bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulus Intensity in Left Ventricular Leads and Response to Cardiac Resynchronization Therapy
Authors: Bavikati Venkata V. , Langberg Jonathan J. , Williams B. Robinson , Kella Danesh , Lloyd Michael S.
Published: May 2013

Background

Increased left ventricular (
LV
) stimulus intensity has been shown to improve conduction velocity and cardiac output. However, high‐output pacing would shorten device battery life. Our prospective trial analyzed the clinical effects of high‐ versus low‐output
LV
pacing.

Methods and Results

Thirty‐nine patients undergoing initial cardiac resynchronization therapy device implantation with bipolar
LV
leads were assigned to 3 months of either high‐output
LV
pacing (Hi) or low‐output
LV
pacing (Lo) in a randomized, blinded crossover fashion. Hi and Lo settings were determined with a rigorous intraoperative protocol specific to each patient. Clinical and echocardiographic data were obtained at randomization, at 3 months, and a subsequent 3 months after crossover. Mean age was 66.4±9.8 years, and mean
QRS
duration was 159.3±23.1 ms. Compared to baseline, both arms had significant improvements in Minnesota Living With Heart Failure score (given as mean [95% confidence interval]) (baseline versus Lo: 43.3 [35.5 to 51.1] versus 21.3 [14.6 to 28.0],
P
<0.01; baseline versus Hi: 43.3 [35.5 to 51.1] versus 23.6 [16.1 to 31.1],
P
<0.01) and 6‐minute walk distance (baseline versus Lo: 692 ft [581 to 804] versus 995 ft [876 to 1114],
P
<0.01; baseline versus Hi: 699 ft [585 to 813] versus 982 ft [857 to 1106],
P
<0.01). Although both Hi and Lo arms had some echocardiographic parameters that significantly improved compared to baseline (baseline end‐diastolic diameter 5.7 cm [5.5 to 6.0] versus Lo 5.5 cm [5.1 to 5.8],
P
<0.01; baseline end‐systolic diameter 4.9 cm [4.6 to 5.3] versus Hi 4.7 cm [4.3 to 5.0],
P
<0.05), there were no significant differences observed when comparing the Hi‐ versus Lo‐output arms.

Conclusions

Low‐output
LV
pacing with a relatively narrow safety margin above capture threshold affords significant improvement from baseline and is clinically equivalent to high‐output
LV
pacing. These data support a strategy of minimizing the programmed
LV
safety margin to increase battery life in cardiac resynchronization therapy devices.

Clinical Trial Registration Information

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01060449
Prospective Relationship of Low Cardiovascular Risk Factor Profile at Younger Ages to Ankle‐Brachial Index: 39‐Year Follow‐Up—The Chicago Healthy Aging Study
Authors: Vu Thanh‐Huyen T. , Stamler Jeremiah , Liu Kiang , McDermott Mary M. , Lloyd‐Jones Donald M. , Pirzada Amber , Garside Daniel B. , Daviglus Martha L.
Published: May 2013

Background

Data are sparse regarding the long‐term association of favorable levels of all major cardiovascular disease risk factors (RFs) (ie, low risk [
LR
]) with ankle‐brachial index (
ABI
).

Methods and Results

In 2007–2010, the
C
hicago
H
ealthy
A
ging
S
tudy reexamined a subset of participants aged 65 to 84 years from the
C
hicago
H
eart
A
ssociation
D
etection
P
roject in
I
ndustry cohort (baseline examination, 1967–1973).
RF
groups were defined as
LR
(untreated blood pressure ≤120/≤80 mm Hg, untreated serum cholesterol <200 mg/dL, body mass index <25 kg/m
2
, not smoking, no diabetes) or as 0
RF
s, 1
RF
, or 2+
RF
s based on the presence of blood pressure ≥140/≥90 mm Hg or receiving treatment, serum cholesterol ≥240 mg/dL or receiving treatment, body mass index ≥30 kg/m
2
, smoking, or diabetes.
ABI
at follow‐up was categorized as indicating
PAD
present (≤0.90), as borderline
PAD
(0.91 to 0.99), or as normal (1.00 to 1.40). We included 1346 participants with
ABI
≤1.40. After multivariable adjustment, the presence of fewer baseline
RF
s was associated with a lower likelihood of
PAD
at 39‐year follow‐up (
P
for trend is <0.001). Odds ratios (95% CIs) for
PAD
in persons with
LR
, 0
RF
s, or 1
RF
compared with those with 2+
RF
s were 0.14 (0.05 to 0.44), 0.28 (0.13 to 0.59), and 0.33 (0.16 to 0.65), respectively; findings were similar for borderline
PAD
(
P
for trend is 0.005). The association was mainly due to baseline smoking status, cholesterol, and diabetes. Remaining free of adverse
RF
s or improving
RF
status over time was also associated with
PAD
.

Conclusions

LR
profile in younger adulthood (ages 25 to 45) is associated with the lowest prevalence of
PAD
and borderline
PAD
39 years later.
Relation Between Serum Total Cholesterol Level and Cardiovascular Disease Stratified by Sex and Age Group: A Pooled Analysis of 65 594 Individuals From 10 Cohort Studies in Japan
Authors: Nagasawa Sin‐ya , Okamura Tomonori , Iso Hiroyasu , Tamakoshi Akiko , Yamada Michiko , Watanabe Makoto , Murakami Yoshitaka , Miura Katsuyuki , Ueshima Hirotsugu ,   for the Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH‐JAPAN) Research Group
Published: May 2013

Background

The relation between serum total cholesterol (
TC
) and cardiovascular disease in women and in the elderly is unclear, especially in
A
sian populations.

Methods and Results

We examined this relation in the largest‐scale pooled analysis of the
J
apanese population, the Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (
EPOCH
‐
JAPAN
) study. A total of 65 594 participants who were 40 to 89 years of age and did not have a past history of cardiovascular disease were examined.
C
ox proportional‐hazards models were used to estimate hazard ratios for death from total stroke, cerebral infarction, intracranial cerebral hemorrhage, or coronary heart disease. The mean follow‐up period was 10.1 years, with the number of deaths from total stroke, cerebral infarction, cerebral hemorrhage, and coronary heart disease being 875, 457, 212, and 374, respectively. The participants were divided into 2 age groups: middle‐aged (40 to 69 years; mean age 55 years) and elderly (70 to 89 years; mean age 75 years). In men, the multivariate‐adjusted hazard ratios for coronary heart disease in the highest
TC
category (≥6.21 mmol/L) compared with the lowest category (<4.14 mmol/L) were 2.52 (95% confidence interval: 1.15–5.07) in middle‐aged participants and 2.77 (1.09–7.03) in elderly participants. In women, the hazard ratios of the highest
TC
category (≥6.72 mmol/L) compared with the lowest category (<4.66 mmol/L) were 3.20 (1.44–7.09) in middle‐aged participants and 1.02 (0.42–2.49) in elderly participants.
TC
levels were not associated with cerebral infarction in any age or sex group and were associated negatively with total stroke and cerebral hemorrhage.

Conclusion

High serum
TC
levels are associated with coronary heart disease in middle‐aged
J
apanese men and women, but evidence in elderly
J
apanese individuals is still limited.
Microvascular Coronary Artery Spasm Presents Distinctive Clinical Features With Endothelial Dysfunction as Nonobstructive Coronary Artery Disease
Authors: Ohba Keisuke , Sugiyama Seigo , Sumida Hitoshi , Nozaki Toshimitsu , Matsubara Junichi , Matsuzawa Yasushi , Konishi Masaaki , Akiyama Eiichi , Kurokawa Hirofumi , Maeda Hirofumi , Sugamura Koichi , Nagayoshi Yasuhiro , Morihisa Kenji , Sakamoto Kenji , Tsujita Kenichi , Yamamoto Eiichiro , Yamamuro Megumi , Kojima Sunao , Kaikita Koichi , Tayama Shinji , Hokimoto Seiji , Matsui Kunihiko , Sakamoto Tomohiro , Ogawa Hisao
Published: May 2013

Background

Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular 
CAS
) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular 
CAS
and the therapeutic efficacy of calcium channel blockers.

Methods and Results

Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular 
CAS
according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular
CAS
who demonstrated significant impairment of the endothelium‐dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular
CAS
. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor–borderline ischemic electrocardiogram findings at rest, limited–baseline diastolic‐to‐systolic velocity ratio, and attenuated adenosine triphosphate–induced coronary flow reserve were independently correlated with the presence of microvascular
CAS
. Receiver‐operating characteristics curve analysis revealed that the aforementioned 5‐variable model showed good correlation with the presence of microvascular
CAS
(area under the curve: 0.820). No patients with microvascular
CAS
treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months.

Conclusions

Microvascular
CAS
causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided.

Clinical Trial Registration

URL:
www.umin.ac.jp/ctr
. Unique identifier: UMIN000003839.
Premature Cardiac Contractions and Risk of Incident Ischemic Stroke
Authors: Ofoma Uchenna , He Fan , Shaffer Michele L. , Naccarelli Gerard V. , Liao Duanping
Published: May 2013

Background

The etiologies of ischemic stroke remain undetermined in 15% to 40% of patients. Apart from atrial fibrillation, other arrhythmias are less well‐characterized as risk factors. Premature cardiac contractions are known to confer long‐term cardiovascular risks, like myocardial infarction. Ischemic stroke as cardiovascular risk outcome remains a topic of interest. We examined the prospective relationships in the Atherosclerosis Risk in Communities (
ARIC
) study, to determine whether premature atrial (
PAC
) or ventricular (
PVC
) contractions are associated with increased risk for incident ischemic stroke.

Methods and Results

We analyzed 14 493 baseline stroke‐free middle‐aged individuals in the
ARIC
public‐use data. The presence of PAC or PVC at baseline was assessed from 2‐minute electrocardiogram. A physician‐panel confirmed and classified all stroke cases. Average follow‐up time was 13 years. Proportional hazards models assessed associations between premature contractions and incident stroke.
PAC
s and
PVC
s were identified in 717 (4.9%) and 793 (5.5%) participants, respectively. In all, 509(3.5%) participants developed ischemic stroke. The hazard ratio (
HR
) (95% confidence interval [
CI
]) associated with
PVC
was 1.77 (1.30, 2.41), attenuated to 1.25 (0.91, 1.71) after adjusting for baseline stroke risk factors. The interaction between
PVC
and baseline hypertension was marginally significant (
P
=0.08). Among normotensives, having
PVC
s was associated with nearly 2‐fold increase in the rate of incident ischemic stroke (
HR
1.69; 95%
CI
1.02, 2.78), adjusting for stroke risk factors. The adjusted risk of ischemic stroke associated with
PAC
s was 1.30 (95%
CI
0.92, 1.83).

Conclusions

Presence of
PVC
s may indicate an increased risk of ischemic stroke, especially in normotensives. This risk approximates risk of stroke from being black, male, or obese in normotensives from this cohort.
Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
Authors: Bonaterra Gabriel A. , Zügel Stefanie , Thogersen Joel , Walter Sabrina A. , Haberkorn Uwe , Strelau Jens , Kinscherf Ralf
Published: May 2013

Background

Growth differentiation factor (
GDF
)‐15 is a distant and divergent member of the transforming growth factor‐β superfamily (TGF‐β) . There is growing evidence indicating the involvement of
GDF
‐15 in various pathologies. Expression of
GDF
‐15 is induced under conditions of inflammation and increased
GDF
‐15 serum levels are suggested as a risk factor for cardiovascular diseases.

Methods and Results

We show here that
GDF
‐15 and proinflammatory cytokine interleukin (
IL
)‐6 levels are highly increased (5‐fold) in cultured oxidized low‐density lipoproteins–stimulated peritoneal macrophages derived from
GDF
‐15
+/+
/apolipoprotein (apo)
E
−/−
, mice. Notably,
IL
‐6 induction on oxidized low‐density lipoproteins stimulation is completely abolished in the absence of
GDF
‐15. Consistent with our in vitro data
GDF
‐15
mRNA
expression and protein levels are upregulated (2.5‐ to 6‐fold) in the atherosclerotic vessel wall of
GDF
‐15
+/+
/apo
E
−/−
mice after a cholesterol‐enriched diet.
GDF
‐15 deficiency inhibits lumen stenosis (52%) and
18
FDG
uptake (34%) in the aortic arch despite increased serum triglyceride/cholesterol levels and elevated body weight. Immunohistomorphometric investigations of atherosclerotic lesions reveal a decreased percentage of inflammatory
CD
11b
+
(57%) or
IL
‐6
+
, leukocytes, and apoptotic cells (74%) after 20 weeks. However, the total number of macrophages and cell density in atherosclerotic lesions of the innominate artery are increased in
GDF
‐15
−/−
/apo
E
−/−
mice.

Conclusions

Our data suggest that
GDF
‐15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and
IL
‐6–dependent inflammatory responses to vascular injury.
Recent Trends in Adherence to Secondary Prevention Guidelines for Patients Undergoing Coronary Revascularization in Washington State: An Analysis of the Clinical Outcomes Assessment Program (COAP) Registry
Authors: Riley Robert F. , Don Creighton W. , Aldea Gabriel S. , Mokadam Nahush A. , Probstfield Jeffrey , Maynard Charles , Goss J. Richard
Published: May 2013

Background

Previous studies indicated that patients undergoing coronary artery bypass graft (
CABG
) surgery are less likely to receive guideline‐based secondary prevention therapy than are those undergoing percutaneous coronary intervention (
PCI
) after an acute myocardial infarction. We aimed to evaluate whether these differences have persisted after the implementation of public reporting of hospital metrics.

Methods and Results

The Clinical Outcomes Assessment Program (COAP) database was analyzed retrospectively to evaluate adherence to secondary prevention guidelines at discharge in patients who underwent coronary revascularization after an acute
ST
‐elevation myocardial infarction in Washington State. From 2004 to 2007, 9260 patients received
PCI
and 692 underwent
CABG
for this indication. Measures evaluated included prescription of aspirin, β‐blockers, angiotensin‐converting enzyme inhibitors or angiotensin
II
receptor blockers, or lipid‐lowering medications; cardiac rehabilitation referral; and smoking‐cessation counseling. Composite adherence was lower for
CABG
than for
PCI
patients during the period studied (79.6% versus 89.7%,
P
<0.01). Compared to patients who underwent
CABG
, patients who underwent
PCI
were more likely to receive each of the pharmacological therapies. There was no statistical difference in smoking‐cessation counseling (91.7% versus 90.3%,
P
=0.63), and
CABG
patients were more likely to receive referral for cardiac rehabilitation (70.9% versus 48.3%,
P
<0.01). Adherence rates improved over time among both groups, with no significant difference in composite adherence in 2006 (85.6% versus 87.6%,
P
=0.36).

Conclusions

Rates of guideline‐based secondary prevention adherence in patients with
ST
‐elevation myocardial infarction who underwent
CABG
surgery have been improving steadily in
W
ashington
S
tate. The improvement possibly is associated with the implementation of public reporting of quality measures.
Relation of Carotid Artery Diameter With Cardiac Geometry and Mechanics in Heart Failure With Preserved Ejection Fraction
Authors: Liao Zhen‐Yu , Peng Ming‐Cheng , Yun Chun‐Ho , Lai Yau‐Huei , Po Helen L. , Hou Charles Jia‐Yin , Kuo Jen‐Yuan , Hung Chung‐Lieh , Wu Yih‐Jer , Bulwer Bernard E. , Yeh Hung‐I , Tsai Cheng‐Ho
Published: May 2013

Background

Central artery dilation and remodeling are associated with higher heart failure and cardiovascular risks. However, data regarding carotid artery diameter from hypertension to heart failure have remained elusive. We sought to investigate this issue by examining the association between carotid artery diameter and surrogates of ventricular dysfunction.

Methods and Results

Two hundred thirteen consecutive patients including 49 with heart failure and preserved ejection fraction (
HFpEF
), 116 with hypertension, and an additional 48 healthy participants underwent comprehensive echocardiography and tissue
D
oppler imaging. Ultrasonography of the common carotid arteries was performed for measurement of intima‐media thickness and diameter (
CCAD
). Cardiac mechanics, including
LV
twist, were assessed by novel speckle‐tracking software. A substantial graded enlargement of
CCAD
was observed across all 3 groups (6.8±0.6, 7.7±0.73, and 8.7±0.95 mm for normal, hypertension, and
HFpEF
groups, respectively;
ANOVA
P
<0.001) and correlated with serum brain natriuretic peptide level (
R
2
=0.31,
P
<0.001). Multivariable models showed that
CCAD
was associated with increased
LV
mass,
LV
mass‐to‐volume ratio (β‐coefficient=10.9 and 0.11, both
P
<0.001), reduced
LV
longitudinal and radial strain (β‐coeffficient=0.81 and −3.1, both
P
<0.05), and twist (β‐coefficient=−0.84,
P
<0.05).
CCAD
set at 8.07 mm as a cut‐off had a 77.6% sensitivity, 82.3% specificity, and area under the receiver operating characteristic curves (
AUROC
) of 0.86 (95% CI 0.80 to 0.92) in discriminating
HFpEF
. In addition,
CCAD
superimposed on myocardial deformation significantly expanded
AUROC
(for longitudinal strain, from 0.84 to 0.90,
P
of Δ
AUROC
=0.02) in heart failure discrimination models.

Conclusions

Increased carotid artery diameter is associated with worse LV geometry, higher brain natriuretic peptide level, and reduced contractile mechanics in individuals with
HFpEF
.
Dipeptidyl Peptidase‐4 Inhibitors Attenuate Endothelial Function as Evaluated by Flow‐Mediated Vasodilatation in Type 2 Diabetic Patients
Authors: Ayaori Makoto , Iwakami Naotsugu , Uto‐Kondo Harumi , Sato Hiroki , Sasaki Makoto , Komatsu Tomohiro , Iizuka Maki , Takiguchi Shunichi , Yakushiji Emi , Nakaya Kazuhiro , Yogo Makiko , Ogura Masatsune , Takase Bonpei , Murakami Takehiko , Ikewaki Katsunori
Published: May 2013

Background

Endothelial dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes (
T2DM
). Glucagon like peptide‐1 (
GLP
‐1) reportedly exerts vasodilatory actions, and inhibitors of dipeptidyl peptidase‐4 (
DPP
‐4), an enzyme‐degrading
GLP
‐1, are widely used to treat
T2DM
. We therefore hypothesized that
DPP
‐4 inhibitors (
DPP
‐4Is) improve endothelial function in
T2DM
patients and performed 2 prospective, randomized crossover trials to compare the
DPP
‐4I sitagliptin and an α‐glucosidase inhibitor, voglibose (in study 1) and the
DPP
‐4Is sitagliptin and alogliptin (in study 2).

Methods and Results

In study 1, 24 men with
T2DM
(46±5 years) were randomized to sitagliptin or voglibose for 6 weeks without washout periods. Surprisingly, sitagliptin significantly reduced flow‐mediated vasodilatation (
FMD
; −51% compared with baseline,
P
<0.05) of the brachial artery despite improved diabetic status. In contrast, voglibose did not affect
FMD
. To confirm this result and determine whether it is a class effect, we conducted another trial (study 2) to compare sitagliptin and alogliptin in 42
T2DM
patients (66±8 years) for 6 weeks with 4‐week washout periods. Both
DPP
‐4Is improved glycemic control but significantly attenuated
FMD
(7.2/4.3%,
P
<0.001, before/after sitagliptin; 7.0/4.8%,
P
<0.001, before/after alogliptin, respectively). Interestingly,
FMD
reduction was less evident in subjects who were on statins or whose
LDL
cholesterol levels were reduced by them, but this was not correlated with parameters including
DPP
‐4 activity and
GLP
‐1 levels or diabetic parameters.

Conclusions

Our 2 independent trials demonstrated that
DPP
‐4 inhibition attenuated endothelial function as evaluated by
FMD
in
T2DM
patients. This unexpected unfavorable effect may be a class effect of
DPP
‐4Is.

Clinical Trial Registration

URL:
http://center.umin.ac.jp
, Unique Identifiers: UMIN000005682 (sitagliptin versus voglibose) and UMIN000005681 (sitagliptin versus alogliptin).
Successful Use of mRNA‐Nucleofection for Overexpression of Interleukin‐10 in Murine Monocytes/Macrophages for Anti‐inflammatory Therapy in a Murine Model of Autoimmune Myocarditis
Authors: Zimmermann Oliver , Homann Jörg M. , Bangert Anna , Müller Anna‐Maria , Hristov Georgi , Goeser Stefan , Wiehe Juliane M. , Zittrich Stefan , Rottbauer Wolfgang , Torzewski Jan , Pfitzer Gabriele , Katus Hugo A. , Kaya Ziya
Published: May 2013

Background

Overexpression of interleukin‐10 (
IL
‐10) in murine
CD
11b
+
monocytes/macrophages via
GMP
‐adapted
mRNA
‐nucleofection was expected to improve clinical outcome and reduce adverse side effects in autoimmune myocarditis. This study represents the proof of principle for a novel anti‐inflammatory therapy using overexpression of
IL
‐10 in murine monocytes/macrophages by
mRNA
‐nucleofection for the treatment of autoimmune myocarditis.

Methods and Results

Autoimmune myocarditis was induced in A/J mice by subcutaneous immunization with troponin I.
CD
11b
+
monocytes/macrophages were isolated from the peritoneum and
IL
‐10 was overexpressed by
mRNA
‐nucleofection. These cells were injected intravenously. Myocardial inflammation was assessed via histological and immunohistochemical examinations. Myocardial fibrosis was analyzed with
M
asson's trichrome staining. Antitroponin I antibodies were determined within the serum. Physical performance was evaluated using a running wheel and echocardiography. In vitro overexpression of
IL
‐10 in
CD
11b
+
monocytes/macrophages resulted in a 7‐fold increased production of
IL
‐10 (n=3). In vivo higher levels of
IL
‐10 and less inflammation were detected within the myocardium of treated compared with control mice (n=4).
IL
‐10–treated mice showed lower antitroponin I antibodies (n=10) and a better physical performance (n=10).

Conclusions

Application of
IL
‐10–overexpressing
CD
11b
+
monocytes/macrophages reduced inflammation and improved physical performance in a murine model of autoimmune myocarditis. Thus, the use of genetically modified monocytes/macrophages facilitated a targeted therapy of local inflammation and may reduce systemic side effects. Because the nucleofection technique is
GMP
adapted, an in vivo use in humans seems basically feasible and the transfer to other inflammatory diseases seems likely.
Detection of Aortic Arch Calcification in Apolipoprotein E‐Null Mice Using Carbon Nanotube–Based Micro‐CT System
Authors: Wait John M. S. , Tomita Hirofumi , Burk Laurel M. , Lu Jianping , Zhou Otto Z. , Maeda Nobuyo , Lee Yueh Z.
Published: May 2013

Background

We performed in vivo micro‐computed tomography (micro‐
CT
) imaging using a novel carbon nanotube (
CNT
)–based x‐ray source to detect calcification in the aortic arch of apolipoprotein
E
(apoE)–null mice.

Methods and Results

We measured calcification volume of aortic arch plaques using
CNT
‐based micro‐
CT
in 16‐ to 18‐month‐old males on 129S6/SvEvTac and C57BL/6J genetic backgrounds (129‐apoE
KO
and B6‐apoE
KO
). Cardiac and respiratory gated images were acquired in each mouse under anesthesia. Images obtained using a
CNT
micro‐
CT
had less motion blur and better spatial resolution for aortic calcification than those using conventional micro‐
CT
, evaluated by edge sharpness (slope of the normalized attenuation units, 1.6±0.3 versus 0.8±0.2) and contrast‐to‐noise ratio of the calcifications (118±34 versus 10±2); both
P
<0.05, n=6. Calcification volume in the arch inner curvature was 4 times bigger in the 129‐apoE
KO
than in the B6‐apoE
KO
mice (0.90±0.18 versus 0.22±0.10 mm
3
,
P
<0.01, n=7 and 5, respectively), whereas plaque areas in the inner curvature measured in dissected aorta were only twice as great in the 129‐apoE
KO
than in the B6‐apoE
KO
mice (6.1±0.6 versus 3.7±0.4 mm
2
,
P
<0.05). Consistent with this, histological calcification area in the plaques was significantly higher in the 129‐apoE
KO
than in the B6‐apoE
KO
mice (16.9±2.0 versus 9.6±0.8%,
P
<0.05, 3 animals for each).

Conclusions

A novel
CNT
‐based micro‐
CT
is a useful tool to evaluate vascular calcifications in living mice. Quantification from acquired images suggests higher susceptibility to calcification of the aortic arch plaques in 129‐apoE
KO
than in B6‐apoE
KO
mice.
H
2
Gas Improves Functional Outcome After Cardiac Arrest to an Extent Comparable to Therapeutic Hypothermia in a Rat Model
Authors: Hayashida Kei , Sano Motoaki , Kamimura Naomi , Yokota Takashi , Suzuki Masaru , Maekawa Yuichiro , Kawamura Akio , Abe Takayuki , Ohta Shigeo , Fukuda Keiichi , Hori Shingo
Published: May 2013

Background

All clinical and biological manifestations related to postcardiac arrest (
CA
) syndrome are attributed to ischemia–reperfusion injury in various organs including brain and heart. Molecular hydrogen (H
2
) has potential as a novel antioxidant. This study tested the hypothesis that inhalation of H
2
gas starting at the beginning of cardiopulmonary resuscitation (
CPR
) could improve the outcome of
CA
.

Methods and Results

Ventricular fibrillation was induced by transcutaneous electrical epicardial stimulation in rats. After 5 minutes of the subsequent
CA
, rats were randomly assigned to 1 of 4 experimental groups at the beginning of
CPR
: mechanical ventilation (
MV
) with 2% N
2
and 98% O
2
under normothermia (37°C), the control group;
MV
with 2% H
2
and 98% O
2
under normothermia;
MV
with 2% N
2
and 98% O
2
under therapeutic hypothermia (
TH
), 33°C; and
MV
with 2% H
2
and 98% O
2
under
TH
. Mixed gas inhalation and
TH
continued until 2 hours after the return of spontaneous circulation (
ROSC
). H
2
gas inhalation yielded better improvement in survival and neurological deficit score (
NDS
) after
ROSC
to an extent comparable to
TH
. H
2
gas inhalation, but not
TH
, prevented a rise in left ventricular end‐diastolic pressure and increase in serum
IL
‐6 level after
ROSC
. The salutary impact of H
2
gas was at least partially attributed to the radical‐scavenging effects of H
2
gas, because both 8‐
OHdG
‐ and 4‐
HNE
‐positive cardiomyocytes were markedly suppressed by H
2
gas inhalation after
ROSC
.

Conclusions

Inhalation of H
2
gas is a favorable strategy to mitigate mortality and functional outcome of post‐
CA
syndrome in a rat model, either alone or in combination with
TH
.
Multiple Risk Factor Intervention Trial Revisited: A New Perspective Based on Nonfatal and Fatal Composite Endpoints, Coronary and Cardiovascular, During the Trial
Authors: Stamler Jeremiah , Neaton James D. , Cohen Jerome D. , Cutler Jeffrey , Eberly Lynn , Grandits Gregory , Kuller Lewis H. , Ockene Judith , Prineas Ronald ,   The MRFIT Research Group
Published: May 2013

Background

The
M
ultiple
R
isk
F
actor
I
ntervention
T
rial evaluated a multifactor intervention on coronary heart disease (
CHD
) in 12 866 men. A priori defined endpoints (
CHD
death,
CHD
death or nonfatal myocardial infarction, cardiovascular disease [
CVD
] death, and all‐cause death) did not differ significantly between the special intervention (
SI
) and usual care (
UC
) groups over an average follow‐up period of 7 years. Event rates were lower than anticipated, reducing power. Other nonfatal
CVD
outcomes were prespecified but not considered in composite outcomes comparing
SI
with
UC
.

Methods and Results

Post‐trial
CVD
mortality risks associated with nonfatal
CVD
events occurring during the trial were determined with
C
ox regression. Nonfatal outcomes associated with >2‐fold risk of
CVD
death over the subsequent 20 years were combined with during‐trial deaths to create 2 new composite outcomes.
SI
/
UC
hazard ratios and 95% confidence intervals were estimated for each composite outcome. Of 10 during‐trial nonfatal events, 6 were associated (
P
<0.001) with >2‐fold risk of
CVD
death. A
CHD
composite outcome (
CHD
death, myocardial infarction [clinical or serial
ECG
change],
CHF
, or coronary artery surgery) was experienced by 520
SI
and 602
UC
men (
SI
/
UC
hazard ratio = 0.86; 95% confidence interval, 0.76–0.97;
P
=0.01). A
CVD
composite outcome (
CHD
[as above], other
CVD
deaths, stroke, or renal impairment) was experienced by 581
SI
and 652
UC
men (hazard ratio = 0.89; 95% confidence interval, 0.79–0.99;
P
=0.04).

Conclusions

In post hoc analyses, composite fatal/nonfatal
CHD
and
CVD
rates over 7 years were significantly lower for
SI
than for
UC
. These findings reinforce recommendations for improved dietary/lifestyle practices, with pharmacological therapy as needed, to prevent and control major
CVD
risk factors.
Very Long‐Term (15 to 23 Years) Outcomes of Successful Balloon Angioplasty Compared With Bare Metal Coronary Stenting
Authors: Yamaji Kyohei , Kimura Takeshi , Morimoto Takeshi , Nakagawa Yoshihisa , Inoue Katsumi , Kuramitsu Shoichi , Soga Yoshimitsu , Arita Takeshi , Shirai Shinichi , Ando Kenji , Kondo Katsuhiro , Sakai Koyu , Iwabuchi Masashi , Yokoi Hiroyoshi , Nosaka Hideyuki , Nobuyoshi Masakiyo
Published: May 2013

Background

Target lesion revascularization (
TLR
) continues to occur beyond 4 years after bare metal stent (
BMS
) implantation. However, long‐term outcomes after balloon angioplasty (
BA
) compared with
BMS
are currently unknown.

Methods and Results

From 1989 to 1990, 659 patients (748 lesions) underwent successful
BA
with final balloon ≥3.0 mm excluding patients with acute myocardial infarction and were compared with 405 patients (424 lesions) with
BMS
implantation from June 1990 to 1993. Cumulative incidences of death and target lesion thrombosis (>1 year) were similar between the
BA
group and the
BMS
group (44.4% versus 45.4%,
P
=0.60; and 1.5% versus 0.7%,
P
=0.99; respectively). Cumulative incidence of
TLR
during overall follow‐up was significantly higher after
BA
than after
BMS
implantation (44.6% versus 36.0%,
P
<0.001), whereas cumulative incidence of late
TLR
(>4 years) tended to be lower in the
BA
group than in the
BMS
group (16.3% versus 21.4%,
P
=0.16). Cumulative incidence of late
TLR
after
BA
was significantly lower in patients with small percent diameter stenosis (%
DS
) at early follow‐up angiography compared with large %
DS
(14.5% versus 28.0%,
P
=0.02). In lesions with serial angiography, late lumen loss from early (6 to 14 months) to long‐term (4 to 10 years) follow‐up angiography was significantly smaller in the
BA
group (n=42) than in the
BMS
group (n=55) (−0.08±0.45 mm versus 0.11±0.46 mm,
P
=0.047).

Conclusions

Compared with
BMS
implantation,
BA
was associated with a trend for less late
TLR
beyond 4 years and with significantly smaller late lumen loss from early to long‐term follow‐up angiography.
Elevated Circulating Adipocyte‐Fatty Acid Binding Protein Levels Predict Incident Cardiovascular Events in a Community‐Based Cohort: A 12‐Year Prospective Study
Authors: Chow Wing Sun , Tso Annette Wai Kwan , Xu Aimin , Yuen Michele Mae Ann , Fong Carol Ho Yi , Lam Tai Hing , Lo Su Vui , Tse Hung Fat , Woo Yu Cho , Yeung Chun Yip , Cheung Bernard Man Yung , Lam Karen Siu Ling
Published: May 2013

Background

Obesity is closely associated with various cardiovascular diseases (
CVD
s). Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of
CVD
. This study aimed to evaluate whether the 2 most abundant adipokines, adipocyte‐fatty acid binding protein (A‐
FABP
) and adiponectin, are independent risk factors predisposing to
CVD
.

Method and Results

We investigated prospectively the 12‐year development of
CVD
in relation to the baseline levels of A‐
FABP
and adiponectin in a population‐based community cohort comprising 1847 Chinese subjects recruited from the
H
ong
K
ong
C
ardiovascular
R
isk
F
actors
P
revalence
S
tudy 2 (
CRISPS
2) cohort without previous
CVD
. Baseline serum levels of A‐
FABP
, adiponectin, and
C
‐reactive protein (
CRP
), an established biomarker predictive of
CVD
, were measured. In all, 182 (9.9%) of the 1847 Chinese subjects developed
CVD
during a median follow‐up of 9.4 years. The
CVD
group had more traditional risk factors, higher baseline levels of A‐
FABP
and
CRP
(both
P
<0.001), but similar adiponectin levels (
P
=0.881) compared with the non‐
CVD
group. In
C
ox regression analysis including both biomarkers, the adjusted
HR
for A‐
FABP
and
CRP
for subjects above the optimal cutoff values were 1.57 (95%
CI
, 1.14 to 2.16;
P
=0.006) and 1.60 (95%
CI
, 1.12 to 2.27;
P
=0.01), respectively, after adjustment for traditional risk factors. The category‐free net reclassification index, but not the c‐statistic, showed improvement in predictive performance by the addition of A‐
FABP
to the traditional risk factor model (
P
=0.017).

Conclusions

Circulating A‐
FABP
level predicts the development of
CVD
after adjustment for traditional risk factors in a community‐based cohort. Its clinical use for
CVD
prediction warrants further validation.
Exercise Training for Blood Pressure: A Systematic Review and Meta‐analysis
Authors: Cornelissen Veronique A. , Smart Neil A.
Published: May 2013

Background

We conducted meta‐analyses examining the effects of endurance, dynamic resistance, combined endurance and resistance training, and isometric resistance training on resting blood pressure (BP) in adults. The aims were to quantify and compare BP changes for each training modality and identify patient subgroups exhibiting the largest BP changes.

Methods and Results

Randomized controlled trials lasting ≥4 weeks investigating the effects of exercise on BP in healthy adults (age ≥18 years) and published in a peer‐reviewed journal up to
F
ebruary 2012 were included. Random effects models were used for analyses, with data reported as weighted means and 95% confidence interval. We included 93 trials, involving 105 endurance, 29 dynamic resistance, 14 combined, and 5 isometric resistance groups, totaling 5223 participants (3401 exercise and 1822 control). Systolic BP (
SBP
) was reduced after endurance (−3.5 mm Hg [confidence limits −4.6 to −2.3]), dynamic resistance (−1.8 mm Hg [−3.7 to −0.011]), and isometric resistance (−10.9 mm Hg [−14.5 to −7.4]) but not after combined training. Reductions in diastolic
BP
(
DBP
) were observed after endurance (−2.5 mm Hg [−3.2 to −1.7]), dynamic resistance (−3.2 mm Hg [−4.5 to −2.0]), isometric resistance (−6.2 mm Hg [−10.3 to −2.0]), and combined (−2.2 mm Hg [−3.9 to −0.48]) training.
BP
reductions after endurance training were greater (
P
<0.0001) in 26 study groups of hypertensive subjects (−8.3 [−10.7 to −6.0]/−5.2 [−6.8 to −3.4] mm Hg) than in 50 groups of prehypertensive subjects (−2.1 [−3.3 to −0.83]/−1.7 [−2.7 to −0.68]) and 29 groups of subjects with normal
BP
levels (−0.75 [−2.2 to +0.69]/−1.1 [−2.2 to −0.068]).
BP
reductions after dynamic resistance training were largest for prehypertensive participants (−4.0 [−7.4 to −0.5]/−3.8 [−5.7 to −1.9] mm Hg) compared with patients with hypertension or normal
BP
.

Conclusion

Endurance, dynamic resistance, and isometric resistance training lower SBP and DBP, whereas combined training lowers only DBP. Data from a small number of isometric resistance training studies suggest this form of training has the potential for the largest reductions in
SBP
.
Long‐term Outcomes of Catheter Ablation of Atrial Fibrillation: A Systematic Review and Meta‐analysis
Authors: Ganesan Anand N. , Shipp Nicholas J. , Brooks Anthony G. , Kuklik Pawel , Lau Dennis H. , Lim Han S. , Sullivan Thomas , Roberts‐Thomson Kurt C. , Sanders Prashanthan
Published: May 2013

Background

In the past decade, catheter ablation has become an established therapy for symptomatic atrial fibrillation (
AF
). Until very recently, few data have been available to guide the clinical community on the outcomes of
AF
ablation at ≥3 years of follow‐up. We aimed to systematically review the medical literature to evaluate the long‐term outcomes of
AF
ablation.

Methods and Results

A structured electronic database search (PubMed, Embase, Web of Science, Cochrane) of the scientific literature was performed for studies describing outcomes at ≥3 years after
AF
ablation, with a mean follow‐up of ≥24 months after the index procedure. The following data were extracted: (1) single‐procedure success, (2) multiple‐procedure success, and (3) requirement for repeat procedures. Data were extracted from 19 studies, including 6167 patients undergoing
AF
ablation. Single‐procedure freedom from atrial arrhythmia at long‐term follow‐up was 53.1% (95%
CI
46.2% to 60.0%) overall, 54.1% (95%
CI
44.4% to 63.4%) in paroxysmal
AF
, and 41.8% (95%
CI
25.2% to 60.5%) in nonparoxysmal
AF
. Substantial heterogeneity (I
2
>50%) was noted for single‐procedure outcomes. With multiple procedures, the long‐term success rate was 79.8% (95%
CI
75.0% to 83.8%) overall, with significant heterogeneity (I
2
>50%).The average number of procedures per patient was 1.51 (95%
CI
1.36 to 1.67).

Conclusions

Catheter ablation is an effective and durable long‐term therapeutic strategy for some
AF
patients. Although significant heterogeneity is seen with single procedures, long‐term freedom from atrial arrhythmia can be achieved in some patients, but multiple procedures may be required.
Aliskiren Effect on Plaque Progression in Established Atherosclerosis Using High Resolution 3D MRI (ALPINE): A Double‐Blind Placebo‐Controlled Trial
Authors: Mihai Georgeta , Varghese Juliet , Kampfrath Thomas , Gushchina Liubov , Hafer Lisa , Deiuliis Jeffrey , Maiseyeu Andrei , Simonetti Orlando P. , Lu Bo , Rajagopalan Sanjay
Published: May 2013

Background

The renin–angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (
ACEIs
/
ARB
s) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high‐resolution magnetic resonance imaging (
MRI
) measurements of arterial wall volume in the thoracic and abdominal aortas of high‐risk patients with preexisting cardiovascular disease.

Methods and Results

This was a single‐center, randomized, double‐blind, placebo‐controlled trial in patients with established cardiovascular disease. After a 2‐week single‐blind placebo phase, patients were randomized to receive either placebo (n=37, mean±SD age 64.5±8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean±SD age 63.9±11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark‐blood, 3‐dimensional
MRI
assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo).
A
liskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31±6.57 vs 0.15±4.39 mm
3
,
P
=0.03, and percentage wall volume 3.37±2.96% vs 0.97±2.02%,
P
=0.04) compared with placebo. In a subgroup analysis of subjects receiving
ACEI
/
ARB
therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group.

Conclusions

MRI
quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving
ACEI
/
ARB
therapy.

Clinical Trial Registration

URL:
http://ClinicalTrials.gov
Unique identifier
:
NCT01417104.
N‐3 Polyunsaturated Fatty Acids to Prevent Atrial Fibrillation: Updated Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Mariani Javier , Doval Hernán C. , Nul Daniel , Varini Sergio , Grancelli Hugo , Ferrante Daniel , Tognoni Gianni , Macchia Alejandro
Published: May 2013

Background

Previous studies have suggested that n‐3 polyunsaturated fatty acids (n‐3
PUFA
s) have antiarrhythmic effects on atrial fibrillation (
AF
). We aimed to assess the effects of therapy with n‐3
PUFA
s on the incidence of recurrent
AF
and on postoperative
AF
.

Methods and Results

Electronic searches were conducted in Web of Science, Medline, Biological Abstracts, Journal Citation Reports, and the Cochrane Central Register of Controlled Trials databases. In addition, data from the recently completed
FOR
ω
ARD
and
OPERA
trials were included. We included randomized controlled trials comparing treatment with n‐3
PUFA
s versus control to (1) prevent recurrent
AF
in patients who underwent reversion of
AF
or (2) prevent incident postoperative
AF
after cardiac surgery. Of identified studies, 12.9% (16 of 124) were included, providing data on 4677 patients. Eight studies (1990 patients) evaluated n‐3
PUFA
effects on
AF
recurrence among patients with reverted
AF
and 8 trials (2687 patients) on postoperative
AF
. Pooled risk ratios through random‐effects models showed no significant effects on
AF
recurrence (
RR
, 0.95; 95%
CI
, 0.79 to 1.13; I
2
, 72%) or on postoperative
AF
(0.86; 95%
CI
, 0.71 to 1.04; I
2
, 53.1%). A funnel plot suggested publication bias among postoperative trials but not among persistent
AF
trials. Meta‐regression analysis did not find any relationship between doses and effects (
P
=0.887 and 0.833 for recurrent and postoperative
AF
, respectively).

Conclusions

Published clinical trials do not support n‐3
PUFA
s as agents aimed at preventing either postoperative or recurrent
AF
.

Clinical Trial Registration

URL:
http://www.crd.york.ac.uk/PROSPERO
. Unique Identifier: CRD42012002199.
Critical Role for the Advanced Glycation End‐Products Receptor in Pulmonary Arterial Hypertension Etiology
Authors: Meloche Jolyane , Courchesne Antony , Barrier Marjorie , Carter Sophie , Bisserier Malik , Paulin Roxane , Lauzon‐Joset Jean‐François , Breuils‐Bonnet Sandra , Tremblay Ève , Biardel Sabrina , Racine Christine , Courture Christian , Bonnet Pierre , Majka Susan M. , Deshaies Yves , Picard Frédéric , Provencher Steeve , Bonnet Sébastien
Published: May 2013

Background

Pulmonary arterial hypertension (
PAH
) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (
PASMC
) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (
STAT
3)/bone morphogenetic protein receptor 2 (
BMPR
2)/peroxisome proliferator‐activated receptor gamma (
PPAR
γ) in
PAH
.
STAT
3 activation induces
BMPR
2 downregulation, decreasing
PPAR
γ, which both contribute to the proproliferative and antiapoptotic phenotype seen in
PAH
. In chondrocytes, activation of this axis has been attributed to the advanced glycation end‐products receptor (
RAGE
). As
RAGE
is one of the most upregulated proteins in
PAH
patients' lungs and a strong
STAT
3 activator, we hypothesized that by activating
STAT
3,
RAGE
induces
BMPR
2 and
PPAR
γ downregulation, promoting
PAH
‐
PASMC
proliferation and resistance to apoptosis.

Methods and Results

In vitro, using
PASMC
s isolated from
PAH
and healthy patients, we demonstrated that
RAGE
is overexpressed in
PAH
‐
PASMC
(6‐fold increase), thus inducing
STAT
3 activation (from 10% to 40% positive cells) and decrease in
BMPR
2 and
PPAR
γ levels (>50% decrease). Pharmacological activation of
RAGE
in control cells by S100A4 recapitulates the
PAH
phenotype (increasing
RAGE
by 6‐fold, thus activating
STAT
3 and decreasing
BMPR
2 and
PPAR
γ). In both conditions, this phenotype is totally reversed on
RAGE
inhibition. In vivo,
RAGE
inhibition in monocrotaline‐ and
S
ugen‐induced
PAH
demonstrates therapeutic effects characterized by
PA
pressure and right ventricular hypertrophy decrease (control rats have an
mPAP
around 15 mm Hg,
PAH
rats have an
mPAP
>40 mm Hg, and with
RAGE
inhibition,
mPAP
decreases to 20 and 28 mm Hg, respectively, in
MCT
and
S
ugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and
BMPR
2/
PPAR
γ axis restoration (increased by ≥60%).

Conclusion

We have demonstrated the implications of
RAGE
in
PAH
etiology. Thus,
RAGE
constitutes a new attractive therapeutic target for
PAH
.
Extent of Mitochondrial Hexokinase II Dissociation During Ischemia Correlates With Mitochondrial Cytochrome c Release, Reactive Oxygen Species Production, and Infarct Size on Reperfusion
Authors: Pasdois Philippe , Parker Joanne Elizabeth , Halestrap Andrew Philip
Published: May 2013

Background

The mechanisms by which ischemic preconditioning (
IP
) inhibits mitochondrial permeability transition pore opening and, hence, ischemia–reperfusion injury remain unclear. Here we investigate whether and how mitochondria‐bound hexokinase 2 (
mtHK2
) may exert part of the cardioprotective effects of
IP
.

Methods and Results

Control and
IP L
angendorff‐perfused rat hearts were subject to ischemia and reperfusion with measurement of hemodynamic function and infarct size. Outer mitochondrial membrane (
OMM
) permeabilization after ischemia was determined by measuring rates of respiration and H
2
O
2
production in the presence and absence of added cytochrome c in isolated mitochondria and permeabilized fibers.
IP
prevented
OMM
permeabilization during ischemia and reduced the loss of
mtHK2
, but not Bcl‐x
L
, observed in control ischemic hearts. By contrast, treatment of permeabilized fibers with glucose‐6‐phosphate at pH 6.3 induced
mtHK2
loss without
OMM
permeabilization. However, metabolic pretreatments of the perfused heart chosen to modulate glucose‐6‐phosphate and intracellular pH
i
revealed a strong inverse correlation between end‐ischemic
mtHK2
content and infarct size after reperfusion. Loss of
mtHK2
was also associated with reduced rates of creatine phosphate generation during the early phase of reperfusion. This could be mimicked in permeabilized fibers after
mtHK2
dissociation.

Conclusions

We propose that loss of
mtHK2
during ischemia destabilizes mitochondrial contact sites, which, when accompanied by degradation of Bcl‐x
L
, induces
OMM
permeabilization and cytochrome c loss. This stimulates reactive oxygen species production and mitochondrial permeability transition pore opening on reperfusion, leading to infarction. Consequently, inhibition of
mtHK2
loss during ischemia could be an important mechanism responsible for the cardioprotection mediated by
IP
and other pretreatments.