Circulation. 2008;117:2309-2310
doi: 10.1161/CIRCULATIONAHA.107.189680
(Circulation. 2008;117:2309-2310.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Depressive Symptoms and the Risk of Atherosclerotic Progression Among Patients With Coronary Artery Bypass Grafts
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Depression and depressive symptoms are highly prevalent among
patients with coronary artery disease and independently predict
adverse cardiovascular events. Several mechanisms have been
proposed to explain this association, including decreased adherence
to treatment and increased prevalence of unfavorable lifestyle
characteristics, among others; however, few studies have investigated
the potential link between depressive symptoms and progression
of atherosclerosis. Accordingly, we evaluated the hypothesis
that depressive symptoms are associated with progression of
atherosclerosis among individuals with previous coronary artery
bypass graft surgery and saphenous vein grafts enrolled in the
Post-CABG Trial. Depressive symptoms over the previous week
were assessed at trial enrollment, and quantitative coronary
angiography was conducted at enrollment and 4 to 5 years later.
We found that the presence of depressive symptoms was associated
with a higher risk of substantial progression of saphenous vein
graft atherosclerosis and a decrease in minimum lumen diameter
and that this association was virtually eliminated by random
assignment to aggressive lipid lowering with high-dose lovastatin.
Our analysis provides prospective evidence for a direct association
between depressive symptoms and atherosclerotic progression
as a potential mechanism for the corresponding association of
depressive symptoms with clinical prognosis. See p
2313.
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Prevalence, Predictors, and Prognostic Value of Renal Dysfunction in Adults With Congenital Heart Disease
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The prognosis of adults with congenital heart disease is importantly
influenced by noncardiac comorbidities. In this study on 1102
adult patients with congenital heart disease from a single specialist
center, renal dysfunction was found to be a common complication
of congenital heart disease, with 41% of patients having mild
and 9% having moderate or severe reduction in glomerular filtration
rate. Renal dysfunction was also found to be a strong predictor
of survival, with a 3-fold adjusted increase in mortality in
patients with moderately or severely impaired renal function.
These data support routine, periodic screening of renal function
in all adult patients with congenital heart disease to obtain
broader prognostic information. See p
2320.
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Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart
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Cardiac myocytes respond to mechanical stress and neurohumoral
factors by undergoing a hypertrophic response. Although some
of this hypertrophy is adaptive, much of it is maladaptive and
can ultimately result in cardiac failure. On the other hand,
apart from acting as circulating hormones, atrial natriuretic
peptide and brain natriuretic peptide have some functionality
as autocrine and/or paracrine factors. Recently, we reported
that in situ activation of cardiac guanylyl cyclase-A (GC-A),
a natriuretic peptide receptor, by locally secreted natriuretic
peptides protects the heart from cardiac hypertrophy by guanosine
3',5'-cyclic monophosphate-dependent protein kinase (PKG)–mediated
inhibition of calcineurin and its downstream mediator, nuclear
factor of activated T cells. However, the molecular mechanism
underlying GC-A–mediated inhibition of the calcineurin–nuclear
factor of activated T cells pathway remains to be elucidated.
GTPase-activating proteins for G
have recently been identified
and named regulator of G-protein signaling (RGS) proteins. In
the present study, we investigated the role of RGS in GC-A–mediated
inhibition of cardiac hypertrophy. Our findings indicate that
GC-A activates RGS4 via PKG in cardiac myocytes; this attenuates
G
q and downstream hypertrophic signaling. Nakayama et al previously
described a functional mutation in the 5'-flanking region of
the human GC-A gene that is associated with essential hypertension
and cardiac hypertrophy. GC-A gene expression is most likely
diminished in these patients because of the mutation, predisposing
them to cardiac hypertrophy similar to that seen in GC-A knockout
mice. In such patients, it is possible that inhibition of the
calcineurin–nuclear factor of activated T cells pathway
by RGS4 would be a useful treatment for the prevention of cardiac
remodeling. See p
2329.
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Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways
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Two therapeutic strategies based on potentiation of glucagon-like
peptide 1 action are now used to treat type 2 diabetes mellitus:
glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl
peptidase-4 (DPP-4) inhibitors. Most GLP-1R agonists under development
for the treatment of diabetes are resistant to cleavage by the
DPP-4 enzyme; many also exhibit structural differences relative
to native GLP-1 and hence may not give rise to GLP-1(9-36) in
vivo. Similarly, DPP-4 inhibitors, although enhancing the stability
of cardioprotective molecules such as SDF-1, prevent the enzymatic
cleavage of native GLP-1 to GLP-1(9-36). The data presented
here extend previous findings on the biology of GLP-1(9-36)
by demonstrating that this peptide metabolite exerts cardioprotective
actions in the murine heart. Moreover, these actions are independent
of the known GLP-1R, invoking a novel signaling mechanism for
the DPP-4–generated GLP-1 metabolite. These findings suggest
that GLP-1(9-36) itself may have therapeutic benefit in the
setting of cardiovascular injury, a hypothesis that can be tested
in future clinical studies. Moreover, the increasing complexity
of the cardiovascular actions of GLP-1 and its cardioactive
metabolite GLP-1(9-36) underscores the need for clinical studies
examining the cardiovascular actions of GLP-1R agonists and
DPP-4 inhibitors in subjects with type 2 diabetes. See p
2340.
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Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137): New Insights Into the Biology of Hydrogen Sulfide
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The potential biological and clinical significance of hydrogen
sulfide (H
2S) has been the subject of intense debate in recent
years. Despite considerable progress in our understanding of
this gas, much still needs to be learned. By analogy with other
gases (eg, nitric oxide, carbon monoxide), a better understanding
of the biological effects of H
2S would be expected by using
drugs with the ability to release this gas over extended periods
of time. Unfortunately, until now, no such drug has been available.
We report here that morpholin-4-IM4 methoxyphenyl(morpholino)
phosphinodithioate (GYY4137) is a water-soluble compound that
releases H
2S over the space of several hours. GYY4137 causes
slow dilation of blood vessels both in vitro and in vivo without
influencing vascular smooth muscle cell viability in culture.
When administered to conscious, spontaneously hypertensive rats,
GYY4137 lowered blood pressure without affecting heart rate
and without weight loss or other signs of toxicity. The vasodepressor
effect of GYY4137 was reversed when drug administration was
halted, and there was no rebound rise in blood pressure. We
believe that the slow release of H
2S from GYY4137 better mimics
the generation of this gas in vivo, and as such the spectrum
of activity of this compound provides a more accurate reflection
of the biological effects of this gas than has hitherto been
available. Moreover, the clear antihypertensive effect of GYY4137
raises the possibility that this compound, or a like slow-releasing
H
2S donor, may be of therapeutic benefit in clinical conditions
associated with excessive vasoconstriction. See p
2351.
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Changes in Insulin Resistance and Cardiovascular Risk During Adolescence: Establishment of Differential Risk in Males and Females
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The present study assessed changes in insulin resistance and
overall cardiovascular risk during the transition from late
childhood through adolescence (ie, age 11 to 19 years). During
these years, boys decreased their percentage of body fat and
become more lean and muscular, whereas girls gained body fat.
Insulin resistance at age 11 years was significantly lower in
boys but increased during adolescence, so that by age 19, boys
were more insulin resistant than girls. Over the same period,
triglycerides increased and high-density lipoprotein cholesterol
decreased in males, whereas the opposite pattern was seen in
females, and systolic blood pressure increased at a greater
rate in males. Total cholesterol and low-density lipoprotein
cholesterol changes did not differ between the sexes. Thus,
adolescence in males was associated with increased insulin resistance
despite decreased adiposity, as well as an increase in cardiovascular
risk. Because this was independent of adverse changes in low-density
lipoprotein and total cholesterol, it suggests that early development
of risk is related to insulin resistance. Although the cause
of these sex-related changes is not clear, it is possible that
the increased cardiovascular risk that emerges in males during
normal adolescence is related to hormonal differences between
the sexes. See p
2361.
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Both Intestinal and Hepatic Lipoprotein Production Are Stimulated by an Acute Elevation of Plasma Free Fatty Acids in Humans
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Dyslipidemia is a prominent feature of both insulin resistance
and type 2 diabetes mellitus and contributes to the increased
risk of cardiovascular events in these conditions. The typical
hypertriglyceridemia of insulin-resistant states has been determined
in numerous previous studies to be due predominantly to overproduction
of hepatic (apolipoprotein B-100–containing) very-low-density
lipoproteins, as well as impairment in the clearance of these
particles from the circulation. The mechanism of hepatic very-low-density
lipoprotein overproduction in insulin resistance is complex,
but elevated free fatty acid flux, predominantly from insulin-resistant
adipose tissue to the liver, is an important mechanism accounting
for this phenomenon. Recent studies in animal models of insulin
resistance and in humans have demonstrated that the production
rate of intestinal (apolipoprotein B-48–containing) chylomicrons
is also increased in insulin-resistant states. Intestinal chylomicron
production is stimulated mainly by fat ingestion, which is efficiently
absorbed from the intestinal lumen by the intestinal enterocyte
and packaged into chylomicron particles, which enter the circulation
via the lymphatic duct. Here we have shown, for the first time
in humans, that an acute elevation of plasma free fatty acids
stimulates not only hepatic but also intestinal triglyceride-rich
lipoprotein production. We speculate that chronic elevation
of plasma free fatty acids, as seen in insulin-resistant and
type 2 diabetic individuals, is likely to play an important
role in the overproduction of intestinal lipoproteins, thereby
contributing to the dyslipidemia of insulin-resistant humans.
See p
2369.
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Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E–Deficient Mice
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Epidemiological studies have shown that elevated heart rate
is a risk factor for cardiovascular morbidity. Experimental
data suggest that sustained elevations of heart rate may play
a role in the pathogenesis of coronary atherosclerosis. Ivabradine,
a selective inhibitor of the I
(f) channel, reduces resting and
exercise heart rates without an effect on cardiac contractility.
In the present study of apolipoprotein E–deficient mice
fed a high-cholesterol diet, ivabradine reduced heart rate without
affecting blood pressure or lipid levels. Endothelium-dependent
relaxation of aortic rings was significantly improved in ivabradine-fed
animals, and ivabradine decreased the development of atherosclerotic
lesions. The main underlying molecular observation was a potent
antioxidative effect of ivabradine that was mediated by the
reduction of heart rate. There was no evidence for a heart rate–independent
action of the drug. In summary, long-term heart rate reduction
by ivabradine leads to inhibition of vascular oxidative stress,
endothelial dysfunction, and atherosclerotic lesion formation
in apolipoprotein E–deficient mice, regardless of blood
pressure and plasma cholesterol levels. The experiments support
the potential of heart rate reduction as an intervention to
improve endothelial function and to attenuate progression of
atherosclerosis in vascular prevention in addition to the symptomatic
treatment of angina pectoris. Pharmacological inhibition of
the I
(f) current may represent a novel intervention to prevent
endothelial dysfunction that should be tested in a prospective
clinical investigation. See p
2377.
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