Circulation. 2008;118:1113-1114
doi: 10.1161/CIRCULATIONAHA.108.190525
(Circulation. 2008;118:1113-1114.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Dynamic Mechanism for Initiation of Ventricular Fibrillation In Vivo
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Our study demonstrates a novel mechanism of induction of ventricular
fibrillation in vivo in intact normal beagle dogs. This work
may contribute to our understanding of the mechanisms leading
to the development of ventricular fibrillation in the structurally
normal heart. For example, in patients with idiopathic ventricular
fibrillation, focal ectopic ventricular activity originating
in the Purkinje network is thought to trigger the onset of ventricular
fibrillation. Our work also may be clinically relevant to patients
with channelopathies, ie, long-QT syndrome, in which typically
a short-long-short sequence of premature stimuli induces ventricular
tachycardia and fibrillation. We showed in our study that such
specific patterns (called CL
VF, cycle lengths inducing VF) can
indeed lead to ventricular fibrillation by creating conduction
block and wave break, depending on the restitution properties
of the action potential duration and conduction velocity. In
that regard, a potential therapeutic application of our work
is to specifically target the restitution parameters with drugs
so that CL
VF would no longer lead to ventricular fibrillation.
We showed that the calcium channel blocker verapamil exerts
antifibrillatory effects by altering restitution parameters
but not at clinically relevant dosages. However, we postulate
that other drugs may prove to have antiarrhythmic effects by
altering the restitution parameters of a patient and thus may
prevent the induction of ventricular fibrillation rather than
by suppressing the premature stimuli. See p
1123.
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Longitudinal Strain Delay Index by Speckle Tracking Imaging: A New Marker of Response to Cardiac Resynchronization Therapy
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Recent results from the PROSPECT and RETHINQ trials might suggest
that a relatively limited and simple quantification of left
ventricular dyssynchrony has suboptimal accuracy for the identification
of responders to cardiac resynchronization therapy. In the present
study, we introduce a new method, the strain delay index, to
quantify response to cardiac resynchronization therapy. Rather
than simply measuring left ventricular dyssynchrony, we propose
to quantify the potential gain of contractility expected after
the best possible cardiac resynchronization. The potential gain,
in turn, should predict reverse remodeling after resynchronization
therapy. The strain delay index combines the importance of left
ventricular dyssynchrony and residual contractility and provides
a better understanding of the physiological response to cardiac
resynchronization therapy. This index should improve the ability
to identify potential responders to cardiac resynchronization
therapy in the future. The sophistication of the strain delay
index relative to Doppler-derived parameters might be of particular
importance in the narrow-QRS population, in whom the degree
of dyssynchrony may be less and thus more challenging to quantify.
Future efforts should focus on validation of the method in current
clinical practice along with implementation of software modifications
to facilitate ease of use. Additionally, because the strain
delay index is computed from regional strain curves, its accuracy
is dependent on the precision of the method used to quantify
myocardial contractility. Importantly, therefore, the strain
delay index can be computed from imaging modalities other than
ultrasound (ie, cardiac magnetic resonance and CT) and should
be tested in patients with poor acoustic windows. See p
1130.
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Delayed Arterial Healing and Increased Late Stent Thrombosis at Culprit Sites After Drug-Eluting Stent Placement for Acute Myocardial Infarction Patients: An Autopsy Study
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The approval of the current generation of polymeric Cypher and
Taxus drug-eluting stents (DES) by the US Food and Drug Administration
was based on randomized clinical trial data demonstrating impressive
reductions in restenosis compared with bare metal stents in
patients without evidence of acute myocardial infarction (AMI).
The long-term clinical safety of DES implantation for AMI indication
remains uncertain. Using autopsy data, we evaluated the pathological
responses of the stented segment in patients treated with DES
for AMI versus stable angina. Coronary plaque morphology in
patients with AMI was significantly different from that in patients
with stable angina and was characterized by greater necrotic
core area, thinner overlying fibrous cap, and a greater number
of struts penetrating the necrotic core. A significantly higher
incidence of late stent thrombosis was observed in patients
with AMI compared with those with stable angina. Culprit sites
(ie, sites of plaque rupture) in patients with AMI were associated
with a substantial delay in healing compared with culprit sites
(fibroatheroma) in patients with stable angina and nonculprit
sites within the same lesion. Furthermore, there was a significant
negative correlation between fibrous cap thickness and the presence
of uncovered struts (ie, the thinner the fibrous cap, the greater
the presence of uncovered struts). Collectively, these results
emphasize the importance of underlying plaque morphology in
the healing response of coronary vessels after DES placement.
Our findings suggest that an increased risk of late thrombotic
complications might be expected in patients treated with DES
for AMI. See p
1130.
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Long-Term Safety and Efficacy of Percutaneous Coronary Intervention With Stenting and Coronary Artery Bypass Surgery for Multivessel Coronary Artery Disease: A Meta-Analysis With 5-Year Patient-Level Data From the ARTS, ERACI-II, MASS-II, and SoS Trials
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Randomized trials that studied clinical outcome after percutaneous
coronary intervention (PCI) with bare metal stenting versus
coronary artery bypass grafting (CABG) are underpowered to properly
assess safety end points like death, stroke, and myocardial
infarction. Pooling data from randomized controlled trials increases
the statistical power and allows better assessment of the treatment
effect in high-risk subgroups. The present pooled analysis of
3051 patients in 4 randomized trials evaluating the relative
safety and efficacy of PCI with stenting and CABG for the treatment
of multivessel coronary artery disease demonstrates that both
treatment modalities provided similar long-term safety profiles.
At 5 years, the cumulative incidence of death, myocardial infarction,
and stroke was similar in patients randomized to PCI with stenting
versus CABG (16.7% versus 16.9%, respectively; hazard ratio,
1.04; 95% confidence interval, 0.86 to 1.27;
P=0.69). Repeat
revascularization, however, occurred significantly more frequently
after PCI than CABG (29.0% versus 7.9%, respectively; hazard
ratio, 0.23; 95% confidence interval, 0.18 to 0.29;
P<0.001).
Several large-scale randomized trials like the Future Revascularization
Evaluation in Patients With Diabetes: Optimal Management of
Multivessel Disease, and Synergy Between Percutaneous Coronary
Intervention With Taxus and Cardiac Surgery are currently comparing
the safety and effectiveness of CABG and PCI with drug-eluting
stents. Whether drug-eluting stents will tip the balance between
safety and efficacy of PCI and CABG is to be examined. See p
1146.
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Drug-Eluting Versus Bare Metal Stents in Patients With ST-Segment–Elevation Myocardial Infarction: Eight-Month Follow-Up in the Drug Elution and Distal Protection in Acute Myocardial Infarction (DEDICATION) Trial
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Primary percutaneous coronary intervention is the treatment
of choice in patients with ST-segment–elevation myocardial
infarction and <12 hours duration of pain, but whereas implantation
of drug-eluting stents is known to reduce the development of
restenosis in most patients, treatment of ST-segment–elevation
myocardial infarction is considered an off-label indication
of their use. We randomized patients with ST-segment–elevation
myocardial infarction to have a drug-eluting or a bare metal
stent implanted in their target vessel in connection with primary
percutaneous coronary intervention and evaluated their angiographic
and clinical outcome. We observed a reduction in the need for
repeat revascularization in the drug-eluting stent group, reflecting
a significant reduction in neointimal hyperplasia as determined
by angiography. We also observed a tendency to an increased
rate of cardiac death in the drug-eluting stent group that was
not explained by a higher rate of stent thrombosis, a finding
that warrants continued clinical follow-up of the patients.
See p
1155.
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Impact of In-Hospital Revascularization on Survival in Patients With Non–ST-Elevation Acute Coronary Syndrome and Congestive Heart Failure
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This study addresses the role of revascularization in patients
with non–ST-elevation acute coronary syndrome who present
with congestive heart failure. It is based on an analysis of
29 844 non–ST-elevation acute coronary syndrome patients
enrolled in the multinational GRACE registry. Patients with
congestive heart failure, who constitute a large subset (17%)
of all patients, undergo in-hospital revascularization less
frequently than those without heart failure (20% versus 35%,
P<0.001). The baseline characteristics of patients with heart
failure demonstrated higher risk than those of patients without.
After adjustment for differences in baseline characteristics
and propensity to undergo revascularization, and after revascularization
was taken into account as a time-varying covariate, it appeared
that revascularization did not affect in-hospital mortality
rates but was associated with a survival benefit at 6-month
follow-up. This benefit was consistent in all patient subgroups
except women. These data from a large multinational registry
reinforce the current guidelines’ recommendation that
high-risk non–ST-elevation acute coronary syndrome patients
should undergo early coronary angiography with a view to revascularization,
and they are consistent with prior trials of revascularization
in non–ST-elevation acute coronary syndrome or in patients
with cardiogenic shock complicating myocardial infarction. Given
that most deaths due to non–ST-elevation acute coronary
syndrome occur in this subset, these observations indicate that
broader use of revascularization in this group may save lives.
Although the finding of a negative interaction between revascularization
and female sex must be interpreted with caution in post hoc
analyses of relatively small subsets, it emphasizes the need
for further study regarding the role of revascularization in
women with high-risk acute coronary syndrome. See p
1163.
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Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque
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Despite intensive management of conventional risk factors, coronary
events continue to recur at an unacceptably high rate. Thus,
novel therapeutic options for treating coronary heart disease
are needed. Inhibition of the enzyme lipoprotein-associated
phospholipase A
2 (Lp-PLA
2) with darapladib has emerged as a
potential approach to addressing residual risk of cardiovascular
events by directly targeting high-risk coronary atheroma. This
multicenter study used intravascular ultrasound–derived
techniques to characterize coronary atheroma in patients receiving
a standard-of-care treatment. The results demonstrate that the
necrotic core, a key determinant of plaque vulnerability, continued
to increase among patients receiving placebo despite a high
level of adherence to recommended therapies. This result is
consistent with a proatherogenic role for Lp-PLA
2 that is postulated
to contribute to plaque vulnerability. In contrast, treatment
with the direct Lp-PLA
2 inhibitor darapladib added to standard
of care prevented necrotic core expansion. Pharmacological intervention
with darapladib exerted favorable effects on coronary atheroma
consistent with plaque stabilization. These findings suggest
that direct Lp-PLA
2 inhibition may represent a novel therapeutic
approach to reducing residual risk in patients with coronary
heart disease. See p
1172.
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Fhl-1, a New Key Protein in Pulmonary Hypertension
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Pulmonary arterial hypertension is a life-threatening disease
that is characterized by aberrant pulmonary vascular remodeling.
Pathological alterations of the vasculature include dysregulated
smooth muscle cell migration and proliferation in the pulmonary
vessel media, which require alterations in cytoskeletal organization.
To date, several factors involved in vascular remodeling remain
to be identified and characterized. In the present study, a
proteome screening approach was used to identify four-and-a-half
LIM domain protein (Fhl-1) as a novel molecule involved in pulmonary
arterial smooth muscle cell proliferation. This protein belongs
to the family of LIM proteins that contain a cysteine-rich,
double zinc finger motif that mediates protein-protein interactions
of transcription factors, signaling, and cytoskeletal proteins.
Proteins containing LIM domains mediate tissue differentiation,
oncogenesis, and cytoskeletal organization. In hypoxia-induced
pulmonary arterial hypertension, Fhl-1 expression was enhanced
at both the onset of the disease and when disease was fully
established. In pulmonary arteries from patients with idiopathic
pulmonary arterial hypertension, strong upregulation of Fhl-1
was noted compared with healthy donor lungs. The cellular role
of Fhl-1 was deciphered by identification of the cytoskeletal
protein Talin1 as a novel binding partner of Fhl-1. Both molecules
colocalized in pulmonary arterial smooth muscle cells in vitro
and in vivo and triggered pulmonary arterial smooth muscle cell
migration and proliferation, suggesting that increased levels
of Fhl-1 alter cytoskeletal dynamics via interaction with Talin.
Furthermore, these observations suggest Fhl-1 as a novel molecular
target with therapeutic efficacy in patients with pulmonary
arterial hypertension. See p
1183.
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