Circulation. 2008;117:2425-2427
doi: 10.1161/CIRCULATIONAHA.107.189727
(Circulation. 2008;117:2425-2427.)
© 2008 American Heart Association, Inc.
Clinical Summaries
 |
Selective Vacuolar Degeneration in Dystrophin-Deficient Canine Purkinje Fibers Despite Preservation of Dystrophin-Associated Proteins With Overexpression of Dp71
|
|---|
In Duchenne muscular dystrophy, a devastating skeletal and cardiac
muscle disorder caused by mutations in the dystrophin gene,
cardiac failure such as dilated cardiomyopathy and arrhythmia
needs to be overcome, although the respiratory management has
significantly improved the life span of the patients. Among
cardiac involvements, ECG findings such as distinctive deep
Q waves have been noted and are ascribed to fibrosis in the
posterobasal region of the left ventricle. When Urasawa et al
(National Institute of Neuroscience, Tokyo, Japan) examined
the hearts of dogs with canine X-linked muscular dystrophy in
Japan (CXMD
J), an appropriate dystrophin-deficient model of
Duchenne muscular dystrophy, the Purkinje fibers showed remarkable
vacuolar degeneration as early as 4 months of age despite no
detectable fibrotic lesions in ventricular myocardium. The degeneration
of CXMD
J Purkinje fibers was coincident with overexpression
of Dp71, a C-terminal truncated form of dystrophin, at the sarcolemma
and translocation of calcium-dependent protease µ-calpain
to the cell periphery near the sarcolemma or in the vacuoles.
Utrophin, a homologue of dystrophin, was highly upregulated
in the earlier stage of CXMD
J Purkinje fibers, but the expression
was dislocated when vacuolar degeneration was recognized at
4 months of age, despite preservation of dystrophin-associated
proteins at the sarcolemma. The selective degeneration of Purkinje
fibers can be associated with distinct deep Q waves on ECG and
the fatal arrhythmia seen in dystrophin deficiency. Further
clarification of the molecular mechanism of selective degeneration
of Purkinje fibers may shed light on the development of new
therapy for cardiac involvement in dystrophin-deficient muscular
dystrophy. See p
2437.
|
Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs
|
|---|
The present study demonstrated that the natural flavone acacetin
from the Chinese medicine
Xuelianhua selectively inhibited the
human atrial ultrarapid delayed rectifier K
+ current (
IKur)
and the transient outward K
+ current (
Ito) and prolonged action
potential duration in human atrial myocytes. The compound blocked
the acetylcholine-activated K
+ current; however, it had no effect
on the Na
+ current, L-type Ca
2+ current, or inward-rectifier
K
+ current in guinea pig ventricular myocytes. Although acacetin
had a weak reduction in the hERG and hKCNQ1/hKCNE1 channels
stably expressed in HEK 293 cells, it did not prolong the corrected
QT interval in rabbit hearts. In anesthetized dogs, acacetin
prolonged the atrial effective refractory period 1 to 4 hours
after intraduodenal administration without prolongation of the
corrected QT interval, whereas sotalol prolonged both. In addition,
acacetin prevented atrial fibrillation induction in anesthetized
dogs. The present study shows that acacetin is an atrium-selective
agent and effectively prevents atrial fibrillation in anesthetized
dogs after intraduodenal administration, which indicates that
oral acacetin is a promising agent for the treatment of atrial
fibrillation in humans. See p
2449.
|
Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden
|
|---|
Previous angiographic studies of statin therapy have shown reduced
progression of coronary stenoses in proportion to average low-density
lipoprotein cholesterol levels during therapy. However, no major
statin monotherapy study has demonstrated either halted progression
or regression of angiographic disease. A Study to Evaluate the
Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary
Atheroma Burden (ASTEROID) tested whether intensive treatment
by rosuvastatin for 24 months could modify the course of coronary
atherosclerosis measured by either intravascular ultrasound
of the artery wall (reported previously) or by quantitative
coronary angiography of the artery lumen (the present report).
Therapy reduced mean low-density lipoprotein cholesterol to
61 mg/dL and increased mean high-density lipoprotein cholesterol
by 13.8% to 48 mg/dL in these patients. Quantitative coronary
angiography showed significant net improvement in the 2 measures
of stenosis: percent diameter stenosis and minimum lumen diameter
of the stenoses. These improvements complement the intravascular
ultrasound results from ASTEROID of the decrease in atheroma
volume that was previously reported. This indicates that 2 imaging
methods that measured different parameters and focused on different
segments of the coronary arteries demonstrated concordant improvements
consistent with regression of atherosclerosis with intensive
statin therapy. In particular, rosuvastatin treatment for 24
months, resulting in mean low-density lipoprotein cholesterol
levels well below 70 mg/dL and significant increases in high-density
lipoprotein cholesterol, decreased coronary artery percent stenosis
and improved minimum lumen diameter in patients with coronary
artery disease. Both imaging and outcome studies suggest that
intensive statin treatment seems warranted in high-risk coronary
artery disease patients. The relative importance of low-density
lipoprotein cholesterol reduction and high-density lipoprotein
cholesterol elevation with statin therapy in producing these
results on atherosclerosis requires further investigation. See
p
2458.
|
Cross-Sectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study
|
|---|
Endothelial dysfunction contributes to atherogenesis and the
development of clinical cardiovascular disease. Digital pulse
amplitude response to hyperemia is a novel method for noninvasively
assessing vascular function in humans. In a large, community-based
sample, we measured digital vascular function using a fingertip
peripheral arterial tonometry device. Hyperemia produced a time-dependent
increase in fingertip pulse amplitude. We related digital vascular
response to hyperemia to cardiovascular risk factors. We observed
that male sex, body mass index, ratio of total to high-density
lipoprotein cholesterol, diabetes mellitus, smoking, and lipid-lowering
treatment were associated with lower pulse amplitude hyperemic
response. Digital vascular function was related to multiple
traditional and metabolic cardiovascular risk factors. Our findings
support further studies to define the clinical utility and predictive
value of digital pulse amplitude. See p
2467.
|
Association of Serum Creatinine With Abnormal Hemodynamics and Mortality in Pulmonary Arterial Hypertension
|
|---|
Pulmonary arterial hypertension is a devastating disease of
the pulmonary vasculature that ultimately leads to right heart
failure and death. Novel risk predictors for mortality in pulmonary
arterial hypertension may assist in the identification of high-risk
patients and may also lead to a better understanding of disease
pathophysiology. Several studies have found serum creatinine
(SCr) and SCr-based estimates of glomerular filtration rate
to be potent predictors of poor outcome in patients with cardiovascular
diseases such as coronary artery disease and heart failure.
We sought to determine whether elevated SCr was associated with
abnormal hemodynamics and predicted death in 500 patients with
World Health Organization group I pulmonary arterial hypertension
who were followed up for a median of 3.5 years (maximum follow-up
21 years). We found that SCr was significantly associated with
abnormal hemodynamics and poor functional status. Furthermore,
a single baseline measurement of SCr predicted death. Compared
with patients with SCr <1.0 mg/dL, those with SCr 1.0 to
1.4 mg/dL and SCr >1.4 mg/dL had an increased hazard ratio
of death (unadjusted hazard ratio 1.65, 95% confidence interval
1.26 to 2.17,
P<0.0001 for SCr 1.0 to 1.4 mg/dL; unadjusted
hazard ratio 2.54, 95% confidence interval 1.73 to 3.71,
P<0.0001
for SCr >1.4 mg/dL). On multivariable analysis, we found
a significant interaction between SCr and right atrial pressures,
whereby increased SCr best predicted death in patients with
right atrial pressure <10 mm Hg. Our results show that measurement
of SCr is practical and offers a simple way to noninvasively
predict abnormal hemodynamics and death. See p
2475.
|
Asymptomatic Peripheral Arterial Disease Is Associated With More Adverse Lower Extremity Characteristics Than Intermittent Claudication
|
|---|
Eight million men and women in the United States have lower
extremity peripheral arterial disease (PAD). Fully 20% to 50%
of persons with PAD have no exertional leg symptoms (ie, are
asymptomatic). Asymptomatic individuals with PAD who develop
leg symptoms during a 6-minute walk test presumably have restricted
their physical activity to avoid exertional leg symptoms during
daily life. The clinical significance of asymptomatic PAD among
those who do not develop leg symptoms during the 6-minute walk
test is unclear. In this study, asymptomatic PAD participants
who did not develop leg symptoms during the 6-minute walk test
were classified as always asymptomatic. Among 429 men and women
with PAD identified by the noninvasive vascular laboratory,
we found that persons with PAD who are always asymptomatic have
significantly smaller calf muscle area, higher calf muscle percent
fat, lower calf muscle density, poorer lower extremity peripheral
nerve function, and poorer lower extremity functional performance
compared with PAD participants with classic symptoms of intermittent
claudication. Our results indicate that clinicians should not
equate lack of exertional leg symptoms with a "benign" form
of PAD. Our results also underscore the importance of ankle
brachial index screening to identify persons with PAD who are
asymptomatic. Further study is needed to identify therapies
that improve walking performance in asymptomatic individuals
with PAD. See p
2484.
|
Mitochondrial Haplogroups: Ischemic Cardiovascular Disease, Other Diseases, Mortality, and Longevity in the General Population
|
|---|
More than 75 human diseases have been associated with rare mutations
in the mitochondrial genome; these mutations either impair mitochondrial
protein synthesis or impair proteins encoded by the mitochondrial
genome. Recently, numerous reports have suggested a role for
mitochondrial haplogroups, defined by the presence or absence
of common polymorphisms, in the pathogenesis of ischemic cardiovascular
disease and other diseases, as well as in longevity. However,
other reports could not confirm such associations, emphasizing
the need for large prospective population-based studies to clarify
this. In the present study, we tested the hypothesis that common
haplogroups predict risk of ischemic cardiovascular disease,
morbidity from other causes, mortality, and longevity in a general
population of European descent. A total of 9254 individuals
from the Danish general population, in the Copenhagen City Heart
Study, were followed prospectively for risk of ischemic cardiovascular
disease, morbidity, and mortality during 25 and 11 years, respectively.
Hazard ratios for hospitalization due to all cardiovascular
disorders and ischemic cerebrovascular disease did not differ
from 1.0 for any haplogroup versus the most common haplogroup
H. Results were similar for hospitalization due to infectious
diseases, respiratory disorders, malignant neoplasms, digestive
disorders, musculoskeletal disorders, and miscarriages. Likewise,
hazard ratios for death from all causes were not different from
1.0 for any haplogroup. Finally, after stratification by major
causes of death, hazard ratios remained insignificant. Our results
do not support an association of mitochondrial haplogroups with
risk of ischemic cardiovascular disease, morbidity from other
causes, mortality, or longevity in a large general population
of European descent. See p
2492.
|
Impact of Time of Presentation on the Care and Outcomes of Acute Myocardial Infarction
|
|---|
Previous studies showed an inconsistent association between
patients’ arrival time for acute myocardial infarction
(AMI) and their subsequent medical care and outcomes. Using
a contemporary national clinical registry, we examined differences
in medical care and in-hospital mortality among AMI patients
admitted during regular hours (weekdays 7
AM to 7
PM) versus
off-hours (weekends, holidays, and 7
PM to 7
AM weeknights).
In the current large cohort study of 62 814 patients with AMI
from the multicenter Get With the Guidelines–Coronary
Artery Disease database, we found that AMI patients arriving
during off-hours were slightly less likely to undergo revascularization
or primary percutaneous coronary intervention, more likely to
receive fibrinolytic therapy, and had no differences in the
use of overall reperfusion therapy compared with those arriving
during regular hours. ST-elevation MI patients, in particular,
were less likely to receive timely mechanical reperfusion. Despite
the slight disparities in revascularization rates and especially
the larger differences in timely mechanical reperfusion, no
measurable differences were found in in-hospital mortality in
the overall AMI cohort and in the ST-elevation MI and non–ST-elevation
MI subpopulations. Similar observations were made across most
age and sex subgroups and using an alternative definition for
arrival time (weekends/holidays versus weekdays). Healthcare
providers should continue to work to enhance the healthcare
system during regular hours and off-hours and to reduce existing
disparities in cardiac care through multifaceted initiatives
aiming to improve the timely delivery of evidence-based therapies.
See p
2502.
|
Hands-On Defibrillation: An Analysis of Electrical Current Flow Through Rescuers in Direct Contact With Patients During Biphasic External Defibrillation
|
|---|
During resuscitation from cardiac arrest due to ventricular
fibrillation or ventricular tachycardia, "all-clear" or "hands-off"
periods are mandated to avoid potential electrocution of rescuers.
These hands-off periods interfere with resuscitation, especially
given that current strategies emphasize the importance of avoiding
any interruption of chest compressions. There have been substantial
changes to external defibrillation technology since hands-off
precautions were developed. We addressed the feasibility and
safety of direct rescuer-patient contact during defibrillation
by measuring the voltage and current through mock rescuers simulating
chest compressions on patients receiving external biphasic countershocks
with adhesive shock electrodes. The main finding of this work
was that the leakage current, the key determinant of potential
harm to a rescuer, was very low. Within the constraints of our
model, uninterrupted manual chest compressions in a patient
being defibrillated are associated with exposure to safe, imperceptible
levels of electrical current. In many cases of cardiac arrest,
these observations would allow for elimination of routine harmful
delays during resuscitation and simplify the resuscitation protocol.
See p
2510.
|
Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin
|
|---|
Inhibition of cholesteryl ester transfer protein (CETP) activity
is regarded as a promising strategy to increase high-density
lipoprotein cholesterol and to reduce atherosclerosis. Torcetrapib
was the first CETP inhibitor tested in large human trials and
was shown to increase high-density lipoprotein cholesterol by
60%. However, the Rating Atherosclerosis Disease Change by Imaging
With a New CETP Inhibitor (RADIANCE) and the Investigation of
Lipid Level Management Using Coronary Ultrasound to Assess Reduction
of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE)
trials revealed no therapeutic benefit of combining torcetrapib
with atorvastatin with respect to atherosclerosis progression.
Moreover, the Investigation of Lipid Level Management to Understand
Its Impact in Atherosclerotic Events (ILLUMINATE) trial was
stopped prematurely because of an excess of (cardiovascular)
deaths in patients receiving torcetrapib. By using hyperlipidemic
APOE*3-Leiden.CETP transgenic mice, which respond in a human-like
manner to the lipid-lowering effect of atorvastatin and the
high-density lipoprotein cholesterol–raising effect of
torcetrapib, we demonstrated that torcetrapib did not increase
the antiatherogenic potency of atorvastatin, but torcetrapib
alone did reduce atherosclerosis progression to a higher extent
than expected on the basis of the cholesterol reduction. On
the other hand, torcetrapib resulted in lesions of a more proinflammatory
phenotype than atorvastatin. Although plaque rupture is a rare
phenomenon in mice, such lesions with a high ratio of macrophage
to collagen are more unstable and may well have caused an increased
incidence of plaque rupture in humans, thereby partially explaining
the increased cardiovascular death in the of trial. Whether
the effects of torcetrapib on cardiovascular events and death
are compound specific or related to CETP inhibition remains
to be evaluated. Taken together, these results suggest that
CETP inhibition per se is still a valid strategy for reducing
cardiovascular risk, given that (novel) CETP inhibitors (eg,
JTT-705 and anacetrapib) do not adversely affect plaque composition.
See p
2515.
Related Articles:
-
Association of Serum Creatinine With Abnormal Hemodynamics and Mortality in Pulmonary Arterial Hypertension
- Sanjiv J. Shah, Thenappan Thenappan, Stuart Rich, Lu Tian, Stephen L. Archer, and Mardi Gomberg-Maitland
Circulation 2008 117: 2475-2483.
[Abstract]
[Full Text]
-
Asymptomatic Peripheral Arterial Disease Is Associated With More Adverse Lower Extremity Characteristics Than Intermittent Claudication
- Mary M. McDermott, Jack M. Guralnik, Luigi Ferrucci, Lu Tian, Kiang Liu, Yihua Liao, David Green, Robert Sufit, Frederick Hoff, Takashi Nishida, Leena Sharma, William H. Pearce, Joseph R. Schneider, and Michael H. Criqui
Circulation 2008 117: 2484-2491.
[Abstract]
[Full Text]
-
Selective Vacuolar Degeneration in Dystrophin-Deficient Canine Purkinje Fibers Despite Preservation of Dystrophin-Associated Proteins With Overexpression of Dp71
- Nobuyuki Urasawa, Michiko R. Wada, Noboru Machida, Katsutoshi Yuasa, Yoshiki Shimatsu, Yoshito Wakao, Shigeki Yuasa, Toshiaki Sano, Ikuya Nonaka, Akinori Nakamura, and Shin’ichi Takeda
Circulation 2008 117: 2437-2448.
[Abstract]
[Full Text]
-
Cross-Sectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study
- Naomi M. Hamburg, Michelle J. Keyes, Martin G. Larson, Ramachandran S. Vasan, Renate Schnabel, Moira M. Pryde, Gary F. Mitchell, Jacob Sheffy, Joseph A. Vita, and Emelia J. Benjamin
Circulation 2008 117: 2467-2474.
[Abstract]
[Full Text]
-
Impact of Time of Presentation on the Care and Outcomes of Acute Myocardial Infarction
- Hani Jneid, Gregg C. Fonarow, Christopher P. Cannon, Igor F. Palacios, Teoman Kilic, George V. Moukarbel, Andrew O. Maree, Kenneth A. LaBresh, Li Liang, L. Kristin Newby, Gerald Fletcher, Laura Wexler, Eric Peterson for the Get With the Guidelines Steering Committee and Investigators
Circulation 2008 117: 2502-2509.
[Abstract]
[Full Text]
-
Mitochondrial Haplogroups: Ischemic Cardiovascular Disease, Other Diseases, Mortality, and Longevity in the General Population
- Marianne Benn, Marianne Schwartz, Børge G. Nordestgaard, and Anne Tybjærg-Hansen
Circulation 2008 117: 2492-2501.
[Abstract]
[Full Text]
-
Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin
- Willeke de Haan, Jitske de Vries-van der Weij, José W.A. van der Hoorn, Thomas Gautier, Caroline C. van der Hoogt, Marit Westerterp, Johannes A. Romijn, J. Wouter Jukema, Louis M. Havekes, Hans M.G. Princen, and Patrick C.N. Rensen
Circulation 2008 117: 2515-2522.
[Abstract]
[Full Text]
-
Hands-On Defibrillation: An Analysis of Electrical Current Flow Through Rescuers in Direct Contact With Patients During Biphasic External Defibrillation
- Michael S. Lloyd, Brian Heeke, Paul F. Walter, and Jonathan J. Langberg
Circulation 2008 117: 2510-2514.
[Abstract]
[Full Text]
-
Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs
- Gui-Rong Li, Hong-Bing Wang, Guo-Wei Qin, Man-Wen Jin, Qiang Tang, Hai-Ying Sun, Xin-Ling Du, Xiu-Ling Deng, Xiao-Hua Zhang, Jing-Bo Chen, Lei Chen, Xiao-Hui Xu, Lik-Cheung Cheng, Shui-Wah Chiu, Hung-Fat Tse, Paul M. Vanhoutte, and Chu-Pak Lau
Circulation 2008 117: 2449-2457.
[Abstract]
[Full Text]
-
Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden
- Christie M. Ballantyne, Joel S. Raichlen, Stephen J. Nicholls, Raimund Erbel, Jean-Claude Tardif, Sorin J. Brener, Valerie A. Cain, Steven E. Nissen for the ASTEROID Investigators
Circulation 2008 117: 2458-2466.
[Abstract]
[Full Text]
Top
Selective Vacuolar Degeneration...
Acacetin, a Natural Flavone,...