Circulation. 2008;118:321-322
doi: 10.1161/CIRCULATIONAHA.108.189736
(Circulation. 2008;118:321-322.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery
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In this comprehensive review of the use of recombinant activated
factor VII in nonhemophiliac patients who underwent cardiac
surgery during the period 2003 through 2006 in Canada (n=503),
we found that recombinant activated factor VII was used primarily
when standard interventions had failed to control blood loss.
Moreover, as far as could be determined within the confines
of this observational study, we found that recombinant activated
factor VII was associated with a reduction in transfusion of
blood products and, after adjustment for patients’ underlying
risk profile and red blood cell transfusion rate, did not appear
to be associated with increased or decreased mortality or major
morbidity. Finally, our data also suggested that the effectiveness
of the drug may be enhanced if it is given early in the course
of refractory blood loss in the setting of adequate amounts
of circulating coagulation factors. Adequately powered randomized
clinical trials are needed to verify these findings. See p
331.
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 -Linolenic Acid and Risk of Nonfatal Acute Myocardial Infarction
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Long-chain n-3 fatty acids from fish, eicosapentaenoic acid
and docosahexaenoic acid, reduce cardiovascular mortality, but
availability of fish is limited and probably insufficient to
meet worldwide needs.
-Linolenic acid, an essential n-3 fatty
acid found in vegetable cooking oils such as soybean and canola
oils and other products of plant origin could be a viable alternative
to fish oils. We determined whether
-linolenic acid was associated
with risk of nonfatal acute myocardial infarction in 1819 case-control
pairs from a population-based study in Costa Rica. Increased
dietary
-linolenic acid assessed by questionnaire and in adipose
tissue was associated with 39% and 59% lower risk of myocardial
infarction, respectively. The relationship between
-linolenic
acid and myocardial infarction was nonlinear, and it was evident
only at low intake levels. Risk of myocardial infarction decreased
by 57% when median intakes of 1.79 g/d (0.65% energy) were compared
with 1.11 g/d (0.42% energy), but it did not decrease further
with intakes >1.79 g/d. The amount of
-linolenic acid associated
with risk reduction was small, and it could be obtained with
2 teaspoons of soybean or canola oils, which are common plant
sources of
-linolenic acid. This level of intake also could
be easily achieved with intake of flaxseed oil (
1 to 2 mL) or
walnuts (
6 to 10 halves). Fish or eicosapentaenoic acid and
docosahexaenoic acid intake at the levels found in this population
did not modify the observed association. In summary, consumption
of vegetable oils rich in
-linolenic acid could confer important
cardiovascular protection. See p
339.
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Aerobic Interval Training Versus Continuous Moderate Exercise as a Treatment for the Metabolic Syndrome: A Pilot Study
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In recent years, consensus has been growing that physical inactivity
accelerates the development of metabolic syndrome and that the
level of aerobic fitness predicts survival in a metabolic syndrome
population even when other traditional risk factors are present.
However, the level and format of exercise that may yield optimal
health benefits remain in dispute. In the present study, we
sought to determine whether exercise intensity is critical in
improving aerobic fitness and endothelial function and in reducing
the degree of the metabolic syndrome and cardiovascular risk
factors in patients with established metabolic syndrome. Patients
40 to 60 years of age of both sexes either were subjected to
high-intensity aerobic interval training or moderate continuous
exercise or received standard advice on physical activity. The
protocols were made isocaloric so that only exercise intensity
differed between the 2 intervention groups. This study demonstrates
that high-intensity training relative to the individual’s
aerobic fitness level is feasible even in overweight patients
with the metabolic syndrome who have several cardiovascular
risk factors. It also shows that the intensity of exercise is
important for reversing factors relating to the metabolic syndrome,
improving aerobic capacity, and improving endothelial function
in patients with metabolic syndrome. Although the safety of
high-intensity exercise has yet to be assessed, these results
suggest that exercise intensity should be seriously considered
by healthcare professionals and policy makers. See p
346.
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Alternative Splicing of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Is Associated With Plasma Low-Density Lipoprotein Cholesterol Response to Simvastatin
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Statins reduce low-density lipoprotein cholesterol by inhibiting
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a rate-limiting
enzyme for cholesterol synthesis. Although statins are generally
efficacious, a wide range of low-density lipoprotein cholesterol–lowering
response exists among individuals. We have identified an alternatively
spliced transcript of
HMGCR that lacks exon 13,
HMGCRv_1, and
measured its expression in 170 simvastatin-incubated immortalized
lymphocyte cell lines derived from participants in the Cholesterol
and Pharmacogenetics (CAP) study who were treated with simvastatin
40 mg/d for 6 weeks. We found that greater upregulation of
HMGCRv_1 in vitro was significantly correlated (
P
0.0001) with smaller
in vivo reductions of plasma total and low-density lipoprotein
cholesterol, triglycerides, and apolipoprotein B and explained
6% to 15% of the variation in the statin response of these measurements.
Artificial enrichment of
HMGCRv_1 via siRNA produced cells relatively
resistant to statin inhibition, consistent with the association
of increased alternative splicing with reduced statin response
in the CAP study. Our findings point to a major role of
HMGCR alternative splicing in influencing cholesterol response to
statin treatment and exemplify how alternative splicing can
act as a modifier of drug response. Although measurement of
HMGCRv_1 expression on its own does not yet have clinical utility,
its importance lies in highlighting new pathways and effects
mediated by alternative splicing and its impacts on mechanisms
related to cholesterol metabolism. This information also may
lead to improved prediction of individuals who would be most
likely to benefit from statin treatment and to the identification
of new drug targets for improving statin efficacy. See p
355.
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Mast Cells Play a Critical Role in the Pathogenesis of Viral Myocarditis
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Mast cells are multifunctional cells that contain various mediators
such as cytokines, histamine, proteases, and leukotrienes. They
are found in nearly all major organs of the body and are involved
in many types of inflammation as well as allergic inflammation.
Recently, we showed that the gene expressions of the mast cells
chymase and tryptase were increased in the acute stages of heart
failure and viral myocarditis, suggesting that viral infection
may also activate mast cells. In the present study, survival
of mice was better in mast cell–deficient mice infected
with encephalomyocarditis virus and in association with less-pronounced
myocardial necrosis, inflammation, and gene expressions of proinflammatory
cytokines. Of note, all of these reactions were restored in
mast cell–reconstituted mice. A histamine H1-receptor
antagonist also alleviated viral myocarditis. These observations
suggest that mast cells participate in the acute inflammatory
reaction and the onset of ventricular remodeling associated
with acute viral myocarditis and that the inhibition of their
function may be therapeutic in this disease. See p
363.
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Mechanisms of Preejection and Postejection Velocity Spikes in Left Ventricular Myocardium: Interaction Between Wall Deformation and Valve Events
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Tissue Doppler echocardiography is used clinically to assess
left ventricular systolic and diastolic function in terms of
myocardial velocities during ejection and filling, respectively.
In addition, brief velocity spikes occur before and after ejection,
but the cause and clinical importance of these velocity spikes
have been debated. This combined experimental and clinical study
indicates that the normal preejection velocity spike is due
to myocardial shortening, which displaces blood toward the mitral
region and causes bulging of the mitral leaflets into the left
atrium; when the valve reaches its final closing position, preejection
shortening is suddenly arrested. Hence, the initial shortening
is reflected by the upstroke of the spike, whereas the downstroke
reflects the interrupted shortening. The postejection velocity
spike appears to be caused by a similar mechanism; reverse blood
flow closes the aortic valve and slightly expands the ventricle
until valve closure interrupts the expansion. The expansion
is seen as a negative velocity at end systole, and the interruption
of lengthening is reflected by the upstroke of the postejection
velocity spike. In the normal heart, onset of shortening occurs
simultaneously throughout the left ventricular wall as indicated
by synchronous preejection velocity spikes in different left
ventricular wall regions. Thus, investigation of preejection
wall deformation may allow assessment of dyssynchronous contraction
and the effects of resynchronization therapy. Furthermore, because
preejection and postejection velocity spikes reflect valve events,
they may represent a means to detect timing of valve closure
and opening. See p
373.
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Randomized, Controlled Trial of Coronary Artery Bypass Surgery Versus Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease: Six-Year Follow-Up From the Stent or Surgery Trial (SoS)
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A number of randomized trials have compared revascularization
by percutaneous coronary intervention or coronary artery bypass
grafting (CABG) in the management of coronary artery disease,
but only the more recent studies have involved the routine use
of coronary stents. The Stent or Surgery (SoS) trial is an international
multicenter trial that randomized patients with multivessel
coronary artery disease to revascularization with CABG or percutaneous
coronary intervention with bare-metal stent technology. A total
of 988 patients (n=488 percutaneous coronary intervention, n=500
CABG) were randomized at 53 centers during the period from 1996
to 1999. The aim of the present study is to report long-term
survival in the SoS trial. Investigators established survival
status from hospital or community medical records or national
databases or by direct contact with patients and their relatives.
At a median follow-up of 6 years, 53 patients (10.9%) died in
the percutaneous coronary intervention group compared with 34
(6.8%) in the CABG group (hazard ratio 1.66, 95% confidence
interval 1.08 to 2.55,
P=0.022). Little evidence was found that
the treatment effect on mortality differed between subgroups
according to baseline angina grade (interaction test
P=0.52),
the severity of coronary disease (
P=0.92), or diabetic status
(
P=0.15). At a median follow-up of 6 years, a continuing survival
advantage was observed for patients managed with CABG, although
this is not consistent with results from other stent-versus-CABG
studies. See p
381.
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Improved Survival After Out-of-Hospital Cardiac Arrest Is Associated With an Increase in Proportion of Emergency Crew–Witnessed Cases and Bystander Cardiopulmonary Resuscitation
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Out-of-hospital cardiac arrest (OHCA) is a leading cause of
death in the Western world and accounts for >50% of deaths
due to adult coronary heart disease. Despite considerable efforts
to improve the various links in the chain of survival, OHCA
remains associated with a poor prognosis. The aim of this study
was to explore the temporal trends of survival after OHCA with
regard to factors mainly related to the prehospital phase and
resuscitation. We examined all patients experiencing OHCA in
whom cardiopulmonary resuscitation (CPR) was attempted between
1992 and 2005 in Sweden (n=38 646). The proportion surviving
for 1 month after arrest increased significantly from 4.8% in
1992 to 7.3% in 2005. The increase in survival was particularly
marked among patients found with a shockable rhythm and was
associated with an increase in the proportion of emergency medical
crew–witnessed arrests and, to a lesser degree, an increase
in the performance of bystander CPR. These findings suggest
that many lives could be saved if patients with cardiac symptoms
such as chest pain received more rapid assessment from emergency
medical teams. Two principal methods can be used to achieve
this result: earlier placement of calls to emergency dispatch
centers and shorter time intervals from OHCA to treatment (ie,
CPR and defibrillation). Education of patients, their families,
and the public may well be ways to reach the first group, whereas
increased use of CPR, public access defibrillation, and early
first-responder defibrillation are methods to reach the latter.
See p
389.
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Mast Cells Play a Critical Role in the Pathogenesis of Viral Myocarditis
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-Linolenic Acid and Risk of Nonfatal Acute Myocardial Infarction
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Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery
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Aerobic Interval Training Versus Continuous Moderate Exercise as a Treatment for the Metabolic Syndrome: A Pilot Study
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Alternative Splicing of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Is Associated With Plasma Low-Density Lipoprotein Cholesterol Response to Simvastatin
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