Circulation. 2008;117:987-989
doi: 10.1161/CIRCULATIONAHA.107.188522
(Circulation. 2008;117:987-989.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Prediction of the Localization of High-Risk Coronary Atherosclerotic Plaques on the Basis of Low Endothelial Shear Stress: An Intravascular Ultrasound and Histopathology Natural History Study
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The present study describes experiments in diabetic hyperlipidemic
swine capable of developing humanlike high-risk plaques (ie,
thin cap fibroatheromas). Local endothelial shear stress (ESS)
was calculated in vivo with the use of vascular profiling techniques
(intravascular ultrasound and coronary angiography) in plaque-free
subsegments of interest at baseline (week 23), and these subsegments
were analyzed histopathologically at follow-up (week 30), demonstrating
that (1) arterial subsegments with the lowest values of ESS
are those regions where high-risk plaques with large lipid core,
intensive inflammation, and thin fibrous cap will develop; (2)
the severity of high-risk plaque characteristics (ie, lipid
accumulation and inflammatory cell infiltration) is correlated
with the magnitude of low ESS; and (3) very low ESS induces
an intense inflammatory response that leads to severe internal
elastic lamina degradation and subsequent excessive expansive
remodeling (ie, excessive lumen and wall expansion). These wall
changes further reduce local ESS, establishing a cascade of
inflammation and excessive expansive remodeling, which can transform
an early atherosclerotic lesion into a high-risk plaque. These
findings indicate that application of vascular profiling methods
for the in vivo understanding of local ESS and vascular remodeling
response, which are responsible for individual plaque behavior
and natural history, may allow for detailed risk stratification
and identification of a high-risk plaque in its early stages
of development. Early in vivo identification of a high-risk
plaque may provide a rationale for highly selective, prophylactic
local coronary interventions (eg, implantation of stents), supplemented
by an intensive systemic pharmacological approach, to avert
a future acute coronary event. See p
993.
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Use of Alternative Thresholds Defining Insulin Resistance to Predict Incident Type 2 Diabetes Mellitus and Cardiovascular Disease
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In population-based studies, insulin resistance (IR) predicts
type 2 diabetes mellitus (DM) and cardiovascular disease (CVD)
and is commonly defined as the top 25% of the distribution of
surrogate IR measure, such as the homeostasis model assessment
of IR (HOMA-IR). The performance characteristics of surrogate
IR measures for DM or CVD prediction have not been assessed.
We assessed baseline IR using fasting insulin, HOMA-IR, and
the reciprocal of the Gutt insulin sensitivity index (ISI) among
2720 Framingham Offspring Study subjects followed up for 7 to
11 years for incident DM (130 cases) or CVD (235 cases) and
estimated test performance at 12 diagnostic thresholds (quantiles)
of IR measures. Risk for DM or CVD increased in relation to
IR quantiles, with no apparent 76th centile threshold effects;
risk gradients were greater for DM than for CVD prediction.
Surrogate IR measures demonstrated limited performance at this
centile, especially for CVD, and alternative thresholds improved
sensitivity or specificity at the cost of higher false-positive
or false-negative rates. HOMA-IR and 1/ISI had similar test
performance, and both measures outperformed fasting insulin
for DM prediction but were essentially equivalent with regard
to CVD prediction. The data suggest that in the community, HOMA-IR
may have value for DM prediction, with a positive likelihood
ratio of 3 and good discrimination for incident events, especially
in multivariate models. However, surrogate IR measures had limited
performance for CVD prediction, with a low positive likelihood
ratio gradient across quantiles and values for the area under
the receiver operating characteristic curve that were well below
those for the Framingham CHD risk score. See p
1003.
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Abdominal Aortic Aneurysms, Increasing Infrarenal Aortic Diameter, and Risk of Total Mortality and Incident Cardiovascular Disease Events: 10-Year Follow-Up Data From the Cardiovascular Health Study
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A 1-time ultrasound screening of the abdominal aorta over a
10-year follow-up may identify men and women over the age of
65 years who develop clinically significant abdominal aortic
aneurysms. Measuring the infrarenal abdominal aorta may help
clinicians identify patients who are at increased risk of future
cardiovascular disease events. The risk of future cardiovascular
disease events was increased even among individuals who were
65 years or older with an infrarenal aortic diameter between
2.0 and 3.0 cm compared with those who had infrarenal aortic
diameters <2.0 cm. Measurement of the infrarenal aortic diameter
with ultrasound may be another potential risk equivalent for
cardiovascular disease. See p
1010.
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Glucometrics in Patients Hospitalized With Acute Myocardial Infarction: Defining the Optimal Outcomes-Based Measure of Risk
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Hyperglycemia on admission is a known risk factor for death
in patients with acute myocardial infarction. Whether persistent
hyperglycemia during acute myocardial infarction hospitalization
is more prognostically important than admission hyperglycemia
has not been well defined. Furthermore, the best summary measure
of persistent hyperglycemia has not been developed. We evaluated
16 871 acute myocardial infarction patients who were hospitalized
in 40 US medical centers from January 2000 to December 2005
and had comprehensive laboratory data. The performance of 3
alternative glucose control metrics (mean glucose, time-averaged
glucose, and hyperglycemic index) was evaluated over 3 time
windows (the first 24 hours, the first 48 hours, and the entire
hospitalization) and compared with admission glucose for their
ability to predict in-hospital death. We found that all measures
of persistent hyperglycemia were better predictors of mortality
than admission glucose. There was no "critical time window"
that was most associated with death; glucose assessments over
the entire hospitalization were incrementally better than assessments
over shorter durations of time. Mean glucose was the most practical
summary metric of glucose control during acute myocardial infarction
given its ease of calculation. This simple metric could be used
routinely for prognosis and, if an intervention is demonstrated
to be prognostically beneficial, as a modifiable therapeutic
target. See p
1018.
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Prevalence, Predictors, and Outcomes of Primary Nonadherence After Acute Myocardial Infarction
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Primary nonadherence, which occurs when a patient does not fill
the first prescription written, is often overlooked as a potentially
significant contributor to failed or suboptimal therapy because
many clinicians assume that patients fill the prescriptions
written for them. For patients to benefit from preventive medications
after myocardial infarction (MI), it is essential that this
first prescription be filled. This population-based cohort study
of >4000 elderly patients used data from the Enhanced Feedback
for Effective Cardiac Treatment (EFFECT) MI clinical registry
from 1999 to 2001 linked to prescription drug claims administrative
data from Ontario, Canada, to determine the prevalence and predictors
of primary nonadherence after MI and to measure its associated
outcomes. We found that if patients are going to fill their
prescriptions, they do so promptly. In our study, patients filled
the vast majority of their discharge prescriptions within 1
week after MI, with cardiac prescriptions having a greater chance
of being filled than noncardiac prescriptions. However, 1 in
4 patients did not fill all of their discharge prescriptions
by 120 days after MI, and the 1-year mortality rate was significantly
higher for these patients. Those patients who filled all of
their discharge prescriptions were more likely to be younger,
to have a lower income, to have received discharge medication
counseling, to have a cardiologist as their in-hospital attending
physician, and to be taking fewer medications before MI. Recognizing
which factors in practice are likely to be associated with adherence
may assist with targeting potentially nonadherent patients and
developing interventions such as discharge medication counseling
and postdischarge follow-up to increase the initial filling
rate of medications after MI. See p
1028.
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Long-Term Benefit of Postconditioning
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Infarct size is a major determinant of prognosis after acute
myocardial infarction. Interventions aimed at reducing infarct
size may therefore be of major clinical interest. Experimental
and clinical reports indicate that reperfusion has deleterious
effects, including myocardial stunning, ventricular arrhythmias,
and no reflow. Zhao et al recently demonstrated in the dog model
that repetition of brief episodes of ischemia immediately at
the onset of reperfusion after a prolonged ischemic insult can
dramatically reduce infarct size. This phenomenon, termed postconditioning,
demonstrates the existence and the importance of reperfusion
necrosis. We previously showed that 4 episodes of ischemia/reperfusion
(1-minute inflation/1-minute deflation of the angioplasty balloon)
immediately after direct stenting of the occluded culprit coronary
artery reduced reperfusion release of total creatine kinase,
an estimate of infarct size, by 36%. However, widespread use
of postconditioning as an adjunct treatment targeting reperfusion
injury in patients with acute myocardial infarction requires
demonstration of a persistent clinical benefit. In the present
prospective randomized controlled trial, we addressed whether
postconditioning might (1) afford a sustained infarct size reduction
(
201thallium single photon emission computed tomography) and
(2) improve myocardial contractile function (echocardiography).
We report here that postconditioned patients exhibited a persistent
reduction of irreversible myocardial injury at 6 months after
acute myocardial infarction and an improvement of regional and
global left ventricular function at 1 year. Thus, targeting
lethal reperfusion injury by postconditioning provides persistent
clinical benefit to patients with acute myocardial infarction.
See p
1037.
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Endothelium-Specific GTP Cyclohydrolase I Overexpression Attenuates Blood Pressure Progression in Salt-Sensitive Low-Renin Hypertension
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Hypertension affects
25% of the adult population worldwide,
of whom
1 in 3 are salt sensitive. It is the major risk factor
for stroke and atherosclerosis. Endothelial dysfunction contributes
to hypertension pathogenesis, and a cardinal feature is the
loss of the protective actions of nitric oxide (NO). Recent
evidence indicates that endothelial NO synthase (eNOS) is a
bifunctional enzyme: When its essential cofactor, tetrahydrobiopterin
(BH4), is reduced by oxidative degradation, eNOS becomes "uncoupled"
to produce superoxide anion (O
2–) instead of NO. In this
way, eNOS uncoupling has a major impact on the redox state and
function of blood vessels. Low-renin deoxycorticosterone acetate
(DOCA)–salt hypertension exhibits typical eNOS uncoupling
with exaggerated vascular oxidative stress; however, the way
in which endogenous BH4 regulates blood pressure in vivo is
incompletely understood. In the present study, we found that
transgenic mice with endothelium-specific overexpression of
GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme for de
novo BH4 synthesis, had preserved arterial BH4 levels that retarded
eNOS uncoupling and hypertension despite DOCA-salt regimens.
In addition, endothelium-dependent NO-mediated relaxation and
vascular remodeling in resistance mesenteric arteries (tertiary
branch outside diameter of
100 µm), which critically regulate
total peripheral resistance, were largely protected through
adequate eNOS phosphorylation. Because BH4 is highly unstable
and easily oxidized (and thus not suitable for chronic oral
administration), our findings may provide a mechanistic basis
for augmentation of endogenous BH4 levels by targeting GTPCH
as a rational therapeutic strategy (eg, by statins and peroxisome
proliferator–activated receptor agonists) to recouple
eNOS and combat endothelial dysfunction in hypertension and
other cardiovascular diseases. See p
1045.
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Cardioprotective Function of the Long Pentraxin PTX3 in Acute Myocardial Infarction
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The short pentraxin C-reactive protein and the long pentraxin
PTX3 are markers of risk or severity in cardiovascular disorders.
However, the actual role of pentraxins in pathogenesis remains
unclear. Using gene-modified mice, we found that PTX3, highly
conserved between mouse and humans, has a regulatory function
in acute myocardial infarction. Thus, PTX3 is more than a marker
in cardiovascular pathology. See p
1055.
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Role of Caveolar Compartmentation in Endothelium-Derived Hyperpolarizing Factor–Mediated Relaxation: Ca2+ Signals and Gap Junction Function Are Regulated by Caveolin in Endothelial Cells
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The present study emphasizes the role played by caveolin-1 at
major steps of the endothelium-derived hyperpolarizing factor–related
signaling cascade. Our study expands our understanding of the
functions of TRPV4 channels in endothelial biology and raises
the possibility of targeting these specific channels to improve
vascular relaxation in the context of coronary or peripheral
ischemic diseases characterized by deficient endothelium-dependent
relaxation. The spread of endothelial hyperpolarization through
gap junctions is crucial to coordinate vascular relaxation along
the vessel wall. Our results highlight the existence of a caveolin-dependent
regulation of these gap junctions. In addition to facilitating
the compartmentation of signaling mediators within microdomains,
caveolin interactions may be keys for the backup role of endothelium-derived
hyperpolarizing factor in pathological conditions. Indeed, we
have previously demonstrated that high levels of low-density
lipoprotein cholesterol decrease nitric oxide production in
endothelial cells by upregulating caveolin-1 abundance and promoting
its inhibitory interaction with endothelial nitric oxide synthase.
Our present results suggest that crucial steps of endothelium-derived
hyperpolarizing factor signaling, that is, calcium influx through
TRPV4 and proper gap junction function, could be preserved or
even facilitated in such pathological conditions. See p
1065.
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Effects of Levosimendan on Left Ventricular Relaxation and Early Filling at Maintained Preload and Afterload Conditions After Aortic Valve Replacement for Aortic Stenosis
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Left ventricular (LV) systolic dysfunction often is accompanied
by impaired LV relaxation, ie, diastolic dysfunction. Levosimendan
enhances myocardial contractility through myofilament calcium
sensitization and offers new therapeutic possibilities in patients
with severe heart failure because of its combined inotropic
and vasodilatory effects. The effects of levosimendan on diastolic
function in humans, however, are not well understood, and results
from recent studies on the effects of levosimendan on diastolic
function in patients with severe heart failure and acute myocardial
infarction are not conclusive. In the present randomized, blinded,
placebo-controlled study, we evaluated the effects of levosimendan
versus placebo on LV early relaxation in patients with LV hypertrophy
and maintained systolic function in patients undergoing aortic
valve surgery for severe aortic stenosis. LV performance, dimensions,
and filling pattern, as well as systemic hemodynamics, were
assessed by transesophageal 2-dimensional Doppler echocardiography
and pulmonary artery catheterization. To circumvent the confounding
effects of the levosimendan-induced hemodynamic changes on Doppler
echocardiographic indexes of LV early relaxation, heart rate,
preload, and afterload were kept constant by atrial pacing,
by blood volume expansion with colloids, and by phenylephrine-induced
vasoconstriction, respectively. We could demonstrate that levosimendan
shortens LV isovolumic relaxation time and improves LV filling
early after valve replacement. We conclude that levosimendan,
in addition to its inotropic effects, exerts a direct positive
lusitropic effect in patients with LV hypertrophy and diastolic
dysfunction. See p
1075.
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Prediction of the Localization...
Use of Alternative Thresholds...