Circulation. 2008;117:1909
doi: 10.1161/CIRCULATIONAHA.107.189186
(Circulation. 2008;117:1909.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Death Without Prior Appropriate Implantable Cardioverter-Defibrillator Therapy: A Competing Risk Study
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Implantable cardioverter-defibrillators (ICDs) improve survival
in selected patients in randomized controlled trials. The contemporary
ICD population, however, is older and has a higher comorbidity
burden than the selected populations of randomized controlled
trials. It is therefore of interest to study the extent to which
patients die before appropriate ICD therapy for ventricular
tachyarrhythmia in a "real-world" ICD population. Such "prior
deaths" are referred to as competing risks and need to be taken
into account when we build models to predict which patients
will and which patients will not use their devices. The present
study indicates that in our routine-care population, about half
of the patients receive appropriate ICD therapy for ventricular
tachycardia or ventricular fibrillation. Eleven percent died
without ever using their devices. Focusing on ventricular fibrillation
only shows that 13% experienced ventricular fibrillation and
23% died before experiencing ventricular fibrillation. In competing
risk models, patients most likely to receive appropriate ICD
therapy were those with a secondary prevention indication, higher
age, or reduced ejection fraction. At the same time, patients
who needed diuretic treatment for congestive heart failure had
a 4-fold increased risk of dying before device use. Future risk
stratification tools should aim to optimize device implantation
and replacement, particularly in a routine-care population.
Here, we demonstrate how the relevant risk of prior death may
be integrated into such risk stratification tools. See p
1918.
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Cardiac Sodium Channel (SCN5A) Variants Associated with Atrial Fibrillation
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The human cardiac sodium channel is responsible for the fast
depolarization upstroke of the cardiac action potential and
is a molecular target for antiarrhythmic drugs, some of which
are effective in treating atrial arrhythmias. Mutations in the
human cardiac sodium channel gene (
SCN5A) have been associated
with inherited susceptibility to ventricular arrhythmias (eg,
long-QT syndrome, Brugada syndrome, and sudden infant death
syndrome), progressive cardiac conduction disorders, and more
complex overlapping phenotypes. Although variants in
SCN5A have
been reported to occur in disorders that are sometimes associated
with atrial fibrillation (AF), no studies have appeared that
have systematically evaluated the prevalence of
SCN5A variants
in a cohort of patients with AF. To address this question, we
resequenced the entire
SCN5A coding region in 375 subjects with
either lone AF (n=118) or AF associated with heart disease (n=257).
Controls (n=360) from the same population were then genotyped
for the presence of mutations or rare variants identified in
the AF cases. In 10 probands (2.7%), 8 novel variants not found
in the control population (0%;
P=0.001) were identified. All
variants affect highly conserved residues in the SCN5A protein.
In 6 families with >1 affected member, the novel variant
cosegregated with AF. These data suggest that mutations in
SCN5A may predispose patients with or without underlying heart disease
to AF, expand the clinical spectrum of disorders of the cardiac
sodium channel to include AF, and represent important progress
toward molecular phenotyping and directed rather than empirical
therapy for this common arrhythmia. See p
1927.
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Complementary Roles for Biomarkers of Biomechanical Strain ST2 and N-Terminal Prohormone B-Type Natriuretic Peptide in Patients With ST-Elevation Myocardial Infarction
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ST2 is a member of the interleukin (IL)-1 receptor family with
a soluble form that is markedly upregulated on application of
biomechanical strain to cardiac myocytes. The ligand for this
receptor is IL-33; we have recently shown that IL-33 protects
the myocardium during experimental pressure overload and that
soluble ST2 can block the antihypertrophic effects of IL-33.
In this study, we measured levels of ST2 and an established
biomarker of ventricular wall stress, N-terminal prohormone
B-type natriuretic peptide, at baseline in 1239 patients with
ST-elevation myocardial infarction from the Clopidogrel as Adjunctive
Reperfusion Therapy–Thrombolysis in Myocardial Infarction
28 trial. We found that ST2 levels on presentation were not
associated with clinical characteristics potentially related
to chronic increased left ventricular wall stress such as age,
sex, hypertension, prior myocardial infarction, or prior heart
failure. This independence was in sharp contrast to N-terminal
prohormone B-type natriuretic peptide levels, which were strongly
related to all of the aforementioned characteristics. Accordingly,
levels of the 2 biomarkers were only weakly correlated. In a
multivariable model that contained both biomarkers and adjusted
for baseline characteristics, elevations in ST2 levels and in
N-terminal prohormone B-type natriuretic peptide levels each
were significant independent predictors of the risk of cardiovascular
death or heart failure through 30 days. When both ST2 and N-terminal
prohormone B-type natriuretic peptide were added to a model
containing traditional clinical predictors, the c statistic
significantly improved. These data highlight the prognostic
value of multiple, complementary biomarkers of biomechanical
strain in ST-elevation myocardial infarction and highlight the
importance of the IL-33/ST2 system as a target of further study
and potential therapeutic intervention. See p
1936.
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Diabetes Patients Requiring Glucose-Lowering Therapy and Nondiabetics With a Prior Myocardial Infarction Carry the Same Cardiovascular Risk: A Population Study of 3.3 Million People
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It is widely acknowledged that the presence of diabetes mellitus
implies the presence of atherosclerotic cardiovascular disease.
Studies of cardiovascular risk in patients with diabetes mellitus,
combined with clinical trials and subgroup analyses of clinical
trials, have resulted in recommendations for treatment with
statins, aspirin, and inhibitors of the renin-angiotensin system
for many patients with diabetes mellitus. Guidelines vary considerably,
particularly for young patients with diabetes. The discrepancies
between guidelines are driven mainly by the uncertainties of
the cardiovascular risk in diabetes. In the present nationwide
study of 3.3 million Danish residents
30 years of age, it was
demonstrated that the risk of cardiovascular death over 5 years
was nearly identical in patients with diabetes mellitus requiring
glucose-lowering therapy and in patients with a prior myocardial
infarction regardless of age, sex, and type of diabetes. Similar
results were obtained for the combined occurrence of myocardial
infarction, stroke, or cardiovascular death, whereas coronary
morbidity/mortality was lower in patients with diabetes mellitus
without a prior myocardial infarction compared with nondiabetics
with a prior myocardial infarction. With limited access to controlled
trials in patients with diabetes mellitus, guidelines for prophylactic
treatment are currently driven mainly by analyses of cardiovascular
risk in these patients. Specific recommendations on aspirin,
statins, and possibly an angiotensin-converting enzyme inhibitor/angiotensin
receptor blocker depend on randomized controlled trial data.
However, our study provides further evidence supporting the
recommendation that all patients
30 years of age with diabetes
mellitus who require glucose-lowering therapy should be considered
for aggressive primary prevention interventions. See p
1945.
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Comparison of "Risk-Adjusted" Hospital Outcomes
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Risk-standardized outcomes are increasingly being used by various
stakeholders to assess the quality of care delivered by healthcare
providers. Although adjusted outcomes represent a substantial
improvement over unadjusted results, they are commonly misinterpreted
and misused, which can have important consequences for the provider
and the healthcare system. Risk-standardized outcomes, as most
commonly constructed, characterize a provider’s performance
for a specific group of patients compared with what would have
been expected had that care been delivered by an average provider
in the reference population (typically a state or a country).
These indirectly standardized outcomes, based on providers’
actual case mix, cannot necessarily be extrapolated to predict
what their performance might be with a different (eg, more complex)
group of patients. Moreover, if the number of providers in the
reference population is small, the inclusion of a true outlying
program in the development of the risk model may decrease the
sensitivity of the resulting algorithm to detect true outliers.
In Massachusetts, this problem is mitigated through the use
of cross-validation, obtained by sequentially removing each
hospital from risk model development and then assessing its
performance with a model derived from the remaining hospitals.
Finally, although risk-standardized outcomes are useful for
comparing individual provider performance with that of the overall
reference population, this does not imply that the outcomes
of 2 providers can be directly compared with one another. This
would only be justified for the group of patients whose risk
profiles overlap the 2 providers because these are the only
patients that they have in common. See p
1955.
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Percutaneous Pulmonary Valve Implantation: Impact of Evolving Technology and Learning Curve on Clinical Outcome
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After the first transcatheter valve implantation in 2000, a
new field in interventional cardiology developed. New techniques
evolved rapidly, with significant improvement in outcomes. We
assessed our results after percutaneous pulmonary valve implantation
over a time frame of 6 years from the first to the 155th patient.
The aim of percutaneous pulmonary valve implantation was to
prolong the lifespan of conduits, which were surgically placed
from the right ventricle to the pulmonary artery. Because of
the limited longevity of conduits, the majority of patients
with right ventricular outflow tract dysfunction traditionally
undergo multiple open heart operations for conduit replacement.
We show that percutaneous pulmonary valve implantation successfully
restores conduit function with a low procedural complication
rate. Explantation-free survival 5 years after percutaneous
pulmonary valve implantation is >70%. This prolonged conduit
lifespan should reduce the number of multiple open heart operations
over the total lifespan of children and young adults with congenital
heart disease and potentially improve life expectancy of these
patients. As with all new procedures, whether surgical or interventional,
the impact of the learning curve on a novel technique must be
recognized. Therefore, we divided our patient population into
a cohort consisting of the first 50 patients and a second cohort
representing the later experience of 105 patients. In our experience,
explantation-free survival was significantly longer in patients
who underwent percutaneous pulmonary valve implantation in the
second cohort. The impact of a learning curve on clinical results
of new interventional procedures is of importance, especially
if interventions and devices are compared with conventional
therapies. See p
1964.
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Enzymatic Activity of Lysosomal Carboxypeptidase (Cathepsin) A Is Required for Proper Elastic Fiber Formation and Inactivation of Endothelin-1
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Our studies in a pediatric genetic disorder, galactosialidosis
(OMIM No. 256540), caused by an inherited defect of lysosomal
carboxypeptidase (cathepsin) A/protective protein unexpectedly
led to the hypothesis that cathepsin A may be involved in hemodynamic
functions. Here, we demonstrate that gene-targeted mice in which
the normal cathepsin A was replaced with an active site (Ser190Ala)
mutant have a reduced degradation rate of the vasoconstrictor
peptide endothelin-1 and significantly increased arterial blood
pressure. Cathepsin A–deficient mice also display scarcity
of elastic fibers in aortic adventitia, lungs, and skin. Our
results provide the first evidence that cathepsin A acts in
vivo as an endothelin-1–inactivating enzyme and has a
crucial role in elastogenesis, revealing a new facet of cardiovascular
biology pertinent to hypertension, vascular resilience, and
the cardiovascular complications of lysosomal diseases. See
p
1973.
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Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension
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Cell-free hemoglobin-based oxygen carriers (HBOC) have been
studied as red blood cell substitutes for decades. These agents
offer the potential of treating patients with anemia or hemorrhage
when red blood cells are not available or desirable. One of
the major obstacles to the clinical acceptance of HBOC is the
intense and pathological vasoconstriction they produce by binding
endothelial nitric oxide (NO), which can jeopardize tissue perfusion.
Breathing high levels of NO attenuates this systemic vasoconstriction
by converting cell-free hemoglobin to methemoglobin but disables
the oxygen-carrying capacity of the infused HBOC. In the present
study, we report that in 2 species (mouse and sheep), pretreatment
by breathing NO prevents the systemic hypertension induced by
subsequent intravenous administration of HBOC without causing
plasma methemoglobinemia. Our data support a definitive link
between cell-free hemoglobin, endothelial NO consumption, and
vasoconstriction. Pretreatment by NO inhalation provides a novel
strategy that may enable the transfusion of HBOC in emergencies
or during surgery without causing vasoconstriction. See p
1982.
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Neuronal Nitric Oxide Synthase Regulates Basal Microvascular Tone in Humans In Vivo
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Nitric oxide (NO) generated by NO synthases (NOS) has a pivotal
role in regulating blood flow. In most vascular beds, continuous
NO generation reduces basal tone and increases blood flow. Seminal
studies that used local forearm infusion of a nonselective NOS
inhibitor, L-NMMA (
NG-monomethyl-
L-arginine), confirmed that
this basal vasodilator effect of NO exists in humans. These
effects have been attributed to local release of NO by endothelial
NOS (eNOS). eNOS-derived NO also mediates increases in blood
flow elicited by agonists such as acetylcholine, and impairment
of these responses (known as "endothelial dysfunction") is a
precursor to atherosclerosis. More recently, it has been appreciated
that a second NOS isoform, neuronal NOS (nNOS), may also be
involved in vascular regulation. This in vivo study investigated
for the first time in humans the contribution of nNOS to the
regulation of microvascular tone and blood flow. With local
infusion of a selective nNOS inhibitor,
S-methyl-
L-thiocitrulline,
basal blood flow in the normal forearm was found to be dependent
on tonic nNOS activity, whereas increases in blood flow stimulated
by acetylcholine were dependent on eNOS. These findings indicate
that nNOS and eNOS make distinct contributions to the physiological
regulation of human vascular tone. Tonic NO generation by nNOS
is important for regulation of basal vasomotor tone and may
therefore influence blood pressure, whereas eNOS-generated NO
facilitates dynamic alterations in blood flow distribution and
has antiatherosclerotic effects at the level of the endothelium.
Elucidation of the relative roles of these 2 NOS isoforms in
disease settings requires further investigation. See p
1991.
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Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection
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Allograft rejection remains a clinically important limitation
to human cardiac transplantation. More than 40% of patients
will experience an episode of rejection that requires therapy
in the first year after transplantation. Severe rejection episodes
can cause heart failure, malignant arrhythmias, and sudden cardiac
death. Higher grades of rejection (International Society for
Heart and Lung Transplantation grade 3 or 4) portend poor outcomes.
Current treatment strategies often resolve the acute episode
effectively and typically include the use of augmented doses
of glucocorticoids or calcineurin inhibitors, cytolytic agents
such as OKT3, and plasmapheresis. However, they are limited
by the inherent toxicities of immunosuppression, including fatal
infections, aggressive malignancies, and renal failure. Furthermore,
antibody-mediated rejection, in particular, has no consensus
treatment to date. Novel therapies are greatly needed not only
to decrease the morbidity of conventional immunosuppression
but also to improve the outcomes of patients with specific forms
of allograft rejection, especially acute antibody-mediated rejection.
Although deficiency of Mac-1 did not prevent chronic rejection
in our study, targeting Mac-1 is an attractive strategy to modulate
acute rejection after cardiac transplantation. Indeed, previous
clinical trials demonstrated improved renal allograft survival
in high-risk patients (either highly immunized or retransplant
recipients) who received a monoclonal antibody to one of the
Mac-1 cognate ligands, intracellular adhesion molecule-1. This
study demonstrates that recipient Mac-1 deficiency reduces accumulation
of graft-infiltrating cells, macrophage antigen-presenting cell
function, T-cell proliferation, and tumor necrosis factor-
production
and attenuates acute allograft rejection. Clinical application
requires future studies evaluating the effect of Mac-1 deficiency
and immunosuppressive therapy, alone or in combination, on allograft
rejection. See p
1997.
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