Circulation. 2008;117:589-591
doi: 10.1161/CIRCULATIONAHA.107.188519
(Circulation. 2008;117:589-591.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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How Much of the Recent Decline in the Incidence of Myocardial Infarction in British Men Can Be Explained by Changes in Cardiovascular Risk Factors? Evidence From a Prospective Population-Based Study
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The incidence of myocardial infarction (MI) in Britain has been
falling since the 1970s. We have estimated that after adjustment
for age, the incidence of first MI declined by 62% from 1979
to 2004 in a representative cohort of middle-aged British men.
Few studies have investigated the contribution of changes in
major cardiovascular risk factors to the decline in MI. Combining
data on risk factor changes with data on MI incidence, we found
that approximately half of the decline in MI incidence in this
cohort of men could be explained by favorable population-wide
time trends in cigarette smoking, systolic blood pressure, high-density
lipoprotein (HDL) cholesterol, and non-HDL cholesterol together.
A large fall in cigarette smoking prevalence explained the greatest
single part of the decline (23%), followed by a fall in mean
systolic blood pressure (13%), a rise in HDL cholesterol (12%),
and a fall in non-HDL cholesterol (10%); however, these contributions
may be underestimated owing to imprecision. A marked increase
in mean body mass index is likely to have limited the extent
of the decline. The results indicate that population-wide changes
in risk factors have considerable potential for reducing MI
incidence in the United Kingdom and in other locations. In the
United Kingdom, although the future impact of smoking changes
may be limited by the already low smoking prevalence, the potential
benefits of further reductions in population systolic blood
pressure and blood lipid levels, by a combination of dietary
and drug management, are still considerable. See p
598.
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Pericardial Fat, Visceral Abdominal Fat, Cardiovascular Disease Risk Factors, and Vascular Calcification in a Community-Based Sample: The Framingham Heart Study
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Pericardial fat may be an important mediator of metabolic risk.
Correlations with cardiovascular disease risk factors and vascular
calcification in a community-based sample are lacking. We sought
to examine associations between pericardial fat, metabolic risk
factors, and vascular calcification. Participants from the Framingham
Heart Study underwent quantification of intrathoracic fat, pericardial
fat, visceral abdominal fat, and coronary artery and aortic
artery calcification. Intrathoracic and pericardial fat were
directly correlated with body mass index and visceral abdominal
fat. Both intrathoracic and pericardial fat were associated
with higher triglycerides, lower high-density lipoprotein, hypertension,
impaired fasting glucose, diabetes mellitus, and metabolic syndrome
after multivariable adjustment. Associations generally persisted
after additional adjustment for body mass index and waist circumference
but not after adjustment for visceral abdominal fat. Pericardial
fat, but not intrathoracic fat, was associated with coronary
artery calcification, whereas intrathoracic fat, but not pericardial
fat, was associated with aortic artery calcification. Pericardial
fat is correlated with multiple measures of adiposity and cardiovascular
disease risk factors, but visceral abdominal fat is a stronger
correlate of most metabolic risk factors. However, intrathoracic
and pericardial fat are associated with vascular calcification,
which suggests that these fat depots may exert local toxic effects
on the vasculature. See p
605.
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Exercise Capacity and Mortality in Black and White Men
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The findings of the present study reinforce the concept that
the fitness status of an individual is inversely and strongly
related to mortality in individuals with and without cardiovascular
disease, regardless of factors related to socioeconomic strata.
The gradient for a reduction in mortality with increasing fitness
was similar in blacks and whites. Specifically, mortality was
13% lower for every 1-MET increase in exercise capacity and
50% lower for both blacks and whites who achieved a moderate
exercise capacity (7 to 10 metabolic equivalents [METs]) compared
with those who achieved a poor exercise capacity (<5 METs)
regardless of cardiovascular disease status. Because exercise
capacity as assessed by an exercise test is a standardized procedure
used throughout the world, inferences can be made for the many
patients undergoing this procedure. The prognostic power of
exercise capacity applies equally to blacks and whites and to
those with and without cardiovascular disease. It also expands
the clinical applications of the relationship between fitness
and mortality to patients treated with β-blockers. Collectively,
the results of the present and other recent studies support
the concept that exercise capacity should be given as much attention
by clinicians as other major risk factors. See p
614.
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Effect of Board Certification on Antihypertensive Treatment Intensification in Patients With Diabetes Mellitus
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Hypertension is the most common treatable cardiovascular risk
factor. Nevertheless, blood pressure of most patients with hypertension
remains above recommended treatment targets. The reasons for
this are not fully understood, but low frequency of antihypertensive
treatment intensification is thought to be a contributing factor.
The low frequency of treatment intensification may be due to
physicians’ lack of knowledge about treatment goals. Board
certification status is commonly regarded as an indicator of
the physician’s fund of knowledge. Recertification every
10 years is required for internists to maintain certification,
but it is unknown whether physicians whose last certification
was more than a decade ago are less likely to practice consistently
with guidelines. We conducted a retrospective cohort study of
8127 hypertensive diabetic patients to determine the relationship
between the time since their internist’s last board certification
and the frequency with which their internist intensified antihypertensive
treatment in response to elevated blood pressure. Frequency
of treatment intensification decreased progressively from 26.7%
for physicians who were board certified the previous year to
6.9% for physicians who were board certified 31 years before
the visit. The treatment intensification rate was 22.5% for
physicians certified
10 years ago versus 16.9% for physicians
last certified >10 years ago. Multivariable analysis adjusted
for patient and visit characteristics and physician age showed
that for every decade since the physician’s last board
certification, the probability of treatment intensification
decreased by 21.3%. These findings support the current policy
of mandatory recertification. See p
623.
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Performance of Delayed-Enhancement Magnetic Resonance Imaging With Gadoversetamide Contrast for the Detection and Assessment of Myocardial Infarction: An International, Multicenter, Double-Blinded, Randomized Trial
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The identification and assessment of myocardial infarction (MI)
are important for therapeutic and prognostic purposes, yet the
current tools for diagnosing MI, which is based fundamentally
on cardiac enzymes and the ECG, have significant limitations.
For instance, cardiac enzymes are insensitive for infarcts more
than a few days old, do not provide information on infarct location,
and are only moderately accurate in determining infarct size.
Likewise, the ECG is insensitive for non–Q-wave infarcts,
and specificity may be poor in the setting of other cardiopulmonary
disorders. In this study, we used delayed-enhancement magnetic
resonance imaging (MRI) with various doses of gadoversetamide
contrast to diagnose and assess infarction in 566 patients with
either acute or chronic MI. The study involved 26 centers throughout
the United States, Europe, and South America. We observed that
the sensitivity of MRI for detecting MI increased with rising
dose of gadoversetamide, reaching 99% in patients with acute
MI and 94% in those with chronic MI. For gadoversetamide doses
of
0.2 mmol/kg, when MI was identified, it was localized to
the correct part of the heart in >97% of patients; ie, it
matched the perfusion territory of the coronary artery that
was occluded by x-ray angiography. Thus, the results indicate
that delayed-enhancement MRI with gadoversetamide doses of
0.2
mmol/kg is effective in the diagnosis of both acute and chronic
MI. This study may have implications for patients who present
with clinical symptoms or signs that suggest prior MI but in
whom cardiac enzymes and the ECG are negative or equivocal.
See p
629.
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Impact of Salusin- and -β on Human Macrophage Foam Cell Formation and Coronary Atherosclerosis
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Human salusin-
and -β are peptides processed from the same
precursor peptide, prosalusin. The present study examined the
potential roles of these peptides in atherosclerosis. Early
events of atherosclerosis (foam cell formation) were oppositely
influenced by salusin-
and -β with in vitro assays of primary
human monocyte-derived macrophages. Salusin-
suppressed foam
cell formation via downregulation of acyl-coenzyme A:cholesterol
acyltransferase-1 (ACAT-1), whereas salusin-β upregulated
ACAT-1 to enhance foam cell formation. The in vitro observations
have clinical relevance in that immunoreactive salusin-
and
-β were detected in human coronary atherosclerotic plaques,
with dominance of salusin-β in vascular smooth muscle cells
and fibroblasts. Serum salusin-
levels were decreased in 173
patients with angiographically proven coronary artery disease
compared with 40 patients with mild hypertension and 55 healthy
volunteers (4.9±0.6 versus 15.4±1.1 and 20.7±1.5
pmol/L, respectively;
P<0.0001). Furthermore, in 60 patients
with acute coronary syndrome, serum salusin-
levels were decreased
in accordance with the severity of coronary atherosclerotic
lesions. These data suggest that salusin-β may contribute
to the pathogenesis of atherosclerosis. Salusin-
could be a
candidate biomarker for atherosclerosis and a therapeutic target
for the prevention of atherosclerotic cardiovascular diseases.
Prospective studies of salusins that examine relationships with
other risk factors and outcomes over time may be warranted.
See p
638.
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Fetal Hemodynamic Adaptive Changes Related to Intrauterine Growth: The Generation R Study
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It has been suggested that an adverse human fetal environment
increases susceptibility to hypertension and cardiovascular
disease in adult life. This increased risk may result from suboptimal
development of the heart and main arteries in utero and to adaptive
cardiovascular changes in reduced fetal growth. In this population-based
study, we found that cardiovascular performance in reduced fetal
growth is consistent with an increase in afterload and increased
end-diastolic ventricular filling pressure. Furthermore, cardiac
and arterial compliance are compromised with diminished fetal
growth. These adaptive fetal hemodynamic changes occur before
the stage of clinically apparent fetal growth restriction. These
fetal circulation alterations may contribute to intrauterine
programming for adult cardiovascular disease. Follow-up studies
in children in the present study are currently being performed
to examine whether and to what extent changes in fetal circulation
hemodynamics persist during childhood and whether they are related
to cardiac function and blood pressure in later life. This may
provide more insight into the origins of cardiovascular disease,
perhaps allowing for the development of screening tests and
customized fetal interventions. See p
649.
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Critical Role of Donor Tissue Expression of Programmed Death Ligand-1 in Regulating Cardiac Allograft Rejection and Vasculopathy
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Chronic allograft vasculopathy is characterized by the gradual
occlusion of arteries within a transplanted organ and is caused
by an ongoing immune response against the allograft. It is also
the hallmark of chronic rejection, a leading cause of loss of
function of transplanted hearts and all other solid-organ transplants.
This immune response is orchestrated by T lymphocytes. In recent
years, we have learned more about the pathways that control
the activation of T cells, and a number of positive, and more
recently negative, costimulatory pathways have been characterized.
The PD1-PDL1 (programmed death-1–programmed death ligand-1)
pathway is now recognized as an important negative costimulatory
pathway capable of downregulating an aggressive T-cell response.
Manipulation of T-cell costimulatory pathways has been shown
to be an effective means of reducing T-cell activation and inducing
immune tolerance to transplanted organs. PDL1 is expressed not
only on circulating bone marrow–derived cells but also
on tissue parenchyma, which leads to the intriguing possibility
that the modification of donor tissue expression of PDL1 might
influence graft survival. The present study confirms this idea
by showing that the absence of donor tissue expression of PDL1
accelerates transplant rejection in a mouse cardiac transplantation
model. The corollary to this would be that an increase of expression
of PDL1 on donor tissue might be able to dampen the immune response
against the transplanted organ. Targeting of PDL1 could be achieved
by gene therapy or by the use of drugs that upregulate expression
of this molecule and is attractive because it avoids the need
for treatment of the recipient, with all the concomitant nonspecific
consequences. See p
660.
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Hypoxic Modulation of Exogenous Nitrite-Induced Vasodilation in Humans
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Advances in cardiovascular treatment could be made through the
understanding and utilization of nitrite as a stable store of
transported nitric oxide, allowing the targeted delivery of
nitric oxide precisely where it is needed, both physiologically
and therapeutically. Data are presented that demonstrate that
nitrite-induced vasodilation in humans is a function of ambient
oxygen tension. Subjects received intrabrachial sodium nitrite
while breathing either room air or 12% oxygen. During normoxia,
the nitrite infusion had modest effects in resistance vessels
but caused a significant vasodilation in the relatively hypoxic
capacitance bed. However, when the oxygen tension in the resistance
vessels decreased because the subjects were breathing 12% oxygen,
nitrite caused a marked dilatation in this bed. Nitrite has
been shown to decrease infarct size by up to 50% in a canine
model of myocardial infarction. Studies are under way to ascertain
whether nitrite is as potent in reducing myocardial damage in
humans. Similarly, nitrite has been shown to mitigate ischemia-reperfusion
injury of the brain, kidney, and liver. The present findings
suggest that nitrite may play a role in the physiological defense
against ischemia. This mechanism lends itself to therapeutic
exploitation in clinical scenarios such as acute coronary syndromes
in which critical ischemia is the primary underlying pathology.
This mechanism potentially may also be used in the treatment
of acute decompensated heart failure. The use of a selective
venodilator could avoid the deleterious hypotensive effects
of current vasodilators that cause a significant degree of arterial
vasodilation. See p
670.
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Endothelial Lipase Is Increased In Vivo by Inflammation in Humans
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Endothelial lipase (EL) is an enzyme unique in its expression
by endothelial cells. In murine models of atherosclerosis, it
has been shown to significantly influence high-density lipoprotein
(HDL) cholesterol levels. Reports in primarily healthy humans
have shown much more modest effects of EL on HDL levels. We
had previously reported that plasma EL concentrations increased
in a linear fashion with increasing numbers of metabolic syndrome
factors. In this report, we examined the possibility that EL
may be a significant factor contributing to low HDL levels in
metabolic syndrome. We found that EL is directly associated
with levels of the proinflammatory adipokines interleukin-6,
tumor necrosis factor receptor II, C-reactive protein, intracellular
adhesion molecule-1, and leptin but inversely associated with
adiponectin, an antiinflammatory and glucose-sensitizing adipokine
that decreases with increasing adiposity. This finding suggests
that EL is part of the proinflammatory milieu present in individuals
with metabolic syndrome. This possibility is further supported
by the increase in EL plasma concentrations and corresponding
decrease in HDL phospholipid found in response to low-dose lipopolysaccharide
injection of healthy volunteers. Activated endothelium is a
key process contributing to cholesterol plaque deposition in
the vascular wall. Cholesterol deposition across the endothelium
is impeded by HDL through the process of reverse cholesterol
transport. Activation of the endothelium results in an increase
in EL on the surface of the vasculature, which may promote HDL
catabolism and decrease reverse cholesterol transport. Weight
loss can be predicted to decrease EL levels and may increase
HDL levels. See p
678.
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