Circulation. 2008;118:2219-2220
doi: 10.1161/CIRCULATIONAHA.108.191128
(Circulation. 2008;118:2219-2220.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II
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Timothy syndrome (TS) is a genetic disorder causing excessive
cellular Ca
2+ entry resulting from defective voltage-dependent
inactivation of the predominant myocardial L-type Ca
2+ channel
(Ca
V1.2) current (I
Ca). TS patients die on average at 2.5 years
of age as a result of malignant cardiac arrhythmias. TS is a
"model" disease whereby a concise biophysical defect in I
Ca activates a cellular signaling cascade that is required for
the cardiac disease phenotypes. Our studies showed that loss
of voltage-dependent inactivation leads to cellular arrhythmias
by recruiting activity of the calmodulin-dependent protein kinase
II (CaMKII). The role of CaMKII was not anticipated by previous
computer models that relied on data obtained from nonexcitable,
heterologous cells. Our studies show that the TS voltage-dependent
inactivation defect activated CaMKII and that CaMKII was the
feed-forward signal required for the proarrhythmic cellular
phenotypes in TS. These findings have potentially broad implications
for other pathological phenotypes in TS such as autism and for
other genetic diseases affecting Ca
2+ channels such as migraine
headache, myasthenia, ataxia, and malignant hyperthermia. Diseases
associated with excitable cells in which ion channels frequently
constitute a final common pathway require careful consideration
of the connections between ion channel gating and signaling
cascades to more comprehensively understand the underlying mechanisms.
See p
2225.
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Association Between Intraoperative and Early Postoperative Glucose Levels and Adverse Outcomes After Complex Congenital Heart Surgery
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Hyperglycemia occurs commonly and has been associated with increased
morbidity and mortality in critically ill adults, including
those undergoing cardiac surgery. The use of insulin to achieve
strict glycemic control may improve outcomes in these patients.
The aim of this cohort study was to determine whether adjusted
associations exist between intraoperative or early postoperative
metrics of glucose control and longer hospitalization or adverse
outcomes after complex congenital heart surgery. After multivariate
analysis, we found that none of the intraoperative glucose variables
were associated with duration of hospitalization, but a minimum
glucose
75 mg/dL was associated with greater adjusted odds of
reaching the composite morbidity-mortality end point. Postoperatively,
greater duration of glucose levels >126 mg/dL during the
first 72 hours after surgery was associated with longer hospital
stay. Patients with average glucose levels <110 or >143
mg/dL, higher peak glucose levels, and lower minimum glucose
levels all have greater adjusted odds for reaching the composite
morbidity-mortality end point. Taken together, the associations
we found between the various metrics of glucose control and
adverse outcomes suggest that the ideal postoperative glucose
range after complex congenital heart surgery is 110 to 126 mg/dL,
which is higher than the target range that some experts recommend
for critically ill adults. The associations we identified between
various metrics of glucose control and the outcome measures
are insufficient to prove causality. Randomized controlled trials
are needed to determine whether achieving strict glycemic control
with an insulin infusion is beneficial for children recovering
from congenital heart surgery. See p
2235.
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C-Reactive Protein and Parental History Improve Global Cardiovascular Risk Prediction: The Reynolds Risk Score for Men
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High-sensitivity C-reactive protein and family history are independently
associated with cardiovascular events and have been incorporated
into risk prediction models for women (the Reynolds Risk Score
for women); however, no cardiovascular risk prediction algorithm
incorporating these variables exists for men. We assessed the
incremental benefit of adding high-sensitivity C-reactive protein
and parental history of premature atherosclerosis to the traditional
factors of age, blood pressure, smoking, and total and high-density
lipoprotein cholesterol in a prospective cohort of 10 724 initially
healthy nondiabetic men. Compared with the traditional model,
the Reynolds Risk Score had better global fit, a superior (lower)
Bayes information criterion, and a larger C-index. More importantly,
use of the Reynolds Risk Score for men reclassified 18% of the
study population (and 20% of those at intermediate risk) into
higher- or lower-risk categories, with markedly improved accuracy
among those reclassified. Thus, as previously shown in women,
a prediction model in men that incorporates high-sensitivity
C-reactive protein and parental history significantly improves
global cardiovascular risk prediction. User-friendly calculators
for the Reynolds Risk Scores for men and women can be freely
accessed at http://www.reynoldsriskscore.org. Beyond computation
of 10-year risk, this World Wide Web site also includes patient-centered
data on lifetime risk and provides estimates of risk reductions
that can be anticipated with the implementation of lifestyle
change, smoking cessation, blood pressure control, and lipid
reduction. Use of the Reynolds Risk Scores could allow more
accurate targeting of lipid-lowering therapy to those with the
most appropriate levels of risk, thus increasing its net benefit
and decreasing toxicity. See p
2243.
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Relations of Biomarkers Representing Distinct Biological Pathways to Left Ventricular Geometry
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Several biological processes have been individually implicated
in left ventricular (LV) remodeling, but the relative contributions
of these pathways are unclear. Such knowledge would be useful
because LV remodeling precedes and predicts cardiovascular morbidity
and mortality, and biological insights may aid risk stratification,
elucidate therapeutic targets, or both. We used a multimarker
strategy, which permitted a comparison of several biomarkers
in relation to their contributions to LV remodeling while limiting
multiple testing, to relate 6 biomarkers representing inflammation
(C-reactive protein), hemostasis (fibrinogen and plasminogen
activator inhibitor-1), neuroendocrine activation (B-type natriuretic
peptide), and the renin-angiotensin-aldosterone system (aldosterone
to renin ratio) to the 4 mutually exclusive patterns of LV geometry
(ie, concentric remodeling, eccentric hypertrophy, concentric
hypertrophy, and normal geometry). We performed this analysis
in a large cohort of free-living individuals without prevalent
cardiovascular disease. In age- and sex-adjusted models, we
observed that all biomarkers were strongly and positively related
to altered LV geometry, specifically to eccentric and concentric
hypertrophy. In multivariable models, aldosterone to renin ratio
emerged as the major correlate of LV geometry, with strong positive
associations with both eccentric and concentric hypertrophy.
Our observations are consistent with a fundamental role for
the renin-angiotensin-aldosterone system in influencing LV remodeling
in the community in individuals free of overt cardiovascular
disease. See p
2252.
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Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
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Hypertension remains the greatest population-attributable risk
for developing heart failure. In the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT) of 42 418 high-risk
hypertensive patients, 1367 developed heart failure during follow-up.
Of 910 with an estimate of left ventricular ejection fraction,
44% and 56% had preserved (ejection fraction
50%) and reduced
ejection fraction, respectively. Mortality risk after heart
failure onset was greatly increased in both the preserved and
reduced ejection fraction groups compared with those who did
not manifest heart failure, and heart failure patients with
preserved ejection fraction had a lower case fatality rate than
those with reduced ejection fraction. Compared with amlodipine
and doxazosin, chlorthalidone reduced the incidence of heart
failure with reduced and preserved ejection fraction; compared
with lisinopril, chlorthalidone reduced the incidence of heart
failure with preserved ejection fraction. See p
2259.
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Novel Cardiac Apoptotic Pathway: The Dephosphorylation of Apoptosis Repressor With Caspase Recruitment Domain by Calcineurin
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Heart failure is a leading cause of mortality worldwide. The
β-adrenergic receptor system is broadly involved in growth
control and apoptosis. Many clinical trials have indicated that
β-adrenergic receptor blockers significantly improve survival
rates in patients with heart failure by decreasing cardiac remodeling.
The β-adrenergic receptor agonist isoproterenol promotes
cardiac dysfunction resulting from cardiac remodeling, including
apoptosis. Aldosterone has recently attracted considerable attention
for its involvement in the pathophysiology of heart failure.
A study performed in patients with cardiac failure shows a significant
reduction in morbidity and mortality with the use of the aldosterone
antagonists spironolactone or eplerenone in the therapy. Hitherto,
the molecular mechanisms by which isoproterenol or aldosterone
induce cardiac apoptosis have not been fully elucidated. Apoptosis
repressor with caspase recruitment domain (ARC) is a cardiac-abundant
antiapoptotic protein. Its antiapoptotic function is dependent
on threonine-149 phosphorylation by protein kinase CK2. The
present study reveals that isoproterenol and aldosterone are
able to induce ARC dephosphorylation through calcineurin, thereby
leading to the inability of ARC to antagonize apoptosis. These
data suggest that the dephosphorylation of ARC by calcineurin
may constitute an apoptotic pathway in the heart. The present
study can provide information for exploring the beneficial effects
of this cardiac-abundant protein on apoptosis-related cardiac
diseases such as heart failure. See p
2268.
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Drug-Eluting or Bare-Metal Stenting in Patients With Diabetes Mellitus: Results From the Massachusetts Data Analysis Center Registry
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Patients with diabetes mellitus are at high risk for restenosis,
myocardial infarction, and cardiac mortality after coronary
stenting. In randomized comparisons, drug-eluting stents (DES)
have reduced restenosis relative to bare-metal stents (BMS);
however, data on the long-term outcomes of DES in diabetes mellitus
are conflicting. This population-based study prospectively collected
clinical and procedural data on all diabetic patients who underwent
percutaneous coronary intervention with stents from April 1,
2003, through September 30, 2004, at all nonfederal hospitals
in Massachusetts. The aim of the study was to evaluate the long-term
safety of DES versus BMS specifically in patients with diabetes
mellitus from a contemporary US population. Rates of mortality,
myocardial infarction, and repeat revascularization procedures
were ascertained over the 3 years after stent placement. Propensity-score–matched
analysis was performed to compare DES- and BMS-treated patients
because the choice of stent was not randomly assigned. Diabetes
mellitus was present in 5051 patients (29% of the overall population)
treated with DES or BMS during the study. Sixty-six percent
of patients with diabetes mellitus received DES compared with
34% who received BMS. In the 1:1–matched DES versus BMS
patients, the risk-adjusted mortality, myocardial infarction,
and target vessel revascularization rates at 3 years were lower
in the diabetic patients treated with DES compared with BMS.
The results of this large population-based study suggest that
DES are safe and effective in patients with diabetes mellitus
undergoing percutaneous coronary intervention with stenting
in long-term follow-up. See p
2277.
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