Circulation. 2008;118:607-608
doi: 10.1161/CIRCULATIONAHA.108.190520
(Circulation. 2008;118:607-608.)
© 2008 American Heart Association, Inc.
Clinical Summaries
 |
Prevention of Ventricular Arrhythmias With Sarcoplasmic Reticulum Ca2+ ATPase Pump Overexpression in a Porcine Model of Ischemia Reperfusion
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Cardiac arrhythmia is a potentially life-threatening complication
of heart failure and ischemic heart disease. In the past, some
therapeutic approaches for both of these conditions were associated
with an increased risk of arrhythmia and/or sudden cardiac death.
Previous work in a variety of animal models has demonstrated
that enhancing sarcoplasmic reticulum calcium uptake through
expression of the sarcoplasmic reticulum ATPase (SERCA2a) can
improve cardiac contractile function, survival, and the energetic
state. Here, we demonstrate in a preclinical large animal model
that, in contrast to some pharmacological agents that improve
inotropy but increase electric instability, SERCA2a expression
actually reduces arrhythmia as a result of calcium overload.
These findings support the notion that enhancing sarcoplasmic
reticulum calcium uptake may hold promise for the prevention
and treatment of arrhythmia for reperfusion and heart failure.
See p
614.
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Tumor Necrosis Factor- and Mortality in Heart Failure: A Community Study
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Mortality among patients with heart failure is high. Interest
has risen recently in the use of biomarkers to aid in identifying
heart failure patients at increased mortality risk. Tumor necrosis
factor-
(TNF
), an inflammatory cytokine, has previously been
reported to be elevated in heart failure clinical trial patients
with reduced ejection fraction and associated with increased
mortality. However, data on patients with preserved EF and those
living in the community were lacking. Among community heart
failure patients with both preserved and reduced ejection fraction,
our study findings indicate that TNF
is elevated in 29% of patients
and that higher levels are more common in patients with increased
comorbidity, including renal insufficiency and anemia. Higher
TNF
was associated with increased mortality, and TNF
significantly
improved mortality risk prediction. These findings suggest that
measurement of TNF
in patients presenting with heart failure
may aid in the identification of patients at highest mortality
risk regardless of ejection fraction. See p
625.
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Prevalence and Prognostic Significance of Preprocedural Cardiac Troponin Elevation Among Patients With Stable Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: Results From the Evaluation of Drug Eluting Stents and Ischemic Events Registry
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Baseline cardiac troponin (cTn) elevation is associated with
periprocedural complications during percutaneous coronary intervention
(PCI) in the setting of acute coronary syndromes. However, the
prevalence and prognostic significance of preprocedural cTn
elevation among patients with stable coronary artery disease
undergoing PCI are unknown. In the multicenter prospective Evaluation
of Drug Eluting Stents and Ischemic Events (EVENT) registry,
2382 consecutive patients with stable angina or positive stress
test undergoing PCI were analyzed with respect to the frequency
of an elevated cTn immediately before PCI and its relationship
to in-hospital and 1-year outcomes. A total of 142 (6.0%) had
a cTn level above the upper limit of normal before the procedure.
Compared with patients who had normal baseline cTn, patients
with elevated cTn had a higher rate of in-hospital death or
myocardial infarction (13.4% versus 5.6%;
P<0.001). In multivariable
analyses, baseline cTn elevation remained independently associated
with the composite of death or myocardial infarction at hospital
discharge (odds ratio, 2.1; 95% confidence interval, 1.2 to
3.8;
P=0.01) and at a 1-year follow-up (odds ratio, 2.0; 95%
confidence interval, 1.2 to 3.3;
P=0.005). Among patients undergoing
PCI for chronic stable angina or abnormal functional testing,
preprocedural elevation of cTn is relatively uncommon but when
present is associated with a 2-fold-increased risk of death
or MI during the associated hospitalization and at a 1-year
follow-up. If these findings are confirmed in future studies,
consideration may be given to routine testing of cTn in patients
with stable coronary artery disease before PCI. See p
632.
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Predictors of Outcome in Patients With Suspected Myocarditis
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Since the introduction of the histopathological Dallas criteria
in 1987, the role of endomyocardial biopsy in the management
of suspected myocarditis has been controversial. We therefore
examined the prognostic role of modern endomyocardial biopsy
with detailed analysis of specimens involving immunohistochemical
staining for characterization of inflammation and polymerase
chain reaction for detection of cardiotropic virus species in
181 young patients with clinically suspected myocarditis. In
181 endomyocardial biopsy procedures with 1018 specimens taken
mainly from the left ventricle, we had a low number of 6 complications
(3.3% per patient, 0.6% per specimen), all of which resolved
without sequelae. Neither the histopathological Dallas criteria
alone nor the detection of viral genome was a predictor of outcome.
Besides functional class, only 2 independent predictors proved
to be significant for future occurrence of the primary end point.
Although β-blocker treatment was protective, immunohistological
evidence of inflammatory infiltrates in the myocardium was associated
with a >3-fold increase in risk of cardiac death or heart
transplantation (
P=0.008). Patients in New York Heart Association
class I/II who took β-blockers without myocardial inflammation
appeared to have an excellent prognosis, with 100% 5-year transplantation-free
survival, whereas New York Heart Association class III/IV patients
with positive immunohistology not on β-blocker therapy
had an event-free survival rate of only 39%. Hence, myocardial
inflammation, which can be detected with high sensitivity by
modern immunohistological staining, confers significant prognostic
information. This underlines the role of endomyocardial biopsy
as an important cornerstone for risk stratification in patients
with clinically suspected myocarditis. See p
639.
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Increased Cardiac Myocyte Progenitors in Failing Human Hearts
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Amid a growing heart failure epidemic, the clinical research
community is aggressively pursuing interventional trials involving
mobilization and/or administration of putative stem/progenitor
cells to promote cardiac regeneration. To date, the therapeutic
success and impact of these interventional trials have been
limited. In this context, the present studies demonstrate that
severely failing human hearts already have and/or attract increased
quantities of endogenous stem/progenitor cells that appear capable
of new cardiac myocyte formation under favorable in vitro conditions.
Our additional finding that many of the stem/progenitor cells
in the human heart have biomarkers indicating a bone marrow
origin implies that the failing heart may elicit homing signals
that promote engraftment of circulating cells. Regardless of
their origin, the discovery of increased myogenic progenitors
in end-stage failing human hearts highlights a potential therapeutic
opportunity to promote myocardial regeneration. However, the
fact that unaided endogenous repair is insufficient in these
hearts also suggests that the central clinical challenge may
not be how to deliver stem/progenitor cells to the heart but
rather how to promote their in vivo differentiation, maturation,
integration, and survival. With or without supplemental cell
delivery to the heart, these data suggest that strategies to
identify and ameliorate adverse local myocardial factors are
necessary to promote clinically meaningful myocardial regeneration.
See p
649.
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Requirement for p38 Mitogen-Activated Protein Kinase Activity in Neointima Formation After Vascular Injury
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Atherosclerotic vascular disease is commonly treated by percutaneous
arterial interventions. Neointima formation often occurs at
the site of intervention and may lead to significant restenosis.
The use of drug-eluting stents to treat atherosclerotic vascular
disease results in a markedly reduced incidence of restenosis,
but delayed in-stent thrombosis can occur that leads to myocardial
infarction. A cause of delayed thrombosis may be inadequate
endothelialization of the inner surface of the drug-eluting
stent resulting from the toxic effects of the embedded agents,
sirolimus or taxol. This issue has led to a search for agents
that inhibit the smooth muscle cell migration and proliferation
required for neointima formation without inhibiting endothelialization.
In this work, mice expressing a dominant-inhibitory form of
p38 mitogen-activated protein kinase (p38 MAPK) only in smooth
muscle cells were resistant to neointima formation after carotid
artery injury. Knockdown of p38 MAPK in cultured smooth muscle
cells blocked cell proliferation. In previous work, inhibition
of p38 MAPK in endothelial cells promoted cell survival and
proliferation. Therefore, p38 MAPK inhibition is predicted to
inhibit smooth muscle cell proliferation while promoting endothelial
cell survival and growth. The use of agents that block p38 MAPK
may block restenosis without preventing stent endothelialization.
See p
658.
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Corticosteroids for Recurrent Pericarditis: High Versus Low Doses: A Nonrandomized Observation
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The present observational study challenges the widespread practice
of using high doses of prednisone or other corticosteroids to
treat pericarditis. Use of corticosteroids should be restricted
in pericarditis, but when indicated, high doses (prednisone
1.0 to 1.5 mg · kg
–1 · d
–1) have been
recommended in reviews and in the European guidelines on the
management of pericardial diseases, although only a single small
retrospective study supported high-dose use in recurrent pericarditis.
Lower doses usually are used to treat pericarditis in autoimmune
diseases. In this nonrandomized observation, it appeared that
higher doses of prednisone (1.0 mg · kg
–1 ·
d
–1) for recurrent pericarditis were associated with more
side effects, recurrences, and hospitalizations (hazard ratio,
3.61; 95% confidence interval, 1.96 to 6.63) than lower doses
(prednisone 0.2 to 0.5 mg · kg
–1 · d
–1).
It is important to search for a cause of recurrent pericarditis
as diligently as possible, with therapy directed at the specific
cause. This observational study challenges the current practice
of routine high-dose corticosteroids for recurrent "idiopathic"
pericarditis and should serve as the basis for a randomized
trial. See p
667.
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