Circulation. 2008;117:2719-2720
doi: 10.1161/CIRCULATIONAHA.108.189728
(Circulation. 2008;117:2719-2720.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Necessity for Surgical Revision of Defibrillator Leads Implanted Long-Term: Causes and Management
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An implantable cardioverter-defibrillator has become standard
care for secondary prevention of sudden cardiac death and for
primary prevention in patients at high risk for sudden cardiac
death. Malfunction of the defibrillator lead is a potential
long-term complication in this population. The aim of this study
was to determine the incidence and causes of lead malfunction
necessitating surgical revision and to evaluate 2 surgical approaches
to treat lead malfunction. For this purpose, we analyzed 1317
patients who received an implantable cardioverter-defibrillator
between 1994 and 2004. During a mean follow-up of 6.5 years,
38 patients required surgery to solve a lead-related problem.
Cumulative lead malfunction incidences were 1.8%, 2.5%, and
4.6% at years 3, 5, and 10 years after implantation. At the
same time, mortality without lead malfunction was much higher,
with cumulative incidences of 14.5%, 22.8%, and 33.6%. The main
reasons for lead malfunction were insulation defects (26%),
artifact oversensing (24%), and lead fractures (24%). Lead malfunction
resulted in inappropriate implantable cardioverter-defibrillator
therapy in 76% of the cases. If the integrity of the high-voltage
part of the defibrillator lead could be ascertained, only an
additional pace/sense lead could be implanted. Otherwise, a
new defibrillator lead was used. However, once a malfunction
has occurred, the cumulative incidence of recurrent lead malfunction
was 8-fold higher and therefore warrants a closer follow-up.
See p
2727.
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Maximal Exercise Electrocardiography Responses and Coronary Heart Disease Mortality Among Men With Diabetes Mellitus
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Although exercise testing is proven to have prognostic value,
studies that examine the relationship between exercise ECG (E-ECG)
responses and coronary heart disease (CHD) mortality risk in
asymptomatic men with existing cardiovascular disease risk factors
are inconsistent. Most studies have shown a positive association
in high-risk subgroups, although others have not. However, these
studies have not focused on individuals with diabetes mellitus,
which is considered a CHD risk equivalent. Therefore, the primary
aim of our study was to evaluate the relationship between E-ECG
testing and CHD mortality in a large population of asymptomatic
men with diabetes mellitus. We examined the association between
E-ECG responses and mortality in men with documented diabetes
who completed a maximal treadmill exercise test and were without
a previous cardiovascular disease event at baseline. We observed
a direct gradient of mortality risk across normal, equivocal,
and abnormal E-ECG groups that remained significant after adjustment
for age, smoking, family history of cardiovascular disease or
diabetes mellitus, abnormal resting ECG responses, fasting glucose
level, cardiorespiratory fitness, and factors that may be intermediate
in the causal pathway between E-ECG and CHD (body mass index,
hypertension, and hypercholesterolemia). A second major finding
was that the association between E-ECG result and CHD generally
was consistent within strata of other CHD predictors. A third
noteworthy issue was that fit men had a higher survival rate
than unfit men within each category of E-ECG outcome. Our data
suggest that abnormal E-ECG response is a significant determinant
of CHD mortality in men with diabetes mellitus. See p
2734.
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Cardiomyocyte Expression of a Polyglutamine Preamyloid Oligomer Causes Heart Failure
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We have previously published evidence that preamyloid oligomers,
the substances thought to be toxic in a variety of neurodegenerative
disorders, are generated in certain mouse models of cardiac
disease and can also be found in cardiomyocytes derived from
the failing human myocardium. This study tested the hypothesis
that preamyloid oligomers can cause cardiomyocyte death that
leads to heart failure. A preamyloidogenic protein comprising
only glutamine was ectopically expressed in the mouse heart
with transgenesis. Very low levels of this protein led to cardiomyocyte
death and heart failure in young adult mice. Future work will
be directed at understanding the role of preamyloid oligomer
accumulation in human heart disease and failure. See p
2743.
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Embolic Protection and Platelet Inhibition During Renal Artery Stenting
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Atherosclerotic renal artery stenosis, an important cause of
secondary hypertension and chronic kidney disease, is increasingly
recognized as imaging improves and the population ages. Renal
stenting has become the dominant revascularization therapy,
although worsening renal function after stenting sometimes occurs
and may result in end-stage renal disease. Several causes of
renal injury have been implicated, including atheroembolization.
Recently, filters and occlusion devices have been developed
to prevent embolization of atheromatous material. Whether embolic
protection or use of a platelet glycoprotein IIb/IIIa inhibitor
is effective in preventing declines in renal function after
stenting is not known. In the present study, patients undergoing
renal artery stenting were randomly assigned to an open-label
embolic protection device, Angioguard, or use of a platelet
glycoprotein IIb/IIIa inhibitor, abciximab. Although a benefit
of abciximab was observed over placebo, an unanticipated interaction
was observed between treatment with abciximab and embolic protection.
Renal artery stenting alone, stenting with Angioguard embolic
protection, and stenting with abciximab were associated with
similar and modest declines in glomerular filtration rate at
a 1-month follow-up; however, allocation to both Angioguard
embolic protection and abciximab was not associated with a decline
in glomerular filtration rate and was superior to the other
3 allocations for the prevention of declines in kidney function.
Further work is needed to confirm these findings and to determine
the longer-term clinical relevance. See p
2752.
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Inhibition of GSK3β by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion
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We previously demonstrated that ischemic postconditioning by
angioplasty can attenuate lethal reperfusion injury and improve
the recovery of left ventricular contractile function in acute
myocardial infarction patients. Because many acute myocardial
infarction patients cannot benefit from angioplasty postconditioning
(eg, acute myocardial infarction patients treated by thrombolysis),
an obvious need exists for a pharmacological mimetic of PCI
postconditioning. It is well accepted that the opening of the
mitochondrial permeability transition pore is a key event in
lethal reperfusion injury. Recent experimental studies suggest
that activation of PI3-kinase/Akt/glycogen synthase kinase-3β
(GSK3β) pathway is involved in cardioprotection. Using
a transgenic mouse model of reperfused myocardial infarction,
we demonstrated here that serine 9 phosphorylation of GSK3β
is required for cardioprotection by postconditioning and likely
acts by inhibiting opening of the mitochondrial permeability
transition pore at the time of reperfusion. These results suggest
that targeting GSK3β at the time of reperfusion may be
a way to indirectly inhibit mitochondrial permeability transition
pore opening and limit infarct size after a prolonged ischemic
insult. Drugs acting either on the GSK3β pathway or directly
on the mitochondrial permeability transition pore could then
be administered in all patients with ongoing acute myocardial
infarction, either as an adjunct to thrombolysis or even just
before coronary angioplasty (in place of ischemic postconditioning).
This represents an encouraging background for the search for
and future development of pharmacological agents that would
attenuate lethal reperfusion injury in patients with ongoing
acute myocardial infarction. See p
2761.
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A Novel Method of Expressing Left Ventricular Mass Relative to Body Size in Children
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The diagnosis of left ventricular hypertrophy (LVH) in children
and adolescents has important implications. Among hypertensive
youth, for example, the presence of LVH may influence the decision
to start or adjust antihypertensive therapy. The presence of
LVH in children with aortic stenosis or other left-sided obstructive
lesions may be an important factor in recommending intervention.
It is therefore important that criteria for the diagnosis of
LVH be valid and reliable. The left ventricular mass index (LVMI),
expressed as g/m
2.7, has been gaining popularity as a method
of normalizing left ventricular mass to body size in children.
Fixed LVMI cutoffs, applicable to all children, have been proposed
to define LVH and have been widely applied in prior pediatric
studies. The present study examines the potential limitations
of the LVMI in children. We demonstrate that the LVMI increases
with decreasing height in healthy children <140 cm tall and
show that a fixed LVMI cutoff for LVH cannot be meaningfully
applied to all children. We propose a new method of normalizing
left ventricular mass for body size using centile curves and
validate this method across a broad range of body sizes. The
new method will allow accurate diagnosis of LVH in children
of all sizes. See p
2769.
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Natural History of Asymptomatic Patients With Normally Functioning or Minimally Dysfunctional Bicuspid Aortic Valve in the Community
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Bicuspid aortic valve, a frequent congenital aortic valve deformation,
often allows the valve to function almost normally at birth
and often into adult life. Affected subjects have no symptoms
and do not require immediate surgery, but we had no information
on their future, outcome, and risk factors and on those who
are at higher risk and require close follow-up. Thus, for up
to 20 years, we followed up 212 patients diagnosed by echocardiography
in the community, incidentally or for a murmur, with asymptomatic
bicuspid aortic valves functioning normally or close to normally.
Our findings are reassuring but uncover patients who need closer
follow-up. Reassuringly, we found no excess mortality compared
with the general population; valve infections (endocarditis)
were rare; and we observed no aortic dissection. Conversely,
morbid events directly linked to the bicuspid valve were frequent
and premature for age. Approximately 4 in 10 patients incurred
morbidity, mostly aortic stenosis leading to symptoms and/or
surgery. Echocardiographic early aortic valve degeneration at
diagnosis predicted higher subsequent morbidity. Aortic dilatation,
also a feature of bicuspid valves, was progressive, sometimes
leading to the formation of aneurysms and requiring surgery
in a limited number of patients. Aortic dilatation at diagnosis
marks patients at risk for aneurysm formation and surgery. Thus,
though reassuring in many aspects, our study emphasizes specific
risks associated with bicuspid valves, even those apparently
normally functioning, and underscores the limited subsets of
patients at notable risk (with valve degeneration or aortic
dilatation) who need closer follow-up. See p
2776.
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Reduced Expression of ATP-Binding Cassette Transporter G1 Increases Cholesterol Accumulation in Macrophages of Patients With Type 2 Diabetes Mellitus
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Macrophage foam cell formation in the aortic wall is a key early
event in atherosclerotic plaque development. In this process,
macrophages uptake oxidized low-density lipoprotein via scavenger
receptor binding and efflux cholesterol to high-density lipoprotein
for reverse cholesterol transport via the actions of the ATP-binding
cassette (ABC) transporters ABCA1 and ABCG1 and scavenger receptor-B1
(SR-B1). ABCA1 and ABCG1 deliver cholesterol to high-density
lipoprotein to aid in reverse cholesterol transport to the liver.
If the balance of influx and efflux of cholesterol from macrophages
is altered, the macrophages become lipid laden and undergo apoptosis
and secondary necrosis, dumping lipid into the extracellular
space in the arterial wall and promoting atherosclerosis progression.
Patients with type 2 diabetes mellitus (T2DM) have an increased
incidence of atherosclerosis. Previous studies in animal models
of T2DM demonstrate a decrease in ABCG1 expression and lipid
efflux to high-density lipoprotein. The present study extends
these finding to humans, providing a potential mechanism for
the accelerated vascular disease in T2DM. ABCG1 expression is
significantly reduced in macrophages isolated from patients
with T2DM compared with control subjects. In contrast, expression
of ABCA1 and SR-B1 was unchanged. Concomitant with reduced ABCG1
expression, macrophages from patients with T2DM had a reduced
ability to efflux cholesterol to high-density lipoprotein, thus
triggering accumulation of cholesteryl esters within macrophages.
Treatment of T2DM macrophages with a liver X receptor
/β
agonist restored ABCG1 expression and reduced cholesterol accumulation,
suggesting that therapies to upregulate liver X receptor β
may be beneficial for preventing macrophage foam cell formation
in the arterial wall in patients with T2DM. Taken together,
these observations suggest that decreased macrophage ABCG1 expression
may contribute to impaired reverse cholesterol transport, macrophage
foam cell formation, and atherosclerosis progression in patients
with T2DM. See p
2785.
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Natural History of Asymptomatic Patients With Normally Functioning or Minimally Dysfunctional Bicuspid Aortic Valve in the Community
- Hector I. Michelena, Valerie A. Desjardins, Jean-François Avierinos, Antonio Russo, Vuyisile T. Nkomo, Thoralf M. Sundt, Patricia A. Pellikka, A. Jamil Tajik, and Maurice Enriquez-Sarano
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Maximal Exercise Electrocardiography Responses and Coronary Heart Disease Mortality Among Men With Diabetes Mellitus
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Embolic Protection and Platelet Inhibition During Renal Artery Stenting
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Necessity for Surgical Revision of Defibrillator Leads Implanted Long-Term: Causes and Management
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Circulation 2008 117: 2727-2733.
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A Novel Method of Expressing Left Ventricular Mass Relative to Body Size in Children
- Bethany J. Foster, Andrew S. Mackie, Mark Mitsnefes, Huma Ali, Silvia Mamber, and Steven D. Colan
Circulation 2008 117: 2769-2775.
[Abstract]
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Reduced Expression of ATP-Binding Cassette Transporter G1 Increases Cholesterol Accumulation in Macrophages of Patients With Type 2 Diabetes Mellitus
- Jeremy P. Mauldin, Melissa H. Nagelin, Allison J. Wojcik, Suseela Srinivasan, Marcus D. Skaflen, Carlos R. Ayers, Coleen A. McNamara, and Catherine C. Hedrick
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Cardiomyocyte Expression of a Polyglutamine Preamyloid Oligomer Causes Heart Failure
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Circulation 2008 117: 2743-2751.
[Abstract]
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Inhibition of GSK3β by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion
- Ludovic Gomez, Mélanie Paillard, Hélène Thibault, Geneviève Derumeaux, and Michel Ovize
Circulation 2008 117: 2761-2768.
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