by the reduced bioavailability
of nitric oxide (NO), which has potent vasodilatory and antiatherosclerotic
properties. Insulin activates endothelial NO synthase (eNOS)
in endothelial cells and stimulates the production of NO, and
insulin resistance in vascular endothelium leads to its dysfunction.
Insulin resistance and endothelial dysfunction are often seen
in diabetes, obesity, and dyslipidemia, major risk factors for
cardiovascular disease. The plasma apolipoprotein (apo) CIII
level is high in these conditions. We recently showed that apoCIII
activates vascular endothelial cells through protein kinase
C-β (PKCβ). Because PKCβ inhibits insulin signaling
in endothelial cells, the present study tested the effect of
apoCIII on endothelial insulin signaling. We showed that apoCIII
in very-low-density lipoprotein inhibited insulin activation
of the eNOS pathway and the production of NO in vascular endothelial
cells. ApoCIII also impaired endothelium-dependent relaxation
of the mice aortas in vivo. This adverse effect of apoCIII was
mediated by its activation of PKCβII, which inhibits the
function of insulin receptor substrate 1. Insulin resistance
and endothelial dysfunction associated with hypertriglyceridemia
have been understood from the traditional view that free fatty
acids and other lipid moieties in triglyceride-rich lipoproteins
impair insulin signaling. However, our findings may add a new
mechanism in which triglyceride-rich lipoproteins are carriers
of a causal factor apoCIII that impairs insulin signaling in
vascular endothelial cells and suggest that apoCIII could link
dyslipidemia with endothelial dysfunction. See p
731.
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Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice
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Lipoprotein(a) [Lp(a)] is composed of apolipoprotein(a) [apo(a)],
which is covalently bound to a low-density lipoprotein by a
single disulfide bond on apoB-100. Lp(a) levels are genetically
determined and vary widely (<0.1 to >250 mg/dL) among
individuals. Lp(a) is an independent risk factor for myocardial
infarction, stroke, and peripheral arterial disease, particularly
in younger patients. However, its pathophysiological role and
the underlying mechanisms through which it contributes to cardiovascular
disease are unknown. It also has not been determined yet whether
lowering Lp(a) levels is clinically beneficial, largely because
of the lack of specific agents to lower Lp(a). We have recently
discovered that Lp(a) preferentially binds oxidized phospholipids
in plasma. In this study, we demonstrate that the antisense
oligonucleotide mipomersen, directed to human apoB-100, significantly
reduced human apoB-100 levels in Lp(a) transgenic mice [expressing
human apoB-100 and apo(a) to make authentic Lp(a) particles],
as expected. However, over the 11-week treatment period, compared
with baseline, it also reduced Lp(a) levels by
75% (
P<0.0001)
in a time-dependent fashion. This was due primarily to limiting
the availability of apoB-100 to bind to apo(a). Furthermore,
it significantly reduced plasma levels of oxidized phospholipids
on apoB and apo(a) particles. This study demonstrates that apoB-100
is a limiting factor in Lp(a) particle synthesis in this Lp(a)
transgenic model. If applicable to humans, mipomersen may represent
a novel therapeutic approach in not only reducing apoB-100 and
low-density lipoprotein cholesterol but also in reducing Lp(a)
and associated oxidized phospholipids. See p
743.
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Reduced Atherosclerotic Lesions in P2Y1/Apolipoprotein E Double-Knockout Mice: The Contribution of Non–Hematopoietic-Derived P2Y1 Receptors
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The P2Y
1 receptor plays a key role in platelet activation and
arterial thrombosis, as has been evidenced in P2Y
1-deficient
mice and through the use of selective P2Y
1 antagonists in vitro
in platelet function studies and in vivo in animal models of
thrombosis. It is thus a potentially promising target for new
antiplatelet drugs. The demonstration that this receptor also
is involved in atherosclerosis obviously adds interest in targeting
simultaneously 2 separate aspects of atherothrombosis, ie, platelet
activation and development of atherosclerosis. Moreover, because
the P2Y
1 receptor plays a more minor role in normal hemostasis
compared with the P2Y
12 receptor, one can expect a smaller risk
of bleeding with P2Y
1-targeting drugs, which is the major limitation
of aggressive antiplatelet therapy, especially when targeting
the P2Y
12 receptor. P2Y
1-targeting drugs might therefore be
efficient on a long-term basis in patients requiring chronic
treatment. See p
754.
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Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries
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Smooth muscle cell (SMC) proliferation and migration in the
vessel wall play pivotal roles in neointimal formation and the
resulting restenosis. The present study showed that balloon
injury in arteries and platelet-derived growth factor in cultured
SMCs stimulate the tyrosine phosphorylation of c-Cbl and that
the c-Cbl mutant deficient in the major tyrosine phosphorylation
sites attenuates the activation of the Akt/mTOR pathway and
inhibits SMC migration and proliferation. These findings indicate
the importance of c-Cbl tyrosine phosphorylation in mediating
the adverse response of SMCs to balloon injury and growth factors.
Importantly, local delivery of c-Cbl-m reduces the migration
and proliferation of SMCs and prevents neointimal hyperplasia
in balloon-injured rat carotid arteries. These findings point
toward a previously unrecognized role of c-Cbl in vascular remodeling
and provide the proof of concept that c-Cbl phosphorylation
might be a promising target for the treatment of restenosis
after angioplasty. See p
764.
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Routine Use of Bilateral...
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