Circulation. 2008;118:979-980
doi: 10.1161/CIRCULATIONAHA.108.190524
(Circulation. 2008;118:979-980.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Feedback Remodeling of Cardiac Potassium Current Expression: A Novel Potential Mechanism for Control of Repolarization Reserve
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Repolarization reserve is an important determinant of the response
to contexts involving action potential prolongation, including
potassium channel–blocking drugs (both antiarrhythmic
agents and compounds with collateral effects on potassium channels),
bradycardic drugs, and electrolyte disturbances like hypokalemia
and hypomagnesemia. Repolarization reserve is generally attributed
to functionally based compensatory increases in potassium currents
in response to action potential duration–prolonging tendencies
that minimize the resulting action potential prolongation. The
possibility that sustained action potential prolongation by
potassium channel inhibition may induce remodeling of ion current
expression has not been tested. Accordingly, we assessed the
effects of sustained rapid delayed-rectifier potassium current
(I
Kr) inhibition with dofetilide on various cardiac ionic currents
in isolated paced/cultured dog cardiomyocytes. Sustained dofetilide
exposure led to abbreviated action potential duration and increased
repolarization reserve (reduced action potential duration–prolonging
response to I
Kr blockade), along with increased slow delayed-rectifier
current (I
Ks) density. A variety of other currents remained
unchanged. The mRNA expression of I
Ks subunits was unchanged,
but their protein expression was increased, suggesting posttranscriptional
regulation. We quantified the muscle-specific microRNA subtypes
miR-133a and
miR-133b, which can posttranscriptionally repress
protein expression of the I
Ks 
-subunit KvLQT1. Expression levels
of
miR-133a and
miR-133b were decreased in cells cultured in
dofetilide, possibly accounting for KvLQT1 protein upregulation.
We conclude that chronic action potential prolongation can cause
compensatory upregulation of potassium currents, possibly mediated
(at least in part) by microRNA changes, adding the regulation
of ion channel expression to the potential mechanisms governing
repolarization reserve. Function and malfunction of this system
could contribute to factors governing the occurrence of cardiac
arrhythmias in repolarization dysfunction paradigms like congenital
and acquired long-QT syndromes. See p
983.
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Fasting Compared With Nonfasting Lipids and Apolipoproteins for Predicting Incident Cardiovascular Events
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Current guidelines recommend measurement of a fasting lipid
profile for cardiovascular risk assessment. Recent studies suggest
that nonfasting triglycerides may better or similarly predict
cardiovascular disease (CVD) events than fasting levels. Measurement
of nonfasting lipids may have many practical advantages for
clinical practice, but it is unknown whether nonfasting status
alters the association of nontriglyceride lipids and apolipoproteins
with CVD. Using prospectively collected data from the Women’s
Health Study with 26 330 healthy women (19 983 fasting; 6347
nonfasting) followed over an 11-year period, we examined the
association of CVD with baseline lipids and apolipoproteins
according to time from last meal. We found that the concentrations
of lipids and apolipoproteins differed minimally when measurements
were performed on nonfasting (<8 hours from last meal) compared
with fasting blood (
8 hours from last meal), except for triglycerides,
which were higher when nonfasting. However, the associations
with CVD were stronger for fasting compared with nonfasting
measurements of total cholesterol, low-density lipoprotein cholesterol,
apolipoprotein B-100, non–high-density lipoprotein (non-HDL)
cholesterol, and the apolipoprotein B-100/A-1 ratio. By contrast,
the associations with CVD were similar for fasting and nonfasting
HDL cholesterol, apolipoprotein A-1, and the total/HDL cholesterol
ratio and stronger for nonfasting triglycerides. These observations
suggest that nonfasting blood draws may be highly effective
and practical when limited to HDL cholesterol, total/HDL cholesterol
ratio, triglycerides, and apolipoprotein A-1. However, these
data also suggest that a fasting sample is preferred if risk
assessment is based on total cholesterol, low-density lipoprotein
cholesterol, non-HDL cholesterol, apolipoprotein B-100, and
apolipoprotein B-100/A-1 ratio. See p
993.
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Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines
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Advanced glycation end products (AGEs) are believed to increase
left ventricular and vascular stiffness, in part via cross-linking
proteins. We determined whether and where AGEs were increased
in elderly hypertensive nondiabetic dogs and whether an AGE
cross-link breaker (ALT-711) improved vascular or ventricular
function.
N
-(Carboxymethyl)lysine, a marker of AGE accumulation,
was markedly increased in aortic and aortic vasa vasorum smooth
muscle but was not localized to areas of collagen or elastin
and was not present in left ventricular myocardium of old hypertensive
dogs. ALT-711 therapy was associated with lower blood pressure
and pulse pressure, decreased systemic vascular resistance,
increased aortic distensibility and arterial compliance, and,
notably, significant aortic dilatation. Neither left ventricular
systolic nor diastolic function was different in ALT-711–treated
dogs. AGE-modifying therapies have been and continue to be tested
in patients with heart failure and hypertension. These data
in a nondiabetic model with clinical relevance to human hypertension
and heart failure suggest that this therapeutic strategy may
favorably modify arterial properties but also that such therapies
may be associated with aortic dilatation, at least in the setting
of persistent hypertension. Thus, aortic size should be monitored
carefully in clinical trials of these agents. Furthermore, at
least in this nondiabetic model, we did not find evidence of
a favorable effect on diastolic function. Whether more prolonged
therapy or therapy in diabetics with heart failure or hypertension
would be associated with benefit on diastolic function remains
to be established. See p
1002.
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Incidence and Prognostic Implication of Unrecognized Myocardial Scar Characterized by Cardiac Magnetic Resonance in Diabetic Patients Without Clinical Evidence of Myocardial Infarction
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With a high prevalence of atypical cardiac symptoms and ECG
findings nonspecific for acute coronary syndrome, a noninvasive
technique that improves the detection of occult myocardial infarction
(MI) in diabetic patients may serve to advance the management
of the cardiovascular complications of this current global epidemic.
In this study, we report the clinical utility and prognostic
implication of late gadolinium enhancement (LGE) by cardiac
magnetic resonance imaging in detecting myocardial scar from
MI in a diabetic cohort without any history or ECG evidence
of MI. With excellent tissue contrast and spatial resolution,
LGE imaging offers a novel method of myocardial characterization
not otherwise captured by regional contractile function and
nuclear scintigraphy. A high prevalence of LGE at 28% was present
among diabetics without a history of MI. This finding was associated
with a >3-fold increase in cardiac events and death. Among
patients who were detected by LGE imaging to have an unrecognized
MI, the reduced median event-free survival was not different
from that of a diabetic control cohort who presented with a
clinical MI. Furthermore, this study demonstrated that LGE findings
provide incremental prognostic value compared with patient age,
sex, ST-T changes on ECG, left ventricular systolic function,
and the validated United Kingdom Prospective Diabetes Study
5-year risk engine. In summary, LGE by cardiac magnetic resonance
imaging can detect subclinical MI and characterize a group of
diabetic patients at high risk of cardiac events and death.
See p
1011.
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Peroxisome Proliferator–Activated Receptor- Agonist Enhances Vasculogenesis by Regulating Endothelial Progenitor Cells Through Genomic and Nongenomic Activations of the Phosphatidylinositol 3-Kinase/Akt Pathway
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Since the early 2000s, peroxisome proliferator–activated
receptors (PPARs), especially PPAR-
, have been under intense
study in various areas, including vascular biology. Although
PPAR-
agonist was found to exert several adverse effects such
as weight gain and low-density lipoprotein elevation, it was
also known to have many beneficial effects on conditions such
as atherosclerosis and postangioplasty restenosis, and the commercial
ligands have been prescribed widely as an antidiabetic drug.
However, recent studies raised important questions about the
cardiovascular safety of PPAR-
agonist. Naturally, other PPARs
have awakened researchers’ interest as an alternative
choice. The function of PPAR-
remained mainly unexplored until
recently. In our study, PPAR-
activation was revealed to regulate
endothelial progenitor cells through the dual activation mechanism
of the phosphatidylinositol 3-kinase/Akt pathway, leading to
vasculogenesis. Metabolically, PPAR-
is a key regulator with
the potential to therapeutically target multiple aspects of
the metabolic syndrome. PPAR-
activation was known to elevate
high-density lipoprotein cholesterol robustly and lower low-density
lipoprotein cholesterol and triglycerides. It was also reported
to be involved in adipose tissue metabolism and to prevent obesity.
In liver, PPAR-
activation was shown to suppress hepatic glucose
output, contributing to improved glucose homeostasis. Metabolic
syndrome has been strongly linked with cardiovascular disease.
Considering the beneficial effects of PPAR-
agonist in metabolic
syndrome, we can expect that its therapeutic potential may be
enormous in cardiovascular disease on the basis of our new findings
that PPAR-
activation modulates endothelial progenitor cell
biology in a positive direction and augments vasculogenesis.
See p
1021.
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Sleep Quality and Elevated Blood Pressure in Adolescents
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Childhood hypertension is a risk factor for adult hypertension
and for target-organ damage. Early recognition and intervention
of childhood hypertension are believed to be important in reducing
the risk of cardiovascular morbidity in adulthood. Traditional
approaches for intervention focus on the role of overweight
as a contributing cause of hypertension and include weight reduction,
increased physical activity, and nutritional changes. The present
report identifies a significant association between increased
blood pressure and poor sleep quality (ie, increased wake time
during the sleep period), found in 26% of a community sample
of adolescents. Independent of obesity, sex, and socioeconomic
status and unrelated to sleep apnea, adolescents with poor sleep
had a 3.5-fold increased risk of prehypertension or hypertension.
This finding suggests that approaches for optimizing sleep quality
and duration in children may complement other behavioral approaches
for preventing or treating pediatric hypertension. Monitoring
sleep quality and duration in children as part of their health
supervision may help to identify children who are at risk for
both sleep problems and hypertension and who would benefit from
behavioral interventions aimed at improving sleep. See p
1034.
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Pilot Study to Assess the Influence of β-Blockade on Mitral Regurgitant Volume and Left Ventricular Work in Degenerative Mitral Valve Disease
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Mitral valve regurgitation increases left ventricular (LV) stroke
volume. Over time, the resulting increase in LV work may cause
progressive LV dysfunction, which may be difficult to detect
clinically. A medical treatment that decreased this risk would
be beneficial. This pilot study determined the short-term effects
of a β
1-adrenergic receptor blocker on mitral regurgitant
volume and LV work in 25 patients with moderate to severe mitral
regurgitation caused by primary degenerative disease of the
mitral valve. Participants were randomized to both metoprolol
and placebo for
14 days using a double-blind crossover study
design. At the end of each treatment period, forward stroke
volume and LV stroke volume were measured by cardiac magnetic
resonance imaging, and mitral regurgitant volume and LV work
were calculated. On β-blocker compared with placebo, no
change was observed in mitral regurgitant volume but a small
increase was found in forward stroke volume. Because the β-blocker
decreased heart rate, cardiac output was lower. However, the
decrease in LV volume pumped per minute was about twice as large
as the decrease in forward cardiac output, and LV work was
20%
lower on metoprolol. These observations suggest that in patients
with degenerative mitral regurgitation, long-term treatment
with a β-blocker may, by decreasing LV work, reduce the
risk of progressive LV dysfunction. A large clinical trial is
needed to confirm this hypothesis. See p
1041.
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