bluuebunny/crossref_metadata_2025_split huggingface dataset:
Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome
Authors: Pinney Jennifer H. , Whelan Carol J. , Petrie Aviva , Dungu Jason , Banypersad Sanjay M. , Sattianayagam Prayman , Wechalekar Ashutosh , Gibbs Simon D. J. , Venner Christopher P. , Wassef Nancy , McCarthy Carolyn A. , Gilbertson Janet A. , Rowczenio Dorota , Hawkins Philip N. , Gillmore Julian D. , Lachmann Helen J. 
Published: May 2013

Background

Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (
ATTR
wt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of
ATTR
wt compared with cardiac‐isolated
AL
amyloidosis and calculate the probability of disease diagnosis of
ATTR
wt from baseline factors.

Methods and Results

All patients with biopsy‐proven
ATTR
wt (102 cases) and isolated cardiac
AL
(36 cases) seen from 2002 to 2011 at the
UK
National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the
ATTR
wt group and 1.7 years in the
AL
group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in
ATTR
wt patients on univariate analysis. All patients with isolated cardiac
AL
and 24.1% of patients with
ATTR
wt had evidence of a plasma cell dyscrasia. Older age and lower
N
‐terminal pro‐
B
‐type natriuretic peptide (
NT
pro‐
BNP
) were factors significantly associated with
ATTR
wt. Patients aged 70 years and younger with an
NT
pro‐
BNP
<183 pmol/L were more likely to have
ATTR
wt, as were patients older than 70 years with an
NT
pro‐
BNP
<1420 pmol/L.

Conclusions

Factors at baseline associated with a worse outcome in
ATTR
wt are positive troponin T, a pacemaker, and
NYHA
class
IV
symptoms. The age of the patient at diagnosis and
NT
pro‐
BNP
level can aid in distinguishing
ATTR
wt from
AL
amyloidosis.
Dietary and Plasma Magnesium and Risk of Coronary Heart Disease Among Women
Authors: Chiuve Stephanie E. , Sun Qi , Curhan Gary C. , Taylor Eric N. , Spiegelman Donna , Willett Walter C. , Manson JoAnn E. , Rexrode Kathryn M. , Albert Christine M. 
Published: May 2013

Background

Magnesium is associated with lower risk of sudden cardiac death, possibly through antiarrhythmic mechanisms. Magnesium influences endothelial function, inflammation, blood pressure, and diabetes, but a direct relation with coronary heart disease (
CHD
) risk has not been established.

Methods and Results

We prospectively examined the association between dietary and plasma magnesium and risk of
CHD
among women in the Nurses' Health Study. The association for magnesium intake was examined among 86 323 women free of disease in 1980. Information on magnesium intake and lifestyle factors was ascertained every 2 to 4 years through questionnaires. Through 2008, 3614 cases of
CHD
(2511 nonfatal/1103 fatal) were documented. For plasma magnesium, we conducted a nested case–control analysis, with 458 cases of incident
CHD
(400 nonfatal/58 fatal) matched to controls (1:1) on age, smoking, fasting status, and date of blood sampling. Higher magnesium intake was not associated with lower risk of total
CHD
(
P
‐linear trend=0.12) or nonfatal
CHD
(
P
‐linear trend=0.88) in multivariable models. However, magnesium intake was inversely associated with risk of fatal
CHD
. The
RR
comparing quintile 5 to quintile 1 of magnesium intake was 0.61 (95%
CI
, 0.45 to 0.84;
P
‐linear trend=0.003). The association between magnesium intake and risk of fatal
CHD
appeared to be mediated partially by hypertension. Plasma magnesium levels above 2.0 mg/
dL
were associated with lower risk of
CHD
, although not independent of other cardiovascular biomarkers (
RR
, 0.67; 95%
CI
, 0.44 to 1.04).

Conclusions

Dietary and plasma magnesium were not associated with total
CHD
incidence in this population of women. Dietary magnesium intake was inversely associated with fatal
CHD
, which may be mediated in part by hypertension.
Apolipoprotein E in VLDL and LDL With Apolipoprotein C‐III is Associated With a Lower Risk of Coronary Heart Disease
Authors: Mendivil Carlos O. , Rimm Eric B. , Furtado Jeremy , Sacks Frank M. 
Published: May 2013

Background

Low‐density lipoprotein (
LDL
) with apolipoprotein C‐
III
(apoC‐
III
) is the lipoprotein species that most strongly predicts initial and recurring coronary heart disease (
CHD
) events in several cohorts. Thus, a large portion of the
CHD
risk conferred by
LDL
may be attributable to
LDL
that contains apoC‐
III
. Very‐low‐density lipoprotein (
VLDL
) and
LDL
with apoC‐
III
have varying amounts of apoE. We hypothesized that a high content of apoE lessens the adverse influence of apoC‐
III
on the risk of
CHD
because it promotes the clearance of
VLDL
and
LDL
from plasma.

Methods and Results

We studied 2 independent cohorts, the Nurses' Health Study, composed of women, and the Health Professionals Follow‐up Study, composed of men. These cohorts contributed to this study 322 women and 418 men initially free of
CVD
who developed a fatal or nonfatal myocardial infarction during 10 to 14 years of follow‐up and matched controls who remained free of
CHD
. The apoE content of
LDL
with apoC‐
III
was inversely associated with
CHD
after multivariable adjustment (relative risk for top versus bottom quintile 0.53, 95%
CI
0.35 to 0.80). The apoE content of
VLDL
with apoC‐
III
had a similar inverse association with
CHD
. The highest risks were associated with a high apoB concentration and a low apoE content of LDL with apoC‐III or of VLDL+LDL with apoC‐III. The observed associations were in both male and female cohorts and independent of traditional
CHD
risk factors and of C‐reactive protein.

Conclusions

An increased apoE content in
VLDL
and
LDL
with apoC‐
III
was associated with a lower risk of
CHD
. Strategies to enrich
VLDL
and
LDL
in apoE are worth exploring for the prevention of
CHD
.
Durable Scar Size Reduction Due to Allogeneic Mesenchymal Stem Cell Therapy Regulates Whole‐Chamber Remodeling
Authors: Williams Adam R. , Suncion Viky Y. , McCall Frederic , Guerra Danny , Mather Jacques , Zambrano Juan P. , Heldman Alan W. , Hare Joshua M. 
Published: May 2013

Background

Intramyocardial injection of mesenchymal stem cells (
MSC
s) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic
MSC
therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy.

Methods and Results

Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (
MI
), and 3 months post‐
MI
animals received either intramyocardial allogeneic
MSC
injection (200 mol/L cells; n=6) or left ventricle (
LV
) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the
LV
. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3‐dimensional cardiac magnetic resonance imaging angiography–derived anatomy to accurately target infarct border zone injections.
MSC
‐treated animals had a 19.62±2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09±2.31% from 3 to 6 months postinjection (
P
<0.0001).
MSC
‐treated animals had unchanged end‐diastolic volume (
EDV
;
P
=0.08) and end‐systolic volume (
ESV
;
P
=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both
EDV
(
P
=0.0002) and
ESV
(
P
=0.0002). In addition,
MSC
‐treated animals had improved
LV
sphericity index. Percentage change in infarct size correlated with percentage change in
EDV
(
r
=0.68;
P
=0.01) and
ESV
(
r
=0.77;
P
=0.001). Ejection fraction increased from 29.69±1.68% to 35.85±2.74% at 3 months post‐
MSC
injection and progressed to 39.02±2.42% 6 months postinjection (
P
=0.0001), whereas controls had a persistently depressed ejection fraction during follow‐up (
P
=0.33).

Conclusion

Intramyocardial injection of allogeneic
MSCs
leads to a sustained and progressive reduction in infarct size, which in turn drives reverse remodeling and increases in ejection fraction. These findings support ongoing biological activity of cell therapy for substantial periods and suggest optimal end points for future clinical trials.
ROS‐Mediated PARP Activity Undermines Mitochondrial Function After Permeability Transition Pore Opening During Myocardial Ischemia–Reperfusion
Authors: Schriewer Jacqueline M. , Peek Clara Bien , Bass Joseph , Schumacker Paul T. 
Published: May 2013

Background

Ischemia–reperfusion (I/R) studies have implicated oxidant stress, the mitochondrial permeability transition pore (
mPTP
), and poly(ADP‐ribose) polymerase (
PARP
) as contributing factors in myocardial cell death. However, the interdependence of these factors in the intact, blood‐perfused heart is not known. We therefore wanted to determine whether oxidant stress,
mPTP
opening, and
PARP
activity contribute to the same death pathway after myocardial I/R.

Methods and Results

A murine left anterior descending coronary artery (
LAD
) occlusion (30 minutes) and release (1 to 4 hours) model was employed. Experimental groups included controls and antioxidant‐treated,
mPTP
‐inhibited, or
PARP
‐inhibited hearts. Antioxidant treatment prevented oxidative damage,
mPTP
opening,
ATP
depletion, and
PARP
activity, placing oxidant stress as the proximal death trigger. Genetic deletion of cyclophilin D (CypD
−/−
) prevented loss of total
NAD
+
and
PARP
activity, and
mPTP
‐mediated loss of mitochondrial function. Control hearts showed progressive mitochondrial depolarization and loss of
ATP
from 1.5 to 4 hours of reperfusion, but not outer mitochondrial membrane rupture. Neither genetic deletion of
PARP
‐1 nor its pharmacological inhibition prevented the initial
mPTP
‐mediated depolarization or loss of
ATP
, but
PARP
ablation did allow mitochondrial recovery by 4 hours of reperfusion.

Conclusions

These results indicate that oxidant stress, the
mPTP
, and
PARP
activity contribute to a single death pathway after I/R in the heart.
PARP
activation undermines cell survival by preventing mitochondrial recovery after
mPTP
opening early in reperfusion. This suggests that
PARP
‐mediated prolongation of mitochondrial depolarization contributes significantly to cell death via an energetic crisis rather than by mitochondrial outer membrane rupture.
Cathepsin‐L Ameliorates Cardiac Hypertrophy Through Activation of the Autophagy–Lysosomal Dependent Protein Processing Pathways
Authors: Sun Mei , Ouzounian Maral , de Couto Geoffrey , Chen Manyin , Yan Ran , Fukuoka Masahiro , Li Guohua , Moon Mark , Liu Youan , Gramolini Anthony , Wells George J. , Liu Peter P. 
Published: May 2013

Background

Autophagy is critical in the maintenance of cellular protein quality control, the final step of which involves the fusion of autophagosomes with lysosomes. Cathepsin‐L (
CTSL
) is a key member of the lysosomal protease family that is expressed in the murine and human heart, and it may play an important role in protein turnover. We hypothesized that
CTSL
is important in regulating protein processing in the heart, particularly under pathological stress.

Methods and Results

Phenylephrine‐induced cardiac hypertrophy in vitro was more pronounced in
CTSL
‐deficient neonatal cardiomyocytes than in in controls. This was accompanied by a significant accumulation of autophagosomes, increased levels of ubiquitin‐conjugated protein, as well as impaired protein degradation and decreased cell viability. These effects were partially rescued with

CTSL
1

replacement via adeno‐associated virus–mediated gene transfer. In the in vivo murine model of aortic banding (
AB
), a deficiency in
CTSL
markedly exacerbated cardiac hypertrophy, worsened cardiac function, and increased mortality.
Ctsl
−/−
AB
mice demonstrated significantly decreased lysosomal activity and increased sarcomere‐associated protein aggregation. Homeostasis of the endoplasmic reticulum was also altered by
CTSL
deficiency, with increases in Bip and
GRP
94 proteins, accompanied by increased ubiquitin–proteasome system activity and higher levels of ubiquitinated proteins in response to
AB
. These changes ultimately led to a decrease in cellular
ATP
production, enhanced oxidative stress, and increased cellular apoptosis.

Conclusions
Lysosomal CTSL attenuates cardiac hypertrophy and preserves cardiac function through facilitation of autophagy and proteasomal protein processing.
Angiopoietin‐Like 2 Promotes Atherogenesis in Mice
Authors: Farhat Nada , Thorin‐Trescases Nathalie , Mamarbachi Maya , Villeneuve Louis , Yu Carol , Martel Cécile , Duquette Natacha , Gayda Mathieu , Nigam Anil , Juneau Martin , Allen Bruce G. , Thorin Eric 
Published: May 2013

Background

Angiopoietin like‐2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (
EC
s) from patients with coronary artery disease (
CAD
). Whether angptl2 contributes to atherogenesis is unknown. We tested the hypothesis that angptl2 promotes inflammation and leukocyte adhesion onto ECs, thereby accelerating atherogenesis in preatherosclerotic dyslipidemic mice.

Methods and Results

In
EC
s freshly isolated from the aorta, basal expression of
TNF
‐α and
IL
‐6
mRNA
was higher in 3‐month‐old severely dyslipidemic mice (
LDL
r
−/−
; hApoB
100
+/+
[
ATX
]) than in control healthy wild‐type (
WT
) mice (
P
<0.05) and was increased in both groups by exogenous angptl2 (100 nmol/L). Angptl2 stimulated the adhesion of leukocytes
ex vivo
on the native aortic endothelium of
ATX
, but not
WT
mice, in association with higher expression of
ICAM
‐1 and P‐selectin in
EC
s (
P
<0.05). Antibodies against these endothelial adhesion molecules prevented leukocyte adhesion. Intravenous administration of angptl2 for 1 month in preatherosclerotic 3‐month‐old
ATX
mice increased (
P
<0.05) total cholesterol and
LDL
‐cholesterol levels, strongly induced (
P
<0.05) the expression of endothelial proinflammatory cytokines and adhesion molecules while accelerating atherosclerotic lesion formation by 10‐fold (
P
<0.05). Plasma and aortic tissue levels of angptl2 increased (
P
<0.05) with age and were higher in 6‐ and 12‐month‐old
ATX
mice than in age‐matched
WT
mice. Angptl2 accumulated to high levels in the atherosclerotic lesions (
P
<0.05). Finally, angptl2 was greatly expressed (
P
<0.05) in
EC
s cultured from
CAD
patients, and circulating angptl2 levels were 6‐fold higher in
CAD
patients compared with age‐matched healthy volunteers.

Conclusions
Angptl2 contributes to the pathogenesis of atherosclerosis.
Clinical Outcomes Strongly Associated With the Degree of Reperfusion Achieved in Target Mismatch Patients
Authors: Inoue Manabu , Mlynash Michael , Straka Matus , Kemp Stephanie , Jovin Tudor G. , Tipirneni Aaryani , Hamilton Scott A. , Marks Michael P. , Bammer Roland , Lansberg Maarten G. , Albers Gregory W. 
Published: May 2013

Background and Purpose—
To investigate relationships between the degree of early reperfusion achieved on perfusion-weighted imaging and clinical outcomes in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution studies. We hypothesized that there would be a strong correlation between the degree of reperfusion achieved and clinical outcomes in target mismatch (TMM) patients.

Methods—
The degree of reperfusion was calculated on the basis of the difference in perfusion-weighted imaging volumes (time to maximum of tissue residue function [Tmax]>6 s) between the baseline MRI and the early post-treatment follow-up scan. Patients were grouped into quartiles, on the basis of degree of reperfusion achieved, and the association between the degree of reperfusion and clinical outcomes in TMM and no TMM patients was assessed. Favorable clinical response was determined at day 30 on the basis of the National Institutes of Health Stroke Scale and good functional outcome was defined as a modified Rankin Scale score ≤2 at day 90.

Results—

This study included 121 patients; 98 of these had TMM. The median degree of reperfusion achieved was not different in TMM patients (60%) versus No TMM patients (64%;
P
=0.604). The degree of reperfusion was strongly correlated with both favorable clinical response (
P
<0.001) and good functional outcome (
P
=0.001) in TMM patients; no correlation was present in no TMM. The frequency of achieving favorable clinical response or good functional outcome was significantly higher in TMM patients in the highest reperfusion quartile versus the lower 3 quartiles (88% versus 41% as odds ratio, 10.3; 95% confidence interval, 2.8–37.5; and 75% versus 34% as odds ratio, 5.9; 95% confidence interval, 2.1–16.7, respectively). A receiver operating characteristic curve analysis identified 90% as the optimal reperfusion threshold for predicting good functional outcomes.

Conclusion—
The degree of reperfusion documented on perfusion-weighted imaging after reperfusion therapies corresponds closely with clinical outcomes in TMM patients. Reperfusion of ≥90% of the perfusion lesion is an appropriate goal for reperfusion therapies to aspire to.
Low Dehydroepiandrosterone Sulfate is Associated With Increased Risk of Ischemic Stroke Among Women
Authors: Jiménez Monik C. , Sun Qi , Schürks Markus , Chiuve Stephanie , Hu Frank B. , Manson JoAnn E. , Rexrode Kathryn M. 
Published: May 2013

Background and Purpose—
Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk of ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic-related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance.

Methods—
Between 1989 and 1990, 32 826 women without prior stroke in the Nurses’ Health Study, an observational cohort, provided blood samples and were followed up for cardiovascular events. Among this sample, using a nested case–control design, 461 ischemic strokes were confirmed by medical records by 2006. Cases were matched to controls free of stroke at the time of the index case and by age, race, menopausal status, postmenopausal hormone use, smoking status, and date of sample collection. Multivariable conditional logistic regression was used.

Results—

Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0;
P
=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk of 1.30 for ischemic stroke (95% confidence interval, 0.88–1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (relative risk=1.33; 95% confidence interval, 0.87–2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared with those with higher levels (relative risk=1.41; 95% confidence interval, 1.03–1.92).

Conclusions—
Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.
MicroRNA-124–Mediated Regulation of Inhibitory Member of Apoptosis-Stimulating Protein of p53 Family in Experimental Stroke
Authors: Liu Xiangrong , Li Fang , Zhao Shangfeng , Luo Yumin , Kang Jun , Zhao Haiping , Yan Feng , Li Sijie , Ji Xunming 
Published: May 2013

Background and Purpose—
p53-mediated neuronal death is a central pathway of stroke pathophysiology, but its mechanistic details remain unclear. Here, we identified a novel microRNA mechanism that downregulation of inhibitory member of the apoptosis-stimulating proteins of p53 family (iASPP) by the brain-specific microRNA-124 (miR-124) promotes neuronal death after cerebral ischemia.

Methods—
In a mouse model of focal permanent cerebral ischemia, the expression of iASPP and miR-124 was quantified by reverse transcription quantitative real-time polymerase chain reaction, immunofluorescence staining, and Western blot. Luciferase reporter assay was used to validate whether miR-124 can directly bind to the 3′-untranslated region of iASPP mRNA. To evaluate the role of miR-124, miR-124 mimic and its inhibitor were transfected into Neuro-2a cells and C57 mice.

Results—
There was no change in the iASPP mRNA level in cerebral ischemia. However, iASPP protein was remarkably decreased, with a concurrent elevation in miR-124 level. Furthermore, miR-124 can bind to the 3′-untranslated region of iASPP in 293T cells and downregulate its protein levels in Neuro-2a cells. In vivo, infusion of miR-124 decreased brain levels of iASPP, whereas inhibition of miR-124 enhanced iASPP levels and significantly reduced infarction in mouse focal cerebral ischemia.

Conclusions—
These data demonstrate that p53-mediated neuronal cell death after stroke can be nontranscriptionally regulated by a novel mechanism involving suppression of endogenous cell death inhibitors by miR-124. Further dissection of microRNA regulatory mechanisms may lead to new therapeutic opportunities for preventing neuronal death after stroke.
Diabetes Mellitus, Admission Glucose, and Outcomes After Stroke Thrombolysis
Authors: Desilles Jean-Philippe , Meseguer Elena , Labreuche Julien , Lapergue Bertrand , Sirimarco Gaia , Gonzalez-Valcarcel Jaime , Lavallée Philippa , Cabrejo Lucie , Guidoux Celine , Klein Isabelle , Amarenco Pierre , Mazighi Mikael 
Published: May 2013

Background and Purpose—
The potential detrimental effect of diabetes mellitus and admission glucose level (AGL) on outcomes after stroke thrombolysis is unclear. We evaluated outcomes of patients treated by intravenous and/or intra-arterial therapy, according to diabetes mellitus and AGL.

Methods—
We analyzed data from a patient registry (n=704) and conducted a systematic review of previous observational studies. The primary study outcome was the percentage of patients who achieved a favorable outcome (modified Rankin score ≤2 at 3 months).

Results—
We identified 54 previous reports that evaluated the effect of diabetes mellitus or AGL on outcomes after thrombolysis. In an unadjusted meta-analysis that included our registry data and previous available observational data, diabetes mellitus was associated with less favorable outcome (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.73–0.79) and more symptomatic intracranial hemorrhage (OR, 1.38; 95% CI, 1.21–1.56). However, in multivariable analysis, diabetes mellitus remained associated with less favorable outcome (OR, 0.77; 95% CI, 0.69–0.87) but not with symptomatic intracranial hemorrhage (OR, 1.11; 95% CI, 0.83–1.48). In unadjusted and in adjusted meta-analysis, higher AGL was associated with less favorable outcome and more symptomatic intracranial hemorrhage; the adjusted OR (95% CI) per 1 mmol/L increase in AGL was 0.92 (0.90–0.94) for favorable outcome, and 1.09 (1.04–1.14) for symptomatic intracranial hemorrhage.

Conclusions—
These results confirm that AGL and history of diabetes mellitus are associated with poor clinical outcome after thrombolysis. AGL may be a surrogate marker of brain infarction severity rather than a causal factor. However, randomized controlled evidences are needed to address the significance of a tight glucose control during thrombolysis on clinical outcome.