Circulation. 2008;118:1605-1606
doi: 10.1161/CIRCULATIONAHA.108.191122
(Circulation. 2008;118:1605-1606.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Atrial Fibrillation After Isolated Coronary Surgery Affects Late Survival
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Atrial fibrillation (AF) is the most common arrhythmia in the
general population and a frequent postoperative complication
of cardiac surgery. AF is now widely recognized as a risk factor
for stroke and other thromboembolic complications and heart
failure. This leads to a substantial disease burden and significant
medical costs. Although many studies have examined the impact
of AF on the perioperative period, none has managed to present
compelling data that support an independent association between
postoperative AF and late mortality. Despite attempts to account
for confounding, it remains a distinct possibility that AF is
as associated with mortality as with potentially fatal comorbidities.
Previously published studies have not provided plausible direct
mechanisms that link postoperative AF with late mortality. In
addition, the causes of death have not been investigated. In
this study, we aimed to ascertain the impact of AF after coronary
surgery on postoperative survival, assessing its prognostic
role on cause-specific mortality. Our data have given perspective
on the possible role of AF among these patients and the effect
of embolic events in causing mortality. See p
1612.
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Milrinone Use Is Associated With Postoperative Atrial Fibrillation After Cardiac Surgery
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Approximately 500 000 patients undergo cardiac surgery in the
United States each year. Postoperative atrial fibrillation is
a common complication after surgery that causes morbidity and
prolongs hospitalization. Milrinone use on the day of surgery
was associated with an increased risk of postoperative atrial
fibrillation even after controlling for other risk factors such
as age, ejection fraction, and increased pulmonary artery pressure.
These findings have clinical and financial implications. Milrinone
was administered in 35% of patients in this single-center study.
On the basis of the incidence of postoperative atrial fibrillation
in the milrinone-treated versus nonexposed patients, similar
rates of milrinone use nationally could result in an excess
of 56 000 cases of postoperative atrial fibrillation per year,
with an attendant excess in postoperative stroke and prolongation
of hospital stay. Randomized, prospective studies are needed
to assess further the risk of postoperative atrial fibrillation
associated with milrinone use. See p
1619.
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Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38
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Patients with diabetes mellitus (DM) are at high risk for recurrent
cardiovascular events after acute coronary syndrome, in part
because of increased platelet reactivity. Patients with DM have
also been reported to be more likely to have a poor antiplatelet
response to clopidogrel. The Trial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet Inhibition With
Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI
38) demonstrated an overall 19% reduction in ischemic events
with more intensive antiplatelet therapy with prasugrel compared
with clopidogrel, but with more bleeding. Of 13/608 subjects,
3146 had a history of DM. We observed that, despite modern therapy
including coronary intervention, DM had an independent adverse
effect on clinical outcomes. Moreover, we found that prasugrel
was especially efficacious in patients with DM. Although key
ischemic end points including the primary end point were significantly
reduced among both patients with and without DM, greater absolute
and relative reductions were seen in favor of prasugrel among
subjects with DM, driven by a 5% absolute and 40% relative reduction
in MI. No difference in TIMI major bleeding was observed in
patients with DM, whereas a significant increase was observed
in patients without DM. Combining safety and efficacy, prasugrel
showed a net clinical benefit that was greater for patients
with DM (26%) than without DM (8%). These data have implications
for the potential use of prasugrel but also in a broader sense
underscore the importance of intensive antiplatelet therapy
for the growing population of patients with DM and acute coronary
syndrome. See p
1626.
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Does Obesity Modify the Effect of Blood Pressure on the Risk of Cardiovascular Disease? A Population-Based Cohort Study of More Than One Million Swedish Men
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Some studies have suggested that increased blood pressure has
a stronger effect on the risk of cardiovascular disease in lean
than in obese persons, although this is not a universal finding.
In a very large population-based cohort study of >1 million
Swedish men, which accumulated 65 611 new cardiovascular disease
events during follow-up, we have been able to analyze this unresolved
research question with greater precision than has been possible
previously. Hazard ratios per 1-SD increase in blood pressure
were computed within established categories of body mass index
(underweight, normal weight, overweight, or obese) with Cox
proportional hazards models. In contrast to the hypothesis,
the strongest associations of diastolic blood pressure with
cardiovascular disease (hazard ratio 1.18), myocardial infarction
(hazard ratio 1.22), and stroke (hazard ratio 1.13) were in
fact observed in the obese category. Similar results were apparent
for systolic blood pressure. Our results suggest that raised
blood pressure should be regarded as an equally important risk
factor for cardiovascular disease in both obese individuals
and normal-weight and underweight persons. See p
1637.
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Serum Potassium and Clinical Outcomes in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
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Aldosterone blockade is effective in reducing all-cause mortality
in patients after myocardial infarction complicated by left
ventricular dysfunction and heart failure. The use of aldosterone
blockade in these patients has been recognized as a class 1
indication in both US and European guidelines; however, many
clinicians have been reluctant to adopt this strategy because
of the fear of inducing serious hyperkalemia (K
+ 
6.0 mEq/L).
We analyzed the relationship between serum K
+ and clinical outcomes
in the Eplerenone Post–Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study (EPHESUS) and found a 1.6%
absolute increase in serious hyperkalemia and a 4.7% absolute
decrease in hypokalemia (K
+ <3.5 mEq/L). The baseline predictors
of serious hyperkalemia were a K
+ level >4.3 mEq/L; an estimated
glomerular filtration rate
60 mL · min
–1 ·
1.73 m
–2; a history of diabetes mellitus; and prior use
of antiarrhythmic agents. No relationship was found between
either baseline serum K
+ or change in serum K
+ from baseline
and the benefit of eplerenone on all-cause mortality, even in
those at risk of developing hyperkalemia. These data support
the further use of aldosterone blockade with eplerenone at a
dose of 25 to 50 mg/d early after myocardial infarction in patients
with left ventricular dysfunction and heart failure who are
treated with standard therapy when periodic monitoring of serum
K
+ is instituted and when patients with a baseline serum K
+ level >5.0 mEq/L, a creatinine level >2.5 mg/dL, or an
estimated glomerular filtration rate <30 mL · min
–1 · 1.73 m
–2 are excluded. See p
1643.
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Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility
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Congestive heart failure is a major cause of morbidity and mortality
despite recent advances in medical therapy. The most commonly
used positive inotropes, β-adrenergic agonists and phosphodiesterase
inhibitors, exert their positive inotropic effects by stimulating
the cAMP–protein kinase A pathway in the myocardium. These
agents provide rapid and dramatic improvements in cardiac performance,
producing immediate relief of heart failure symptoms. However,
the prolonged use of these agents may lead to serious adverse
cardiac effects. Therefore, an urgent need exists to identify
novel signaling mechanisms regulating cardiac contractility.
This report demonstrates the functional importance of 2 members
of the mitogen-activated protein kinase (MAPK) family, extracellular
signal-regulated kinase 1/2 (ERK1/2) and p38-MAPK, in the acute
regulation of cardiac contractility in the intact adult rat
heart. Our results reveal that MAPKs play opposing roles in
that the ERK1/2-mediated positive inotropic response to endothelin-1
is counterbalanced by simultaneous activation of p38-MAPK. Moreover,
our data suggest that inhibition of p38-MAPK may enhance contractility
by suppressing the function of phospholamban, the inhibitory
protein for the sarcoplasmic reticulum Ca
2+ pump. ERK1/2 signaling
has been reported to confer protection against stress-induced
myocyte apoptosis. A signaling pathway that promotes cardiomyocyte
survival while improving contractile function may offer an attractive
approach for treating patients with heart failure. Therefore,
further studies are required to test the hypothesis that activation
of ERK1/2 signaling can eventually rescue the failing heart.
See p
1651.
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Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age: Results From a Large Family Cohort Study
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Hereditary deficiency of protein S, protein C, or antithrombin
is among the most potent risk factors for venous thromboembolism.
Whether these deficiencies also are associated with arterial
thromboembolism (ATE) is controversial, whereas data increasingly
indicate that venous thromboembolism also may predispose for
subsequent ATE. Moreover, several studies reported a potential
association between major cardiovascular risk factors and venous
thromboembolism. In this family cohort study, we assessed the
risk of ATE conferred by protein S, protein C, or antithrombin
deficiency and investigated whether subjects with a history
of venous thromboembolism are at elevated risk for subsequent
ATE. Compared with nondeficient family members, subjects with
protein S or protein C deficiency had a 4.6- to 6.9-fold higher
risk for ATE before 55 years of age. After 55 years of age,
the risk for ATE in these subjects was similar to that in nondeficient
family members. In contrast, antithrombin deficiency was not
related to significantly higher risk for ATE either before or
after 55 years of age. Venous thromboembolism was not associated
with elevated risk for subsequent ATE. In thrombophilic families,
deficiency of protein S and protein C should be considered in
atherothrombotic risk assessment before 55 years of age. After
55 years of age, the risk of ATE is most likely overruled by
major cardiovascular risk factors (ie, hypertension, hyperlipidemia,
and smoking), and deficiency of protein S or protein C may not
have additional value in atherothrombotic risk assessment in
these families. See p
1659.
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Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility
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Does Obesity Modify the Effect of Blood Pressure on the Risk of Cardiovascular Disease?: A Population-Based Cohort Study of More Than One Million Swedish Men
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Atrial Fibrillation After Isolated Coronary Surgery Affects Late Survival
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Serum Potassium and Clinical Outcomes in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
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Milrinone Use Is Associated With Postoperative Atrial Fibrillation After Cardiac Surgery
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Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38
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