bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development
Authors: Kushiyama Akifumi , Sakoda Hideyuki , Oue Naohide , Okubo Masamichi , Nakatsu Yusuke , Ono Haruya , Fukushima Toshiaki , Kamata Hideaki , Nishimura Fusanori , Kikuchi Takako , Fujishiro Midori , Nishiyama Koichi , Aburatani Hiroyuki , Kushiyama Sakura , Iizuka Masaki , Taki Naoyuki , Encinas Jeffrey , Sentani Kazuhiro , Ogonuki Narumi , Ogura Atsuo , Kawazu Shoji , Yasui Wataru , Higashi Yukihito , Kurihara Hiroki , Katagiri Hideki , Asano Tomoichiro
Published: May 2013

Objective—

Resistin-like molecule (RELM) β is a secretory protein homologous to resistin and reportedly contributes to local immune response regulation in gut and bronchial epithelial cells. However, we found that activated macrophages also express RELMβ and thus investigated the role of RELMβ in the development of atherosclerosis.

Approach and Results—

It was demonstrated that foam cells in atherosclerotic lesions of the human coronary artery abundantly express RELMβ. RELMβ knockout (
−/−
) and wild-type mice were mated with apolipoprotein E–deficient background mice. RELMβ
−/−
apolipoprotein E–deficient mice exhibited less lipid accumulation in the aortic root and wall than RELMβ

+/+

apolipoprotein E–deficient mice, without significant changes in serum lipid parameters. In vitro, RELMβ
−/−
primary cultured peritoneal macrophages (PCPMs) exhibited weaker lipopolysaccharide-induced nuclear factor-κB classical pathway activation and inflammatory cytokine secretion than RELMβ
+/+
, whereas stimulation with RELMβ upregulated inflammatory cytokine expressions and increased expressions of many lipid transporters and scavenger receptors in PCPMs. Flow cytometric analysis revealed inflammatory stimulation–induced RELMβ in F4/80(+) CD11c(+) PCPMs. In contrast, the expressions of CD11c and tumor necrosis factor were lower in RELMβ
−/−
PCPMs, but both were restored by stimulation with recombinant RELMβ.

Conclusions—

RELMβ is abundantly expressed in foam cells within plaques and contributes to atherosclerosis development via lipid accumulation and inflammatory facilitation.
Therapeutic Silencing of MicroRNA-33 Inhibits the Progression of Atherosclerosis in
Ldlr
−/−
Mice—Brief Report
Authors: Rotllan Noemi , Ramírez Cristina M. , Aryal Binod , Esau Christine C. , Fernández-Hernando Carlos
Published: May 2013

Objective—

To study the efficacy of anti–miRNA-33 therapy on the progression of atherosclerosis.

Approach and Results—

Ldlr
−/−
mice were injected subcutaneously with PBS, control, or anti–miR-33 oligonucleotides weekly and fed a Western diet for 12 weeks. At the end of treatment, the expression of miR-33 target genes was increased in the liver and aorta, demonstrating effective inhibition of miR-33 function. Interestingly, plasma high-density lipoprotein (HDL)-cholesterol was significantly increased in anti–miR-33-treated mice but only when they were fed a chow diet. However, HDL isolated from anti–miR-33-treated mice showed an increase cholesterol efflux capacity compared with HDL isolated from nontargeting oligonucleotide-treated mice. Analysis of atherosclerosis revealed a significant reduction of plaque size and macrophage content in mice receiving anti–miR-33. In contrast, no differences in collagen content and necrotic areas were observed among the 3 groups.

Conclusions—

Long-term anti–miR-33 therapy significantly reduces the progression of atherosclerosis and improves HDL functionality. The antiatherogenic effect is independent of plasma HDL-cholesterol levels.
Treatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and Gradient Resistant to First-Line Therapy With β-Blockade or Verapamil
Authors: Sherrid Mark V. , Shetty Aneesha , Winson Glenda , Kim Bette , Musat Dan , Alviar Carlos L. , Homel Peter , Balaram Sandhya K. , Swistel Daniel G.
Published: May 2013

Background—

There is controversy about preferred methods to relieve obstruction in hypertrophic cardiomyopathy patients still symptomatic after β-blockade or verapamil.

Methods and Results—

Of 737 patients prospectively registered at our institution, 299 (41%) required further therapy for obstruction for limiting symptoms, rest gradient 61±45, provoked gradient 115±49 mm Hg, and followed up for 4.8 years. Disopyramide was added in 221 (74%) patients and pharmacological control of symptoms was achieved in 141 (64%) patients. Overall, 138 (46%) patients had surgical relief of obstruction (91% myectomy) and 6 (2%) alcohol septal ablation. At follow-up, resting gradients in the 299 patients had decreased from 61±44 to 10±25 mm Hg (
P
<0.0001); New York Heart Association class decreased from 2.7±0.7 to 1.8±0.5 (
P
<0.0001). Kaplan–Meier survival at 10 years in the 299 advanced-care patients was 88% and did not differ from nonobstructed patients (
P
=0.28). Only 1 patient had sudden death, a low annual rate of 0.06%/y. Kaplan–Meier survival at 10 years in the advanced-care patients did not differ from that expected in a matched cohort of the US population (
P
=0.90).

Conclusions—

Patients with obstruction and symptoms resistant to initial pharmacological therapy with β-blockade or verapamil may realize meaningful symptom relief and low mortality through stepped management, adding disopyramide in appropriately selected patients, and when needed, by surgical myectomy.
Good Prognosis for Pericarditis With and Without Myocardial Involvement
Authors: Imazio Massimo , Brucato Antonio , Barbieri Andrea , Ferroni Francesca , Maestroni Silvia , Ligabue Guido , Chinaglia Alessandra , Cumetti Davide , Casa Giovanni Della , Bonomi Federica , Mantovani Francesca , Di Corato Paola , Lugli Roberta , Faletti Riccardo , Leuzzi Stefano , Bonamini Rodolfo , Modena Maria Grazia , Belli Riccardo
Published: May 2013

Background—

The natural history of myopericarditis/perimyocarditis is poorly known, and recently published studies have presented contrasting data on their outcomes. The aim of the present article is to assess the prognosis of myopericarditis/perimyocarditis in a multicenter, prospective cohort study.

Methods and Results—

A total of 486 patients (median age, 39 years; range, 18–83 years; 300 men) with acute pericarditis or a myopericardial inflammatory syndrome (myopericarditis/perimyocarditis; 85% idiopathic, 11% connective tissue disease or inflammatory bowel disease, 5% infective) were prospectively evaluated from January 2007 to December 2011. The diagnosis of acute pericarditis was based on the presence of 2 of 4 clinical criteria (chest pain, pericardial rubs, widespread ST-segment elevation or PR depression, and new or worsening pericardial effusion). Myopericardial inflammatory involvement was suspected with atypical ECG changes for pericarditis, arrhythmias, and cardiac troponin elevation or new or worsening ventricular dysfunction on echocardiography and confirmed by cardiac magnetic resonance. After a median follow-up of 36 months, normalization of left ventricular function was achieved in >90% of patients with myopericarditis/perimyocarditis. No deaths were recorded, as well as evolution to heart failure or symptomatic left ventricular dysfunction. Recurrences (mainly as recurrent pericarditis) were the most common complication during follow-up and were recorded more frequently in patients with acute pericarditis (32%) than in those with myopericarditis (11%) or perimyocarditis (12%;
P
<0.001). Troponin elevation was not associated with an increase in complications.

Conclusions—

The outcome of myopericardial inflammatory syndromes is good. Unlike acute coronary syndromes, troponin elevation is not a negative prognostic marker in this setting.
Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia
Authors: Wang Keqing , Ahmad Shakil , Cai Meng , Rennie Jillian , Fujisawa Takeshi , Crispi Fatima , Baily James , Miller Mark R. , Cudmore Melissa , Hadoke Patrick W. F. , Wang Rui , Gratacós Eduard , Buhimschi Irina A. , Buhimschi Catalin S. , Ahmed Asif
Published: May 2013

Background—

The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H
2
S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension.

Methods and Results—

Plasma levels of H
2
S were significantly decreased in women with preeclampsia (
P
<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by
DL
-propargylglycine reduced placental growth factorproduction from first-trimester (8–12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of
DL
-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H
2
S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by
DL
-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H
2
S production.

Conclusions—

These results imply that endogenous H
2
S is required for healthy placental vasculature and that a decrease in CSE/H
2
S activity may contribute to the pathogenesis of preeclampsia. (Circulation. 2013;127:2514-2522.)
Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis
Authors: Mani Sarathi , Li Hongzhu , Untereiner Ashley , Wu Lingyun , Yang Guangdong , Austin Richard C. , Dickhout Jeffrey G. , Lhoták Šárka , Meng Qing H. , Wang Rui
Published: May 2013

Background—

Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H
2
S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H
2
S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H
2
S in atherosclerosis development.

Methods and Results—

Six-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not
N
-acetylcysteine or ezetimibe, inhibited the accelerated atherosclerosis development. Double knockout of CSE and apolipoprotein E gene expression in mice exacerbated atherosclerosis development more than that in the mice with only apolipoprotein E or CSE knockout.

Conclusions—

Endogenously synthesized H
2
S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H
2
S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H
2
S pathway is an important therapeutic target for protection against atherosclerosis.
Impaired Collagen Biosynthesis and Cross‐linking in Aorta of Patients With Bicuspid Aortic Valve
Authors: Wågsäter Dick , Paloschi Valentina , Hanemaaijer Roeland , Hultenby Kjell , Bank Ruud A. , Franco‐Cereceda Anders , Lindeman Jan H. N. , Eriksson Per
Published: May 2013

Background

Patients with bicuspid aortic valve (
BAV
) have an increased risk of developing ascending aortic aneurysm. In the present study, collagen homeostasis in nondilated and dilated aorta segments from patients with
BAV
was studied, with normal and dilated aortas from tricuspid aortic valve (
TAV
) patients as reference.

Methods and Results

Ascending aortas from 56 patients were used for biochemical and morphological analyses of collagen.
mRNA
expression was analyzed in 109 patients. Collagen turnover rates were similar in nondilated and dilated aortas of
BAV
patients, showing that aneurysmal formation in
BAV
is, in contrast to
TAV
,
not
associated with an increased collagen turnover. However,
BAV
in general was associated with an increased aortic collagen turnover compared with nondilated aortas of
TAV
patients. Importantly, the ratio of hydroxylysyl pyridinoline (HP) to lysyl pyridinoline (LP), 2 distinct forms of collagen cross‐linking, was lower in dilated aortas from patients with
BAV
, which suggests that
BAV
is associated with a defect in the posttranslational collagen modification. This suggests a deficiency at the level of lysyl hydroxylase (

PLOD
1

), which was confirmed by
mRNA
and protein analyses that showed reduced

PLOD
1

expression but normal
lysyl oxidase
expression in dilated aortas from patients with
BAV
. This suggests that impaired collagen cross‐linking in
BAV
patients may be attributed to changes in the expression and/or activity of

PLOD
1

.

Conclusions

Our results demonstrate an impaired biosynthesis and posttranslational modification of collagen in aortas of patients with
BAV
, which may explain the increased aortic aneurysm formation in
BAV
patients.
Mortality From Myocardial Infarction After the Death of a Sibling: A Nationwide Follow‐up Study From Sweden
Authors: Rostila Mikael , Saarela Jan , Kawachi Ichiro
Published: May 2013

Background

Death of a sibling represents a stressful life event and could be a potential trigger of myocardial infarction (MI). We studied the association between loss of an adult sibling and mortality from MI up to 18 years after bereavement.

Methods and Results

We conducted a follow‐up study for Swedes aged 40 to 69 years between 1981 and 2002, based on register data covering the total population (N=1 617 010). Sibling deaths could be observed from 1981 and on. An increased mortality rate from MI was found among women (1.25
CI
1.02 to 1.54) and men (1.15
CI
1.03 to 1.28) who had experienced death of an adult sibling. An elevated rate some years after bereavement was found among both women (during the fourth to sixth half‐years after the death) and men (during the second to sixth half‐years after the death), whereas limited support for a short‐term elevation in the rate was found (during the first few months since bereavement). External causes of sibling death were associated with increased
MI
mortality among women (1.54
CI
1.07 to 2.22), whereas nonexternal causes showed associations in men (1.23
CI
1.09 to 1.38). However, further analyses showed that if the sibling also died from MI, associations were primarily found among both women (1.62
CI
1.00 to 2.61) and men (1.98
CI
1.59 to 2.48).

Conclusions

Our study provided the first large‐scale evidence for mortality from MI associated with the death of a sibling at an adult age. The fact that findings suggested associations primarily between concordant causes of death (both died of MI) could indicate genetic resemblance or shared risk factors during childhood. Future studies on bereavement should carefully deal with the possibility of residual confounding.
CD14 Directs Adventitial Macrophage Precursor Recruitment: Role in Early Abdominal Aortic Aneurysm Formation
Authors: Blomkalns Andra L. , Gavrila Daniel , Thomas Manesh , Neltner Bonnie S. , Blanco Victor M. , Benjamin Stephanie B. , McCormick Michael L. , Stoll Lynn L. , Denning Gerene M. , Collins Sean P. , Qin Zhenyu , Daugherty Alan , Cassis Lisa A. , Thompson Robert W. , Weiss Robert M. , Lindower Paul D. , Pinney Susan M. , Chatterjee Tapan , Weintraub Neal L.
Published: May 2013

Background

Recruitment of macrophage precursors to the adventitia plays a key role in the pathogenesis of abdominal aortic aneurysms (
AAA
s), but molecular mechanisms remain undefined. The innate immune signaling molecule
CD
14 was reported to be upregulated in adventitial macrophages in a murine model of
AAA
and in monocytes cocultured with aortic adventitial fibroblasts (AoAf) in vitro
,
concurrent with increased interleukin‐6 (IL‐6) expression. We hypothesized that
CD
14 plays a crucial role in adventitial macrophage precursor recruitment early during
AAA
formation.

Methods and Results

CD
14
−/−
mice were resistant to
AAA
formation induced by 2 different
AAA
induction models: aortic elastase infusion and systemic angiotensin
II
(Ang
II
) infusion.

CD
14

gene deletion led to reduced aortic macrophage infiltration and diminished elastin degradation. Adventitial monocyte binding to Ang
II
‐infused aorta in vitro was dependent on
CD
14, and incubation of human acute monocytic leukemia cell line‐1 (THP‐1) monocytes with
IL
‐6 or conditioned medium from perivascular adipose tissue (
PVAT
) upregulated
CD
14 expression. Conditioned medium from AoAf and
PVAT
induced
CD
14‐dependent monocyte chemotaxis, which was potentiated by
IL
‐6.
CD
14 expression in aorta and plasma
CD
14 levels were increased in
AAA
patients compared with controls.

Conclusions

These findings link
CD
14 innate immune signaling via a novel
IL
‐6 amplification loop to adventitial macrophage precursor recruitment in the pathogenesis of
AAA
.
Association of Anxiety and Depression With All‐Cause Mortality in Individuals With Coronary Heart Disease
Authors: Watkins Lana L. , Koch Gary G. , Sherwood Andrew , Blumenthal James A. , Davidson Jonathan R.T. , O'Connor Christopher , Sketch Michael H.
Published: May 2013

Background

Depression has been related to mortality in coronary heart disease (
CHD
) patients, but few studies have evaluated the role of anxiety or the role of the co‐occurrence of depression and anxiety. We examined whether anxiety is associated with increased risk of mortality after accounting for depression in individuals with established
CHD
.

Methods and Results

The cohort was composed of 934 men and women with confirmed
CHD
(mean age, 62±11 years) who completed the Hospital Anxiety and Depression scale (
HADS
) during hospitalization for coronary angiography. Over the 3‐year follow‐up period, there were 133 deaths. Elevated scores on the
HADS
anxiety subscale (
HADS
‐A≥8) were associated with increased risk of mortality after accounting for established risk factors including age, congestive heart failure, left ventricular ejection fraction, 3‐vessel disease, and renal disease (hazard ratio [
HR
], 2.27; 95%
CI
, 1.55 to 3.33;
P
<0.001). Elevated scores on the
HADS
depression subscale (
HADS
‐D≥8) were also associated with increased risk of mortality (
HR
, 2.18; 95%
CI
, 1.47 to 3.22;
P
<0.001). When both psychosocial factors were included in the model, each maintained an association with mortality (anxiety,
HR
, 1.83; 95%
CI
, 1.18 to 2.83;
P
=0.006; depression,
HR
, 1.66; 95%
CI
, 1.06 to 2.58;
P
=0.025). Estimation of the
HR
for patients with both anxiety and depression versus those with neither revealed a larger
HR
than for patients with either factor alone (
HR
, 3.10; 95%
CI
, 1.95 to 4.94;
P
<0.001).

Conclusions

Anxiety is associated with increased risk of mortality in
CHD
patients, particularly when comorbid with depression. Future studies should focus on the co‐occurrence of these psychosocial factors as markers of increased mortality risk.
Associations of Glycemic Index and Load With Coronary Heart Disease Events: A Systematic Review and Meta‐Analysis of Prospective Cohorts
Authors: Mirrahimi Arash , de Souza Russell J. , Chiavaroli Laura , Sievenpiper John L. , Beyene Joseph , Hanley Anthony J. , Augustin Livia S. A. , Kendall Cyril W. C. , Jenkins David J. A.
Published: May 2013

Background

Glycemic index (
GI
) and glycemic load (
GL
) have been associated with coronary heart disease (
CHD
) risk in some but not all cohort studies. We therefore assessed the association of
GI
and
GL
with
CHD
risk in prospective cohorts.

Methods and Results

We searched
MEDLINE
,
EMBASE
, and
CINAHL
(through April 5, 2012) and identified all prospective cohorts assessing associations of
GI
and
GL
with incidence of
CHD
. Meta‐analysis of observational studies in epidemiology (
MOOSE
) methodologies were used. Relative measures of risk, comparing the group with the highest exposure (mean
GI
of cohorts=84.4
GI
units, range 79.9 to 91; mean
GL
of cohorts=224.8, range 166 to 270) to the reference group (mean
GI
=72.3
GI
units, range 68.1 to 77; mean
GL
=135.4, range 83 to 176), were pooled using random‐effects models, expressed as relative risk (
RR
) with heterogeneity assessed by χ
2
and quantified by I
2
. Subgroups included sex and duration of follow‐up. Ten studies (n=240 936) were eligible. Pooled analyses showed an increase in
CHD
risk for the highest
GI
quantile compared with the lowest, with
RR
=1.11 (95% confidence interval [
CI
] 0.99 to 1.24) and for
GL
,
RR
=1.27 (95%
CI
1.09 to 1.49), both with evidence of heterogeneity (I
2
>42%,
P
<0.07). Subgroup analyses revealed only a significant modification by sex, with the female cohorts showing significance for
GI RR
=1.26 (95%
CI
1.12 to 1.41) and for
GL RR
=1.55 (95%
CI
1.18 to 2.03).

Conclusions

High
GI
and
GL
diets were significantly associated with
CHD
events in women but not in men. Further studies are required to determine the relationship between
GI
and
GL
with
CHD
in men.
Prevalence of Dyslipidemia and Lipid Goal Attainment in Statin‐Treated Subjects From 3 Data Sources: A Retrospective Analysis
Authors: Jones Peter H. , Nair Radhika , Thakker Kamlesh M.
Published: May 2013

Background

Evidence‐based randomized clinical trials have shown significant benefit of statin treatment with regard to cardiovascular disease. In anticipation of the National Cholesterol Education Program Adult Treatment Panel IV guidelines, we wanted to assess the current state of lipid goal attainment in the high‐risk secondary prevention population in the United States. The objectives of the study were to estimate the proportion of high‐risk patients treated with statin monotherapy who achieved Adult Treatment Panel III–recommended low‐density lipoprotein cholesterol (
LDL‐C
) goals (<100 mg/dL; optional <70 mg/dL) as well as non–high‐density lipoprotein cholesterol goals (<130 mg/dL; optional <100 mg/dL).

Methods and Results

This is a cross‐sectional, retrospective study of 3 data sources: electronic medical records (2003–September 2010), administrative claims data (2003–2010), and National Health and Nutrition Examination Survey data (2007–2008). High‐risk patients (≥18 years of age) were defined as those with a history of coronary heart disease or coronary heart disease risk equivalent who had the latest complete lipid panel measurement and had been treated with statin monotherapy for >90 days at the time of the lipid panel. Cardiovascular disease, coronary heart disease, and coronary heart disease risk equivalents were defined on the basis of availability, specific to each data source. Across the 3 data sources, 20% to 26% of high‐risk patients treated with statin monotherapy for >90 days had
LDL‐C
<70 mg/dL, and 67% to 77% had
LDL‐C
<100 mg/dL. The percentages of those attaining both
LDL‐C
goals and non–high‐density lipoprotein cholesterol goals were quantitatively smaller (13.5% to 19.0% and 46% to 70%).

Conclusions

Across the 3 data sources, there was consistency in the proportion of high‐risk patients treated with statin monotherapy who were at
LDL‐C
goal. A significant number of these statin‐treated patients had additional dyslipidemias.
Racial Differences in Arterial Stiffness and Microcirculatory Function Between Black and White Americans
Authors: Morris Alanna A. , Patel Riyaz S. , Binongo Jose Nilo G. , Poole Joseph , Mheid Ibhar al , Ahmed Yusuf , Stoyanova Neli , Vaccarino Viola , Din‐Dzietham Rebecca , Gibbons Gary H. , Quyyumi Arshed
Published: May 2013

Background

Compared with whites, black
A
mericans suffer from a disproportionate burden of cardiovascular disease (
CVD
). We hypothesized that racial differences in the prevalence of
CVD
could be attributed, in part, to impaired vascular function in blacks after adjustment for differences in risk factor burden.

Methods and Results

We assessed vascular function in 385 black and 470 white subjects (mean age, 48±11 years; 45% male). Using digital pulse amplitude tonometry (Endo
PAT
) we estimated the reactive hyperemia index (
RHI
), a measure of microvascular endothelial function, and peripheral augmentation index (
PAT
‐
AI
x). Central augmentation index (
C
‐
AI
x) and pulse‐wave velocity (
PWV
) were measured as indices of wave reflections and arterial stiffness, respectively, using applanation tonometry (Sphygmocor). Compared with whites, blacks had lower
RHI
(2.1±0.6 versus 2.3±0.6,
P
<0.001), greater arterial wave reflections assessed as both
PAT
‐
AI
x (20.4±21.5 versus 17.0±22.4,
P
=0.01) and
CAI
x (20.8±12.3 versus 17.5±13.3,
P
=0.001), and greater arterial stiffness, measured as
PWV
(7.4±1.6 versus 7.1±1.6 m/s,
P
=0.001). After adjustment for traditional
CVD
risk factors, black race remained a significant predictor of lower
RHI
and higher
PAT
‐
AI
x and
CAI
x (all
P
<0.001) in all subjects and of higher
PWV
in men (
P
=0.01). Furthermore, these associations persisted in a subgroup analysis of “healthy” individuals free of
CVD
risk factors.

Conclusion

Black race is associated with impaired microvascular vasodilatory function, and greater large arterial wave reflections and stiffness. Because impairment in these vascular indices may be associated with worse long‐term outcomes, they may represent underlying mechanisms for the increased
CVD
risk in blacks.
Type 2 Diabetes Restricts Multipotency of Mesenchymal Stem Cells and Impairs Their Capacity to Augment Postischemic Neovascularization in
db/db
Mice
Authors: Yan Jinglian , Tie Guodong , Wang Shouying , Messina Katharine E. , DiDato Sebastian , Guo Sujuan , Messina Louis M.
Published: May 2013

Background

This study tested the hypothesis that type 2 diabetes restricts multipotency of
db/db
mesenchymal stem cells (
MSC
s), promotes their terminal differentiation into adipocytes rather than endothelial cells, thereby promotes adipocytic infiltration into ischemic muscles, and reduces their capacity to participate in postischemic neovascularization.

Methods and Results

To test this hypothesis, we transplanted
MSC
s from
db/db
or wild‐type (
WT
) mice into
WT
recipients after induction of hind limb ischemia.
WT
recipients of
db/db
MSC
s demonstrated adipocyte infiltration of ischemic muscle and impaired neovascularization;
WT
recipients of
WT MSC
s showed no intramuscular adipocyte infiltration and had significantly enhanced neovascularization (
P
<0.05; n=6). Confocal microscopy showed that the percentage of
MSC
s that differentiated into an adipocyte phenotype was greater and into an endothelial cell was less in
WT
recipients transplanted with
db/db
MSC
s than those transplanted with
WT MSC
s (
P
<0.05; n=6). In vitro,
db/db
MSC
s exhibited greater oxidant stress, greater adipocyte differentiation, and less endothelial differentiation than
WT MSC
s, and these differences were reversed by treatment with
N
‐acetylcysteine or
Nox4 siRNA
(
P
<0.05; n=6). Insulin increased
Nox4
expression, oxidant stress, and adipocyte differentiation in
WT MSC
s, and these insulin‐induced effects were reversed by
Nox4 siRNA
(
P
<0.05; n=6). Reversal of
db/db
MSC
oxidant stress by in vivo pretreatment with
Nox4 siRNA
before transplantation reversed their impaired capacity to augment postischemic neovascularization.

Conclusions

Type 2 diabetes–induced oxidant stress restricts the multipotency of
MSC
s and impairs their capacity to increase blood flow recovery after the induction of hind‐limb ischemia. Reversal of
MSC
oxidant stress might permit greater leverage of the therapeutic potential of
MSC
transplantation in the setting of diabetes.
Near Infrared Imaging and Photothermal Ablation of Vascular Inflammation Using Single‐Walled Carbon Nanotubes
Authors: Kosuge Hisanori , Sherlock Sarah P. , Kitagawa Toshiro , Dash Rajesh , Robinson Joshua T. , Dai Hongjie , McConnell Michael V.
Published: May 2013

Background

Macrophages are critical contributors to atherosclerosis. Single‐walled carbon nanotubes (
SWNT
s) show promising properties for cellular imaging and thermal therapy, which may have application to vascular macrophages.

Methods and Results

In vitro uptake and photothermal destruction of mouse macrophage cells (
RAW
264.7) were performed with
SWNT
s (14.7 nmol/L) exposed to an 808‐nm light source.
SWNT
s were taken up by 94±6% of macrophages, and light exposure induced 93±3% cell death. In vivo vascular macrophage uptake and ablation were then investigated in carotid‐ligated
FVB
mice (n=33) after induction of hyperlipidemia and diabetes. Two weeks postligation, near‐infrared fluorescence (
NIRF
) carotid imaging (n=12) was performed with
SWNT
‐Cy5.5 (8 nmol of Cy5.5) given via the tail vein. Photothermal heating and macrophage apoptosis were evaluated on freshly excised carotid arteries (n=21).
NIRF
of
SWNT
s showed higher signal intensity in ligated carotids compared with sham, confirmed by both in situ and ex vivo
NIRF
imaging (
P
<0.05, ligation versus sham). Immunofluorescence staining showed colocalization of
SWNT
‐Cy5.5 and macrophages in atherosclerotic lesions. Light (808 nm) exposure of freshly excised carotids showed heating and induction of macrophage apoptosis in ligated left carotid arteries with
SWNT
s, but not in control groups without
SWNT
s or without light exposure.

Conclusions

Carbon nanotubes accumulate in atherosclerotic macrophages in vivo and provide a multifunctional platform for imaging and photothermal therapy of vascular inflammation.
Peroxiredoxin 4, A Novel Circulating Biomarker for Oxidative Stress and the Risk of Incident Cardiovascular Disease and All‐Cause Mortality
Authors: Abbasi Ali , Corpeleijn Eva , Postmus Douwe , Gansevoort Ron T. , de Jong Paul E. , Gans Rijk O. B. , Struck Joachim , Schulte Janin , Hillege Hans L. , van der Harst Pim , Peelen Linda M. , Beulens Joline W. J. , Stolk Ronald P. , Navis Gerjan , Bakker Stephan J. L.
Published: May 2013

Background

Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (
CVD
). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (
Prx
4), a hydrogen peroxide–degrading peroxidase, with incident
CVD
and all‐cause mortality. We subsequently examined the incremental value of
Prx
4 for the risk prediction of
CVD
compared with the
F
ramingham risk score (
FRS
).

Methods and Results

We performed
C
ox regression analyses in 8141 participants without history of
CVD
(aged 28 to 75 years; women 52.6%) from the
P
revention of
R
enal and
V
ascular
E
nd‐stage
D
isease (
PREVEND
) study in
G
roningen, The
N
etherlands. Serum
Prx
4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident
CVD
events or
CVD
mortality and (2) all‐cause mortality during a median follow‐up of 10.5 years. In total, 708 participants (7.8%) developed
CVD
events or
CVD
mortality, and 517 participants (6.3%) died. Baseline serum
Prx
4 levels were significantly higher in participants with incident
CVD
events or
CVD
mortality and in those who died than in participants who remained free of outcomes (both
P
<0.001). In multivariable models with adjustment for
F
ramingham risk factors, hazard ratios were 1.16 (95%
CI
1.06 to 1.27,
P
<0.001) for incident
CVD
events or
CVD
mortality and 1.17 (95%
CI
1.06 to 1.29,
P
=0.003) for all‐cause mortality per doubling of
Prx
4 levels. After the addition of
Prx
4 to the
FRS
, the net reclassification improvement was 2.7% (
P
=0.01) using 10‐year risk categories of
CVD
.

Conclusions

Elevated serum
Prx
4 levels are associated with a significantly higher risk of incident
CVD
events or
CVD
mortality and all‐cause mortality after adjustment for clinical risk factors. The addition of
Prx
4 to the
FRS
marginally improved risk prediction of future
CVD
.
OPA1 Mutation and Late‐Onset Cardiomyopathy: Mitochondrial Dysfunction and mtDNA Instability
Authors: Chen Le , Liu Tingting , Tran Alice , Lu Xiyuan , Tomilov Alexey A. , Davies Vanessa , Cortopassi Gino , Chiamvimonvat Nipavan , Bers Donald M. , Votruba Marcela , Knowlton Anne A.
Published: May 2013

Background

Mitochondrial fusion protein mutations are a cause of inherited neuropathies such as Charcot–Marie–Tooth disease and dominant optic atrophy. Previously we reported that the fusion protein optic atrophy 1 (
OPA
1) is decreased in heart failure.

Methods and Results

We investigated cardiac function, mitochondrial function, and
mtDNA
stability in a mouse model of the disease with
OPA
1 mutation. The homozygous mutation is embryonic lethal. Heterozygous
OPA
+/−
mice exhibit reduced
mtDNA
copy number and decreased expression of nuclear antioxidant genes at 3 to 4 months. Although initial cardiac function was normal, at 12 months the
OPA
1
+/−
mouse hearts had decreased fractional shortening, cardiac output, and myocyte contraction. This coincided with the onset of blindness. In addition to small fragmented mitochondria, aged
OPA
1
+/−
mice had impaired cardiac mitochondrial function compared with wild‐type littermates.

Conclusions

OPA
1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late‐onset cardiomyopathy.
Fasting Serum C‐Peptide Levels Predict Cardiovascular and Overall Death in Nondiabetic Adults
Authors: Patel Nileshkumar , Taveira Tracey H. , Choudhary Gaurav , Whitlatch Hilary , Wu Wen‐Chih
Published: May 2013

Background

Insulin resistance, characterized by hyperinsulinemia and normal or elevated serum glucose, is an established precursor to diabetes and cardiovascular disease. Despite fasting serum C‐peptide levels being an accurate and stable marker of endogenous insulin production used in patients with diabetes, it is unknown whether C‐peptide could serve as a marker of insulin resistance and predict outcomes in patients without diabetes.

Method and Results

This is a retrospective cohort study using data from the
NHANES
‐3 (1988–1994) survey with mortality follow‐up through
D
ecember 31, 2006. Participants included 5153 subjects, 40 to 74 years of age with fasting glucose ≥70 mg/dL, without diabetes by history or laboratory testing. Receiver‐operating‐curve analysis compared fasting C‐peptide against known insulin resistance measures such as fasting plasma glucose, serum insulin,
HOMA
‐
IR
, quantitative‐insulin‐sensitivity‐check‐index, and metabolic syndrome for the prediction of cardiovascular and overall death. Subjects were then stratified by quartiles of C‐peptide levels.
C
ox proportional‐hazards modeling compared hazards of cardiovascular and overall death amongst C‐peptide quartiles and adjusted for potential confounders of cardiovascular and diabetes risk. Fasting serum C‐peptide levels predicted cardiovascular and overall death better than other studied measures (
AUC
=0.62 and 0.60 respectively vs the rest, with
AUC
≤0.58 and ≤0.57 respectively,
P
<0.001). When compared with the lowest C‐peptide quartile, subjects in the highest quartile had significantly higher adjusted hazard ratios (
HR
) of cardiovascular death (
HR
=1.60, 95%
CI
1.07 to 2.39) and overall mortality (
HR
=1.72, 95%
CI
1.34 to 2.21) after controlling for confounders.

Conclusions

C‐peptide levels significantly related to hazards of cardiovascular and overall death in nondiabetic adults and was a better predictor of these outcomes than serum insulin and/or glucose derived measures.
MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE
−/−
Mice
Authors: Horie Takahiro , Baba Osamu , Kuwabara Yasuhide , Chujo Yoshimasa , Watanabe Shin , Kinoshita Minako , Horiguchi Masahito , Nakamura Tomoyuki , Chonabayashi Kazuhisa , Hishizawa Masakatsu , Hasegawa Koji , Kume Noriaki , Yokode Masayuki , Kita Toru , Kimura Takeshi , Ono Koh
Published: May 2013

Background

Cholesterol efflux from cells to apolipoprotein A‐I (apoA‐I) acceptors via the
ATP
‐binding cassette transporters
ABCA
1 and
ABCG
1 is thought to be central in the antiatherogenic mechanism. Micro
RNA
(miR)‐33 is known to target
ABCA
1 and
ABCG
1 in vivo.

Methods and Results

We assessed the impact of the genetic loss of miR‐33 in a mouse model of atherosclerosis. MiR‐33 and apoE double‐knockout mice (miR‐33
−/−
Apoe
−/−
) showed an increase in circulating
HDL‐C
levels with enhanced cholesterol efflux capacity compared with miR‐33
+/+
Apoe
−/−
mice. Peritoneal macrophages from miR‐33
−/−
Apoe
−/−
mice showed enhanced cholesterol efflux to apoA‐I and
HDL‐C
compared with miR‐33
+/+
Apoe
−/−
macrophages. Consistent with these results, miR‐33
−/−
Apoe
−/−
mice showed reductions in plaque size and lipid content. To elucidate the roles of miR‐33 in blood cells, bone marrow transplantation was performed in these mice. Mice transplanted with miR‐33
−/−
Apoe
−/−
bone marrow showed a significant reduction in lipid content in atherosclerotic plaque compared with mice transplanted with miR‐33
+/+
Apoe
−/−
bone marrow, without an elevation of
HDL‐C
. Some of the validated targets of miR‐33 such as
RIP
140 (
NRIP
1) and
CROT
were upregulated in miR‐33
−/−
Apoe
−/−
mice compared with miR‐33
+/+
Apoe
−/−
mice, whereas
CPT
1a and
AMPK
α were not.

Conclusions

These data demonstrate that miR‐33 deficiency serves to raise
HDL‐C
, increase cholesterol efflux from macrophages via
ABCA
1 and
ABCG
1, and prevent the progression of atherosclerosis. Many genes are altered in miR‐33‐deficient mice, and detailed experiments are required to establish miR‐33 targeting therapy in humans.
High Familial Risk of Atrial Fibrillation/Atrial Flutter in Multiplex Families: A Nationwide Family Study in Sweden
Authors: Zöller Bengt , Ohlsson Henrik , Sundquist Jan , Sundquist Kristina
Published: May 2013

Background

Although the heritability of atrial fibrillation/atrial flutter (
AF
/
AF
l) has been determined, the familial risk in multiplex families is unclear. The main aim of this nationwide study was to determine the familial risk of
AF
/
AF
l in multiplex families.

Methods and Results

We examined the familial risk of
AF
/
AF
l in the entire Swedish population. We linked Multigeneration Register data on individuals aged 0 to 76 years with Hospital Discharge Register data for 1987–2008 and Outpatient Register data for 2001–2008 to compare
AF
/
AF
l risk among relatives of all 300 586 individuals with
AF
/
AF
l with that among relatives of unaffected individuals. We used conditional logistic regression to investigate differences in exposure between cases and controls. Parents (odds ratio [
OR
] 1.95 [95% CI 1.89 to 2.00]) and siblings (
OR
=3.08 [3.00 to 3.16]) of cases had higher odds of
AF
/
AF
l than did parents and siblings of controls.
AF
/
AF
l
OR
s were increased in both sexes. For 2% of cases, both parents had
AF
/
AF
l, compared with only 0.7% of controls (
OR
=3.60 [3.30 to 3.92]). Moreover, 3% of cases had ≥2 siblings with
AF
/
AF
l, compared with 1% of controls (
OR
=5.72 [5.28 to 6.19]). In premature cases (diagnosed at age <50 years), the
OR
s were 5.04 (4.36 to 5.82) and 8.51 (6.49 to 11.15) for
AF
/
AF
l in both parents and
AF
/
AF
l in ≥2 siblings, respectively. The overall spouse
OR
was 1.16 (1.13 to 1.19).

Conclusions

Family history of
AF
/
AF
l increases the odds of
AF
/
AF
l in first‐degree relatives. High familial risks were observed in multiplex families.
Arterial Retention of Remnant Lipoproteins Ex Vivo Is Increased in Insulin Resistance Because of Increased Arterial Biglycan and Production of Cholesterol‐Rich Atherogenic Particles That Can Be Improved by Ezetimibe in the JCR:LA‐
cp
Rat
Authors: Mangat Rabban , Warnakula Samantha , Borthwick Faye , Hassanali Zahra , Uwiera Richard R.E. , Russell James C. , Cheeseman Christopher I. , Vine Donna F. , Proctor Spencer D.
Published: May 2013

Background

Literature supports the “response‐to‐retention” hypothesis—that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA‐
cp
rat model of metabolic syndrome (
MetS
) to determine the extent of arterial accumulation of intestinal‐derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance.

Methods and Results

Arteries from control and
MetS
(insulin‐resistant) JCR:LA‐
cp
rats were perfused ex vivo with Cy5‐labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and
MetS
rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in
MetS
rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol‐rich intestinal‐derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant‐derived cholesterol ex vivo as compared to untreated controls.

Conclusions

Increased progression of atherosclerotic cardiovascular disease in
MetS
and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol‐rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and
MetS
.
Adipocyte Triglyceride Turnover Is Independently Associated With Atherogenic Dyslipidemia
Authors: Frayn Keith , Bernard Samuel , Spalding Kirsty , Arner Peter
Published: May 2013

Background

Inappropriate storage of fatty acids as triglycerides in adipocytes and their removal from adipocytes through lipolysis and subsequent oxidation may cause the atherogenic dyslipidemia phenotype of elevated apolipoprotein B levels and subsequent hypertriglyceridemia. We tested whether turnover of triglycerides in fat cells was related to dyslipidemia.

Methods and Results

The age of triglycerides (reflecting removal) and triglyceride storage in adipocytes was determined under free living conditions by measuring incorporation of atmospheric
14
C into these lipids within the adipocytes in 47 women and 26 men with a large interindividual variability in body mass index. Because limited
14
C data were available, triglyceride age was also determined in 97 men and 233 women by using an algorithm based on adipocyte lipolysis, body fat content, waist‐to‐hip ratio, and insulin sensitivity. This cohort consisted of nonobese subjects since obesity per se is related to all components in the algorithm. Triglyceride turnover (age and storage) was compared with plasma levels of apolipoproteins and lipids. Plasma levels of apolipoprotein B and triglycerides were positively related to triglyceride age in adipocytes, when measured directly using radiocarbon analyses (
r
=0.45 to 0.47;
P
<0.0001). This effect was independent of subject age, waist circumference measures, and insulin sensitivity (partial
r
=0.29 to 0.45;
P
from 0.03 to <0.0001). Triglyceride storage showed no independent correlation (partial
r
=0.02 to 0.11;
P
=0.42 to 0.91). Algorithm‐based values for adipocyte removal of triglycerides were positively associated with plasma triglycerides and apolipoprotein B (
r
=0.44 to 0.45;
P
<0.0001) and (also positively) with the inflammation status of adipose tissue (
r
=0.39 to 0.47;
P
<0.05). These correlations were statistically independent of subject age and observed in men and women as well as in lean and overweight subjects when subgroups were examined separately.

Conclusions

Decreased removal of adipocyte triglycerides (as indicated by a high triglyceride age in fat cells) is independently associated with circulating apolipoprotein B and triglycerides. This suggests a hitherto unknown role of triglyceride turnover in adipocytes for the development and/or maintenance of atherogenic dyslipidemia.
Risks of Death and Graft Failure After Surgical Versus Percutaneous Coronary Revascularization in Renal Transplant Patients
Authors: Charytan David M. , Li Shuling , Liu Jiannong , Qiu Yang , Herzog Charles A.
Published: May 2013

Background

Reliable data regarding absolute and relative risks of death and graft failure after coronary artery bypass graft surgery (
CABG
) and percutaneous coronary intervention (
PCI
) in renal transplant patients are unavailable.

Methods and Results

Renal transplant patients undergoing inpatient
CABG
(n=1400) or
PCI
(n=4097) were identified from
U
nited
S
tates
R
enal
D
ata
S
ystem data. Cumulative incidence of nonfatal graft failure and death was reported for observed events. A
C
ox model with the
F
ine–
G
ray method was used to account for competing risks in assessing relative hazards. Age and race were similarly distributed; patients who underwent
CABG
were more likely to have acute arrhythmia and congestive heart failure but less likely to have acute myocardial infarction on index admission. In‐hospital death was more frequent after
CABG
(5.6% versus 3.0%,
P
<0.001). Cumulative incidence of death, graft failure, and the combined outcome at 3 years were 23.1%, 15.4%, and 38.5% after
CABG
and 22.9%, 13.3%, and 36.1% after
PCI
, respectively. In adjusted analyses,
CABG
was not associated with increased risk of graft failure versus
PCI
during the first 6 months (hazard ratio 1.06, 95% CI 0.79 to 1.43) or from 6 to 36 months (0.98, 0.78 to 1.22). Risk of death increased after
CABG
during the first 3 months (1.37, 1.08 to 1.73), but decreased from 6 months on (0.76, 0.63 to 0.93).

Conclusions

CABG
does not appear to be associated with a difference in risk of graft failure compared with
PCI
in renal transplant patients. Compared with
PCI
, adjusted risk of early death is higher after
CABG
; however, mortality from 6 months on is lower.