bluuebunny/crossref_metadata_2025 huggingface dataset:
Arrhythmogenic Marker for the Sudden Unexplained Death Syndrome in Thai Men
Authors: Nademanee Koonlawee , Veerakul Gumpanart , Nimmannit Sumalee , Chaowakul Vipada , Bhuripanyo Kiertijai , Likittanasombat Khanchit , Tunsanga Kriang , Kuasirikul Surachai , Malasit Prida , Tansupasawadikul Sudarat , Tatsanavivat Pyatat
Published: June 2012

Background
Between 1981 and 1988, the Centers for Disease Control and Prevention reported a very high incidence of sudden death among young male Southeast Asians who died unexpectedly during sleep. The pattern of death has long been prevalent in Southeast Asia. We carried out a study to identify the clinical markers for patients at high risk of developing sudden unexplained death syndrome (SUDS) and long-term outcomes.

Methods and Results
We studied 27 Thai men (mean age, 39.7±11 years) referred because they had cardiac arrest due to ventricular fibrillation, usually occurring at night while asleep (n=17), or were suspected to have had symptoms similar to the clinical presentation of SUDS (n=10). We performed cardiac testing, including EPS and cardiac catheterization. The patients were then followed at ≈3-month intervals; our primary end points were death, ventricular fibrillation, or cardiac arrest. A distinct ECG abnormality divided our patients who had no structural heart disease (except 3 patients with mild left ventricular hypertrophy) into two groups: group 1 (n=16) patients had right bundle-branch block and ST-segment elevation in V
1
through V
3
, and group 2 (n=11) had a normal ECG. Group 1 patients had well-defined electrophysiological abnormalities: group 1 had an abnormally prolonged His-Purkinje conduction time (HV interval, 63±11 versus 49±6 ms;
P
=.007). Group 1 had a higher incidence of inducible ventricular fibrillation (93% for group 1 versus 11% for group 2;
P
=.0002) and a positive signal-averaged ECG (92% for group 1 versus 11% for group 2;
P
=.002), which was associated with a higher incidence of ventricular fibrillation or death (
P
=.047). The life-table analysis showed that the group 1 patients had a much greater risk of dying suddenly (
P
=.05).

Conclusions
Right bundle-branch block and precordial injury pattern in V
1
through V
3
is common in SUDS patients and represents an arrhythmogenic marker that identifies patients who face an inordinate risk of ventricular fibrillation or sudden death.
Is Epinephrine Contraindicated During Cardiopulmonary Resuscitation?
Authors: Thrush David N. , Downs John B. , Smith Robert A.
Published: June 2012

Background
Why pulmonary gas exchange deteriorates after administration of epinephrine during cardiopulmonary resuscitation (CPR) is unclear.

Methods and Results
Forty-four anesthetized swine received an infusion of six inert gases. Animals underwent ventricular fibrillation with CPR and intravenous administration of saline (control), epinephrine (15 μg/kg), or methoxamine (150 μg/kg). Cardiac output, aortic blood pressure, pH, and arterial oxygen saturation were recorded. Distributions of V̇
a
and Q̇ were determined by the multiple inert gas elimination technique. Ventricular fibrillation and CPR caused significant decreases in cardiac output, aortic blood pressure, and arterial pH. With epinephrine (versus saline), diastolic blood pressure was significantly higher (23±7 versus 8±4 mm Hg), but the increase in shunt (from 7±4% to 29±17%) and the reduction in Sa
o
2
(from 99.7% to 76.8%) were significantly larger. Also, the increase in dead space was greater and elimination of CO
2
less. There were no differences between animals given methoxamine or saline, except for increased diastolic blood pressure.

Conclusions
During experimental ventricular fibrillation and CPR, epinephrine increased intrapulmonary shunt ≈300% more than saline or methoxamine and significantly reduced arterial oxygen saturation. We suspect that the β-adrenergic receptor activity of epinephrine attenuated hypoxic pulmonary vasoconstriction. Methoxamine is as effective a pressor as epinephrine for CPR and devoid of β-adrenergic activity. We recommend that such an agent be considered, instead of epinephrine, for CPR.
Detection of High-Grade Restenosis After PTCA Using Contrast-Enhanced Electron Beam CT
Authors: Achenbach Stephan , Moshage Werner , Bachmann Kurt
Published: June 2012

Background
Contrast-enhanced electron beam computed tomography (EBCT) has been shown to permit noninvasive visualization of the coronary arteries. We determined the value of EBCT to noninvasively detect high-grade restenosis after percutaneous transluminal coronary angioplasty (PTCA).

Methods and Results
Fifty patients (37 to 68 years of age), were investigated by EBCT at a mean interval of 9 months after PTCA of coronary artery stenoses. Forty axial cross-sections of the heart (3-mm slice thickness, 1-mm overlap) were acquired triggered to the ECG after intravenous injection of contrast agent. Three-dimensional reconstructions of the coronary arteries were rendered with a lower threshold of 80 HU to selectively visualize the contrast-enhanced vessel lumen. EBCT results were compared with conventional quantitative coronary angiography (QCA) performed within 1 week. In 6 patients, the PTCA segment could not be evaluated because of impaired image quality. Sixteen of the remaining 44 patients had high-grade restenoses in QCA (>70% diameter reduction), which was correctly detected by EBCT in 15 cases (94% sensitivity). There were 5 false-positive EBCT results of high-grade restenosis (82% specificity).

Conclusions
EBCT with intravenous injection of contrast agent permits the noninvasive diagnosis of restenosis after PTCA, with high sensitivity and sufficient specificity.
Implantable Cardioverter-Defibrillators and Pregnancy
Authors: Natale Andrea , Davidson Theresa , Geiger Mary J. , Newby Keith
Published: June 2012

Background
The purpose of this investigation was to evaluate the outcome of pregnancy in women with implantable cardioverter-defibrillators (ICDs).

Methods and Results
A multicenter retrospective analysis was performed on women with an ICD who became pregnant. Data were collected on 44 patients. The mean age and ejection fraction at the time of the initial ICD implant were 25.6±4.9 years and 49.8±9.7%, respectively. The mean follow-up after the ICD implant was 4.8±2.8 years. Forty-two women had abdominally implanted generators, and 2 had a prepectoral device. Thirty had epicardial lead sensing systems, and 14 had transvenous. Thirty-six (82%) experienced no complications, and 8 (18%) had a medical or device-related complication. The ICD-related problems included tenderness at the ICD pocket scar (2 patients), generator migration (1), and pericarditis secondary to the epicardial patches (1). Medical complications were pulmonary embolism (1), therapeutic abortion (1), worsening hyperthyroidism (1), congestive heart failure (1), and weight loss (1). Thirty-seven women delivered vaginally, and 7 underwent cesarean section. Thirty-nine babies were born healthy, 1 was stillborn, 2 were small for gestational age, 1 had transient hypoglycemia, and 1 woman had a therapeutic abortion unrelated to the ICD. During pregnancy, 33 women received no ICD therapy, 8 had 1 shock, 1 had 5 discharges, 1 had 11 shocks, and 1 had 5 shocks. The total number of shocks during pregnancy ranged from 0 to 11, with an average of 0.66±1.9 discharges. Five women had 7 additional pregnancies without an ICD shock.

Conclusions
The mere presence of an ICD should not defer a women from becoming pregnant unless she has an underlying structural cardiac disease that is considered a contraindication. Pregnancy does not increase the risk of major ICD-related complications or result in a high number of ICD discharges.
Metabolic Response of Normal Human Myocardium to High-Dose Atropine-Dobutamine Stress Studied by
31
P-MRS
Authors: Lamb Hildo J. , Beyerbacht Hugo P. , Ouwerkerk Ronald , Doornbos Joost , Pluim Babette M. , van der Wall Ernst E. , van der Laarse Arnoud , de Roos Albert
Published: June 2012

Background
31
P-MRS during cardiac stress may provide (patho)physiological insights into the high-energy phosphate metabolism of the myocardium. Accordingly, the purpose of the present study was to determine the metabolic response of normal human myocardium to severe atropine-dobutamine (A-D) stress. To corroborate the results from the present in vivo study, a
31
P-MRS experiment was performed with a moving phantom to simulate respiratory motion.

Methods and Results
The phantom experiment showed no relation (
P
=.371) between the intensity ratio of two separate phosphate peaks and amplitude of phantom excursions. The phosphocreatine (PCr) and ATP signal strength and the PCr/ATP ratio were determined from the left ventricular wall in 20 healthy subjects (posttest likelihood for coronary artery disease was <2.5%) with
31
P-MRS at rest and during high-dose A-D stress (rate-pressure product increased threefold). Stress-induced changes were −21% for PCr (
P
<.001) and −9% for ATP (
P
<.05). The average PCr/ATP value at rest was 1.42±0.18 and decreased by 14% to 1.22±0.20 during stress (
P
<.001).

Conclusions
The phantom experiment shows that the in vivo decrease of myocardial PCr/ATP due to high-dose A-D stress we observed is not a motion artifact. Consequently, this indicates that myocardial high-energy phosphate metabolism of the normal human heart is altered at high workloads.
Left Ventricular Pressure-Volume Relationships Before and After Cardiomyoplasty in Patients With Heart Failure
Authors: Schreuder J.J. , van der Veen F.H. , van der Velde E.T. , Delahaye F. , Alfieri O. , Jegaden O. , Lorusso R. , Jansen J.R.C. , Hoeksel S.A.A.P. , Finet G. , Volterrani M. , Kaulbach H.-G. , Baan J. , Wellens H.J.J.
Published: June 2012

Background
The aim of this study was to elucidate whether beneficial effects of cardiomyoplasty (CMP) in patients with dilated cardiomyopathy are the result of a decrease in existing ventricular dilatation or a prevention of further dilatation.

Methods and Results
Combined micromanometer-conductance catheters were used to evaluate left ventricular pressure-volume relationships in six patients with dilated cardiomyopathy before and at 6 and 12 months after CMP. Acute changes in preload and afterload were induced by a standardized leg-tilting intervention and a bolus infusion of nitroglycerin. After CMP, end-diastolic volume (EDV) decreased from 138±10 to 103±18 mL/m
2
(
P
<.01) at 6 months and to 83±17 mL/m
2
(
P
<.01) at 12 months. End-diastolic pressure (EDP) decreased from 20.2±6.4 to 13.9±7.7 mm Hg (
P
<.01) at 6 months after CMP. Peak ejection rate and ejection fraction increased at 6 months after CMP from 594±214 to 799±214 mL/s (
P
<.05) and from 26.6±4.7% to 40.1±8.3% (
P
<.05), respectively. Peak −dP/dt decreased at 12 months after CMP from −842±142 to −712±168 mm Hg/s (
P
<.05). Leg-tilting before CMP increased EDP from 20.2±6.4 to 25.6±5.2 mm Hg (
P
<.01), end-systolic pressure (ESP) from 118±17 to 122±17 mm Hg (
P
<.05), and τ from 50.8±2.8 to 53.8±2.3 ms (
P
<.05). Six months after CMP, leg-tilting also increased EDV from 103±18 to 110±22 mL/m
2
(
P
<.05) and ESV from 62±14 to 66±14 mL/m
2
(
P
<.05). Before CMP, nitroglycerin decreased EDP from 20.2±6.4 to 10.4±3.8 mm Hg (
P
<.01), ESP from 118±17 to 96±11 mm Hg (
P
<.05), ESV from 100±11 to 89±7 mL/m
2
(
P
<.05), and τ from 50.8±2.8 to 44.5±3.7 ms (
P
<.05). Six months after CMP, nitroglycerin decreased EDP, ESP, and τ to similar values.

Conclusions
Our findings show that up to 1 year after CMP, marked decreases in left ventricular volume are present. Our measurements suggest that CMP actively reduced the dilated ventricle but did not prevent a higher EDV on an increased venous return. The latissimus dorsi muscle wrap contraction results in better synchronization of contraction and more rapid emptying of the left ventricle.
Inflammatory Cytokines Impair Endothelium-Dependent Dilatation in Human Veins In Vivo
Authors: Bhagat Kiran , Vallance Patrick
Published: June 2012

Background
Endothelial dysfunction occurs in many diseases associated with increased cardiovascular risk. We examined the effects of pro-inflammatory cytokines on endothelial function.

Methods and Results
Subjects lay with one hand placed on an angled support. The diameter of a vein was recorded by measuring the linear displacement of a probe placed on the skin overlying the vein when the pressure in a congesting cuff placed around the upper arm was deflated from 40 to 0 mm Hg. A length of the vein was isolated by two wedges. TNF-α (1 ng), IL-1β (1 ng), or IL-6 (100 pg) were instilled for 1 hour, either individually or together. At the end of the hour, the wedges were removed and the vein reconnected with the circulation. Dose-response curves (bradykinin: 2, 4, and 8 pmol/min; arachidonic acid: 0.2, 2, and 20 nmol/min; and glyceryl trinitrate 1, 2, and 4 pmol/min) were constructed before and 1, 6, 24, and 48 hours after instillation. In another study, hydrocortisone (100 mg) was given 2 hours before the study. In a different study, subjects were given oral aspirin (75 mg or 1 g) 2 hours before the study. TNF-α and IL-1β alone but not IL-6 attenuated the dilatation to bradykinin and arachidonic acid; the response was greatest at 1 hour with recovery occurring by 6 hours. Combination of IL-1β and TNF-α prolonged the endothelial dysfunction, resulting in recovery at 24 hours. Hydrocortisone and high-dose aspirin prevented endothelial dysfunction.

Conclusions
The results demonstrate that pro-inflammatory cytokines induce transient and reversible endothelial dysfunction and indicate that cyclooxygenase activity may contribute to the genesis of the effect. If other vessels behave similarly, this may provide further insight into the mechanisms precipitating acute cardiovascular events after inflammatory disorders.
Structural Changes of Atrial Myocardium due to Sustained Atrial Fibrillation in the Goat
Authors: Ausma Jannie , Wijffels Maurits , Thoné Fred , Wouters Luc , Allessie Maurits , Borgers Marcel
Published: June 2012

Background
After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known.

Methods and Results
Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There were virtually no signs of cellular degeneration, and the interstitial space remained unaltered. The duration of sustained AF did not significantly affect the degree of myolytic cell changes.

Conclusions
Sustained AF in goats leads to predominantly structural changes in the atrial myocytes similar to those seen in ventricular myocytes from chronic hibernating myocardium. These structural changes may explain the depressed contractile function of atrial myocardium after cardioversion. This goat model of AF offers a new approach to study the cascade of events leading to sustained AF and its maintenance.
Antibodies Against the Fibrin β-Chain Amino-Terminus Detect Active Canine Venous Thrombi
Authors: Morris Timothy A. , Marsh James J. , Konopka Ronald , Pedersen Craig A. , Chiles Peter G. , Fagnani Roberto , Hagan Michael , Moser Kenneth M.
Published: June 2012

Background
This study was performed to determine whether antibodies against the amino-terminus of the β-chain of fibrin (anti-β) could noninvasively distinguish actively enlarging thrombi from thrombi stabilized with anticoagulants.

Methods and Results
Dogs with unilateral femoral vein thrombi were allocated into three groups: (1) no anticoagulation, (2) intravenous heparin maintained in the “therapeutic” range (0.2 to 0.5 U/mL plasma), and (3) “excess” heparin, maintained at >1.0 U/mL plasma. Thrombolysis was suppressed with tranexamic acid.
111
In-labeled anti-β was infused, and gamma scans of the legs were performed at regular intervals for 24 hours. Scans were interpreted in a blinded fashion. In addition, for each scan, the number of gamma counts from the femoral area on the thrombosed side was compared with the contralateral side. Clot/blood isotope density was determined postmortem. Leg thrombi in the no-anticoagulation group were 100% detectable, mean (±SD) relative count in the thrombosed femoral area was 186% (±30%) of the contralateral side, and clot/blood ratio was 14.7 (±2.0). Thrombi in the therapeutic heparin group were only 75% detectable, relative counts in the thrombosed femoral areas decreased to 125% (±20%), and clot/blood ratio declined to 11.3 (±3.5). In the “excess heparin” group, leg thrombi were only 50% detectable, the thrombosed femoral area had relative counts of 118%±17%, and the clot/blood ratio fell to 7.8±1.9.

Conclusions
Radiolabeled anti-β noninvasively distinguishes propagating thrombi from those stabilized by anticoagulants. They may be useful for detecting thrombosis clinically as well as for monitoring the efficacy of anticoagulation.
Inhibitory Role of Plasminogen Activator Inhibitor-1 in Arterial Wound Healing and Neointima Formation
Authors: Carmeliet Peter , Moons Lieve , Lijnen Roger , Janssens Stefaan , Lupu Florea , Collen Désiré , Gerard Robert D.
Published: June 2012

Background
Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1
(PAI-1)
gene inactivation and adenoviral
PAI-1
gene transfer on arterial neointima formation.

Methods and Results
Neointima formation was evaluated in PAI-1–deficient (PAI-1
−/−
) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001±0.001 mm
2
in PAI-1
+/+
and 0.016±0.008 mm
2
in PAI-1
−/−
mice within 1 week after electric injury (
P
<.02) and 0.055±0.008 mm
2
in PAI-1
+/+
and 0.126±0.006 mm
2
in PAI-1
−/−
mice within 3 weeks after mechanical injury (
P
<.001). Proliferation of smooth muscle cells was not affected by PAI-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1
−/−
smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than wild-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1
−/−
mice were intravenously injected with replication- defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61±8 μg/mL with 2×10
9
plaque-forming units (pfu) virus. Luminal stenosis was 35±13% in control AdRR5-treated (2×10
9
pfu) and suppressed to 5±5% in AdCMVPAI-1–treated (6×10
8
pfu) PAI-1
−/−
mice (
P
<.002).

Conclusions
By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral
PAI-1
gene transfer reduces arterial neointima formation in mice.
Hyperpolarization-Activated Inward Current in Ventricular Myocytes From Normal and Failing Human Hearts
Authors: Hoppe Uta C. , Jansen Erik , Südkamp Michael , Beuckelmann Dirk J.
Published: June 2012

Background
—The hyperpolarization-activated inward current (I
f
) was found to be overexpressed in hypertrophied rat ventricular myocytes, indicating that I
f
might favor arrhythmias in hypertrophied or failing ventricular myocardium. In the present study, we evaluated whether I
f
is expressed in human ventricular myocardium, if it may be increased in human heart failure, and if its autonomic modulation may be altered.

Methods and Results
—The whole-cell patch-clamp technique was used to record I
f
in isolated ventricular myocytes from 34 failing (dilated [DCM] or ischemic [ICM] cardiomyopathy) and 13 donor hearts (NF). I
f
was observed in all myocytes showing typical current properties, ie, time and voltage dependence, block by [Cs
+
]
o
, permeability for K
+
and Na
+
, and current increase with raising [K
+
]
o
. There was a trend toward larger current densities in myopathic (at −130 mV in [K
+
]
o
25 mmol/L; DCM: −1.37±0.12 pA/pF, n=50; ICM: −1.39±0.24 pA/pF, n=30) than in nonfailing cells (−1.18±0.21 pA/pF, n=24), although this difference did not reach statistical significance (
P
=.23). Boltzmann distributions yielded an activation threshold of −80 mV and half-maximal activation at −110.96±0.06 mV in myopathic and normal myocytes. Isoproterenol (10
−5
mol/L) shifted the current activation by 10 mV (31 myopathic, 5 NF). Carbachol and adenosine had no direct effect on I
f
(6 and 12 myopathic, 3 and 3 NF, respectively) but reversibly antagonized β-adrenergic stimulation (5 and 7 myopathic, 2 and 2 NF, respectively). Autonomic modulation was similar in failing and nonfailing cells.

Conclusions
—In end-stage heart failure, no significant change of I
f
could be found, although there was a trend toward increased I
f
. Together with an elevated plasma norepinephrine concentration and a previously reported reduction in I
K1
in human heart failure, I
f
might favor diastolic depolarization in individual myopathic cells.
Inhibition of α
4
Integrin and ICAM-1 Markedly Attenuate Macrophage Homing to Atherosclerotic Plaques in ApoE-Deficient Mice
Authors: Patel Shilpesh S. , Thiagarajan Ram , Willerson James T. , Yeh Edward T. H.
Published: June 2012

Background
—Monocytes/macrophages play a central role in many stages of development of atherosclerotic plaques, including the conversion to an unstable morphology with rupture and fissuring. A better understanding of the mechanism of attachment of monocytes to activated endothelial cells would prove useful in developing strategies aimed at blocking this initial step. Here we describe a novel in vivo model that directly demonstrates homing of macrophages to atherosclerotic plaques.

Methods and Results
—Macrophages were loaded with fluorescent microspheres and injected intravenously into 40-week-old apolipoprotein E–deficient mice. After 48 hours, labeled macrophages were observed adhering to all stages of atherosclerotic plaques from the early fatty streak to mature calcified lesion. The mean number of macrophages adherent to atherosclerotic plaques located in the proximal 1 mm of the aortic root was quantitated by counting serial frozen sections and found to be 143±17 macrophages per aortic root. Pretreatment of the apolipoprotein E–deficient mice with monoclonal antibodies directed against the α-subunit of the α
4
β
1
integrin and against intracellular cell adhesion molecule (ICAM-1) reduced macrophage homing by 75% and 65%, respectively, as compared with isotype-matched controls (
P
<.05). Pretreatment with a monoclonal antibody directed against E-selectin did not significantly reduce macrophage homing.

Conclusions
—These data demonstrate that α
4
integrin and ICAM-1 play major roles in the recruitment of macrophages to atherosclerotic plaques, whereas E-selectin does not appear to contribute significantly to macrophage recruitment. This model will be useful for studying the mechanism of macrophage recruitment to atherosclerotic plaques and for evaluating the efficacy of inhibitors to adhesion molecules in preventing macrophage recruitment.
Vascular Endothelial Growth Factor/Vascular Permeability Factor Enhances Vascular Permeability Via Nitric Oxide and Prostacyclin
Authors: Murohara Toyoaki , Horowitz Jeffrey R. , Silver Marcy , Tsurumi Yukio , Chen Dongfen , Sullivan Alison , Isner Jeffrey M.
Published: June 2012

Background
—Vascular endothelial growth factor (VEGF), an endothelial cell mitogen that promotes angiogenesis, was initially identified as a vascular permeability factor (VPF). Abundant evidence suggests that angiogenesis is preceded and/or accompanied by enhanced microvascular permeability. The mechanism by which VEGF/VPF increases vascular permeability (VP), however, has remained enigmatic. Accordingly, we used an in vivo assay of VP (Miles assay) to study the putative mediators of VEGF/VPF-induced permeability.

Methods and Results
—VEGF/VPF and positive controls (platelet-activating factor [PAF], histamine, and bradykinin) all increased vascular permeability. Prior administration of the tyrosine kinase inhibitors genistein or herbimycin A prevented VEGF/VPF-induced permeability. Placenta growth factor, which binds to
Flt
-1/VEGF-R1 but not
Flk
-1/KDR/VEGF-R2 receptor tyrosine kinase, failed to increase permeability. Other growth factors such as basic fibroblast growth factor (FGF), acidic FGF, platelet-derived growth factor-BB, transforming growth factor-β, scatter factor, and granulocyte macrophage-colony stimulating factor (8 to 128 ng) failed to increase permeability. VEGF/VPF-induced permeability was significantly attenuated by the nitric oxide (NO) synthase inhibitors
N
ω
-nitro-
l
-arginine (10 mg/kg) or
N
ω
-nitro-
l
-arginine methyl ester (20 mg/kg) and the cyclooxygenase inhibitor indomethacin (5 mg/kg). The inactive enantiomer
N
ω
-nitro-
d
-arginine methyl ester (20 mg/kg) did not inhibit VEGF/VPF-induced permeability. In vitro studies confirmed that VEGF/VPF stimulates synthesis of NO and prostaglandin metabolites in microvascular endothelial cells. Finally, NO donors and the prostacyclin analogue taprostene administered together but not alone reproduced the increase in permeability observed with VEGF/VPF.

Conclusions
—These results implicate NO and prostacyclin produced by the interaction of VEGF/VPF with its
Flk
-1/KDR/VEGF-R2 receptor as mediators of VEGF/VPF-induced vascular permeability. Moreover, this property appears unique to VEGF/VPF among angiogenic cytokines.
Positron Emission Tomography Analysis of [1-
11
C]Acetate Kinetics in Short-term Hibernating Myocardium
Authors: Schulz Rainer , Kappeler Christian , Coenen Heinz , Bockisch Andreas , Heusch Gerd
Published: June 2012

Background
—Modeling of the time-[1-
11
C]acetate activity curve assumes a constant concentration of labeled tricarboxylic acid cycle intermediates and associated metabolites, such as glutamate and aspartate, which may, however, decrease in short-term hibernating myocardium.

Methods and Results
—In 12 anesthetized pigs, [1-
11
C]acetate was injected as a bolus into the cannulated left anterior descending coronary artery during normoperfusion, inotropic stimulation, and early (5 to 45 minutes) and prolonged ischemia (60 to 90 minutes). Regional myocardial oxygen consumption (MV̇
o
2
, microliters per minute per gram) was measured, and the absence of necrosis was verified by triphenyl tetrazolium chloride staining. Inotropic stimulation increased MV̇
o
2
from 52.5±7.4 to 195.4±36.2 (mean±SD) and the rate constant (k
mono
, minutes
−1
) of [1-
11
C]acetate clearance from 0.094±0.018 to 0.322±0.076. During early ischemia, MV̇
o
2
and k
mono
were decreased to 24.3±8.5 and 0.061±0.011, respectively. K
mono
closely correlated to MV̇
o
2
during normoperfusion, inotropic stimulation, and early ischemia. In short-term hibernating myocardium, however, at an unchanged MV̇
o
2
, k
mono
increased toward control values (0.080±0.014). Myocardial glutamate and aspartate concentrations (biopsies) decreased to 47±26% and 77±18%; the peak count rate decreased to 66±22% of its respective control value. After correction for the decreases in glutamate and aspartate or in peak count rate, k
mono
was again decreased (0.050±0.016 or 0.052±0.014, respectively), and a close relationship to MV̇
o
2
was restored.

Conclusions
—K
mono
correlates to MV̇
o
2
in short-term hibernating myocardium when the decreases in aspartate and glutamate or in peak count rate are considered.
Triglyceride Concentration and Ischemic Heart Disease
Authors: Jeppesen J ørgen , Hein Hans Ole , Suadicani Poul , Gyntelberg Finn
Published: June 2012

Background
—The role of triglycerides as a risk factor of ischemic heart disease (IHD) remains controversial. For the present study, we examined the relation between fasting triglycerides and risk of IHD in the Copenhagen Male Study.

Methods and Results
—Baseline measurements of fasting lipids and other IHD risk factors were obtained for 2906 white men (age range, 53 to 74 years) who were initially free of overt cardiovascular disease. During an 8-year follow-up period, 229 men had a first IHD event. Crude cumulative incidence rates of IHD were 4.6% for the lowest, 7.7% for the middle, and 11.5% for the highest third of triglyceride levels (
P
for trend <.001). Compared with the lowest third level and adjusted for age, body mass index, alcohol, smoking, physical activity, hypertension, non–insulin-dependent diabetes mellitus, social class, and LDL and HDL cholesterol, relative risks of IHD (95% confidence interval) were 1.5 (1.0 to 2.3;
P
=.05) and 2.2 (1.4 to 3.4;
P
<.001) for the middle and highest third of triglyceride levels, respectively. When triglyceride levels were stratified by HDL cholesterol levels (triglyceride third multiplied by HDL cholesterol third), a clear gradient of risk of IHD was found with increasing triglyceride levels within each level of HDL cholesterol, including high HDL cholesterol level, which are thought to provide protection against IHD.

Conclusions
—In middle-aged and elderly white men, a high level of fasting triglycerides is a strong risk factor of IHD independent of other major risk factors, including HDL cholesterol.
Expression of LDL Receptor, VLDL Receptor, LDL Receptor–Related Protein, and Scavenger Receptor in Rabbit Atherosclerotic Lesions
Authors: Hiltunen Timo P. , Luoma Jukka S. , Nikkari Tapio , Ylä-Herttuala Seppo
Published: June 2012

Background
—Atherosclerotic lesions contain foam cells that arise from monocyte-macrophages and smooth muscle cells (SMCs) by excessive uptake of lipoproteins. There are many candidate receptors for the lipid accumulation, such as LDL receptor (LDLR), VLDL receptor (VLDLR), LDL receptor-related protein (LRP), and scavenger receptors (SRs). However, little quantitative information exists on the expression of these receptors in normal and atherosclerotic arteries.

Methods and Results
—Competitive reverse transcription–polymerase chain reaction and in situ hybridization were used for the studies in New Zealand White (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbit aortic intima-medias. NZW rabbits were fed a 1% cholesterol diet for 0 (control group), 3, 6, or 14 weeks. LDLR mRNA expression was low in aortic intima-medias of all groups. Of the analyzed receptors, LRP had the highest expression in the control group, and its mRNA was induced threefold in the 14-week group, the aortas of which had extensive lesions. SR expression was low and VLDLR expression moderate in the control group. Both receptors were highly induced during cholesterol feeding (SRs, 3-fold and 270-fold induction; VLDLR, 15-fold and 100-fold induction in the 3-week and 14-week groups, respectively). Comparable results were obtained from WHHL rabbits: high basal LRP mRNA in normal intima-medias; moderate induction of LRP and marked induction of SRs and VLDLR in fatty streaks and fatty plaques. In situ hybridization indicated that LRP and VLDLR were expressed in SMCs and macrophages. VLDLR expression was also observed in endothelial cells. SR expression was detected only in macrophages.

Conclusions
—SR and VLDLR mRNAs were highly induced in atherosclerotic lesions. VLDLR and LRP may be involved in the formation of both SMC–and macrophage-derived foam cells, whereas SRs play an important role in lipid uptake in macrophages.
Recent National Patterns of Warfarin Use in Atrial Fibrillation
Authors: Stafford Randall S. , Singer Daniel E.
Published: June 2012

Background
—Studies of selected populations suggest that anticoagulation in atrial fibrillation is underused and that nonclinical factors influence the use of this stroke-preventing therapy. We wished to examine recent national trends and predictors of warfarin sodium use in atrial fibrillation.

Methods and Results
—A nationally representative sample of office visits from the 1989 to 1996 National Ambulatory Medical Care Surveys was used. We selected 1125 visits by patients with atrial fibrillation, including 877 visits to cardiologists and primary care physicians in which apparent contraindications for anticoagulation were absent. The principal outcome measure was the proportion of visits with warfarin reported. We analyzed trends in warfarin use and statistically evaluated the predictors of warfarin use. Warfarin use increased from 13% of atrial fibrillation visits in 1989 to 40% in 1993 (
P
for trend <.001) in patients without contraindications. Between 1993 and 1996, however, there was no change in warfarin use. Independent of other factors, warfarin was significantly more likely to be reported in patients with a history of stroke and in patients residing outside of the South.

Conclusions
—Warfarin use in atrial fibrillation has not increased recently, indicating inadequate implementation of this highly effective therapy. Barriers to anticoagulation in real-world clinical practice need to be identified and addressed.
Assessment of the Contribution That Direct Allorecognition Makes to the Progression of Chronic Cardiac Transplant Rejection in Humans
Authors: Hornick Philip I. , Mason Philip D. , Yacoub Magdi H. , Rose Marlene L. , Batchelor Richard , Lechler Robert I.
Published: June 2012

Background
—Two populations of T cells contribute to allograft rejection. T cells with direct allospecificity are activated after recognition of intact MHC alloantigens displayed at the surface of donor passenger leukocytes carried within the graft. In contrast, T cells with indirect allospecificity recognize donor alloantigens as processed peptides associated with self (recipient)–MHC class II molecules. In small animal models of transplantation, direct pathway T cells dominate the acute rejection process and are rendered tolerant to the graft after the loss of donor passenger leukocytes. It has been argued that indirect pathway T cells contribute substantially to continual graft damage after passenger cell loss. The purpose of this study was to determine whether donor-specific tolerance could be detected in T cells with direct anti-donor allospecificity in human heart transplant recipients after prolonged graft residence.

Methods and Results
—Alloreactive helper (HTLf) and cytotoxic (CTLf) T cells were enumerated by use of limiting dilution analysis. These assay systems were refined to make them specific for the direct pathway of allorecognition and more sensitive in the case of the HTLf assay. Recipient:anti-donor frequencies were generated in 10 long-term recipients of heart grafts with progressive chronic rejection and compared with those against equivalently HLA mismatched recipient:third-party controls. For HTLf, direct pathway donor-specific hyporesponsiveness was detected in 5 of the 10 recipients (HTLf <1:100 000). Of these 5 recipients, 4 also had low anti-donor CTLf (<1:100 000). In the 5th recipient, although the CTLf was >1:100 000, it was significantly lower than that estimated against the third-party control.

Conclusions
—Donor-specific hyporesponsiveness is demonstrated in 50% of recipients in both the HTLf and CTLf compartments of the direct alloresponse. Direct allorecognition therefore appears unlikely to be responsible for the progression of chronic rejection, implicating indirect allorecognition as the predominant immunological driving force. Furthermore, these data have potential implications for graft outcome, adjustment of immunosuppression, and recipient monitoring.
N
-Methyl-1-Deoxynojirimycin (MOR-14), an α-Glucosidase Inhibitor, Markedly Reduced Infarct Size in Rabbit Hearts
Authors: Arai Masazumi , Minatoguchi Shinya , Takemura Genzou , Uno Yoshihiro , Kariya Tatsuya , Takatsu Hisato , Fujiwara Takako , Higashioka Masaya , Yoshikuni Yoshiaki , Fujiwara Hisayoshi
Published: June 2012

Background
—
N
-methyl-1-deoxynojirimycin (MOR-14), an α-glucosidase inhibitor, reduces the glycogenolytic rate by inhibiting the α-1,6-glucosidase of glycogen-debranching enzyme in the liver, in addition to possessing an antihyperglycemic action by blocking α-1,4-glucosidase in the intestine. Because the reduction of the glycogenolytic rate may be one of the mechanisms of myocardial protection in ischemic preconditioning, the compounds inhibiting myocardial α-1,6-glucosidase may be protective against ischemic damage. Thus, we investigated whether MOR-14 could inhibit α-1,6-glucosidase and reduce the infarct size in rabbit hearts without collateral circulation.

Methods and Results
—MOR-14 dose-dependently decreased the α-1,6-glucosidase activity in rabbit heart extract. A tracer study demonstrated the myocardial uptake of a considerable amount of MOR-14 sufficient to fully inhibit α-1,6-glucosidase. To assess the infarct size–reducing effect of MOR-14, 54 rabbits were subjected to 30-minute coronary occlusion followed by 48-hour reperfusion. Preischemic treatment with 25, 50, and 100 mg/kg of MOR-14 dose-dependently reduced the infarct size (to 26±4%, 19±3%, and 14±2% of the area at risk, respectively), compared with the saline control (45±5%) without altering the blood pressure or heart rate. Another 40 rabbits given 100 mg of MOR-14 or saline 10 minutes before ischemia were euthanized at 10 or 30 minutes of ischemia for biochemical analysis. MOR-14 decreased the α-1,6-glucosidase activity to ≈20% in vivo, reduced the glycogen breakdown, and attenuated the lactate accumulation at both 10 and 30 minutes of ischemia.

Conclusions
—Preischemic treatment with MOR-14 preserved glycogen, attenuated the accumulation of lactate, and reduced the myocardial infarct size by 69%. This cardioprotective effect was independent of changes of blood pressure and heart rate or regional blood flow. It may be associated with α-1,6-glucosidase inhibition, because MOR-14 markedly decreased the α-1,6-glucosidase activity in the heart.
Tumor Necrosis Factor-α Confers Resistance to Hypoxic Injury in the Adult Mammalian Cardiac Myocyte
Authors: Nakano Masayuki , Knowlton Anne A. , Dibbs Ziad , Mann Douglas L.
Published: June 2012

Background
—Previous studies in isolated cardiac myocytes have shown that tumor necrosis factor (TNF)-α provokes increased expression of 27- and 70-kD stress proteins as well as manganese superoxide dismutase, suggesting that TNF-α might play a role in mediating stress responses in the heart.

Methods and Results
—To determine whether TNF-α stimulation would protect isolated cardiac myocytes against environmental stress, myocyte cultures were pretreated with TNF-α for 12 hours and then subjected to continuous hypoxic injury (O
2
content, 3 to 5 ppm) for 12 hours, followed by reoxygenation. Cell injury was assessed in terms of lactic dehydrogenase (LDH) release,
45
Ca
2+
uptake, and MTT metabolism. Pretreatment with TNF-α concentrations ≥50 U/mL significantly attenuated LDH release by hypoxic cells compared with diluent-treated hypoxic cells. Similar findings were observed with respect to
45
Ca
2+
uptake and MTT metabolism in TNF-α–pretreated cells that were subjected to prolonged hypoxia. To determine the mechanism for the TNF-α–induced protective effect, the cells were pretreated with heat shock protein (HSP) 72 antisense oligonucleotides. These studies showed that the protective effect of TNF-α was not inhibited by antisense oligonucleotides, despite use of a concentration of antisense that was sufficient to attenuate the TNF-α–induced increase in HSP 72 expression. Subsequent studies using mutated TNF ligands showed that activation of both types 1 and 2 TNF receptors was sufficient to confer a protective response in isolated cardiac myocytes through an as yet unknown pathway(s).

Conclusions
—Taken together, the above observations demonstrate that TNF-α pretreatment confers resistance to hypoxic stress in the adult cardiac myocyte through a novel mechanism that appears to be different from but not necessarily exclusive of the protective response conferred by HSP 72 expression.
Extended Mortality Benefit of Early Postinfarction Reperfusion
Authors: Ross Allan M. , Coyne Karin S. , Moreyra Eduardo , Reiner Jonathan S. , Greenhouse Samuel W. , Walker Pamela L. , Simoons Maarten L. , Draoui Yasmine C. , Califf Robert M. , Topol Eric J. , Van de Werf Frans , Lundergan Conor F.
Published: June 2012

Background
—Reperfusion therapy for myocardial infarction, understood to reduce mortality by preserving left ventricular function, was initially expected to provide increasing benefits over time. Surprisingly, large controlled thrombolysis trials demonstrated maximum benefit at 4 to 6 weeks with no subsequent increased treatment advantage. Such studies, however, compared groups by assigned treatment, not physiological effectiveness.

Methods and Results
—We calculated 2-year survival differences among 2431 myocardial infarction patients according to early infarct artery patency and outcome left ventricular ejection fraction using Kaplan-Meier curves. Hazard ratios for significant survival determinants were derived from Cox regression models. Two-year vital status (minimum, 688 days) was determined in 2375 patients (97.7%). A substantial mortality advantage for early complete reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3) and for preserved ejection fraction occurred beyond 30 days. The unadjusted hazard ratio for the TIMI 3 group compared with lesser grades at 30 days was 0.57 (95% confidence interval [CI], 0.35 to 0.94) and 30 days to ≥688 days was 0.39 (95% CI, 0.22 to 0.69). Consequently, early TIMI 3 flow was associated with approximately a 3 patient per 100 mortality reduction the first month with an additional 5 lives per 100 from 30 days to 2 years. For ejection fraction >40% compared with ≤40%, the unadjusted hazard ratio was 0.25 (95% CI, 0.16 to 0.37) at 30 days and 0.22 (95% CI, 0.15 to 0.33) after 30 days through 2 years (lives saved, ≈9 and 11 per 100, respectively).

Conclusions
—Successful reperfusion and myocardial salvage produce significant mortality benefits that are amplified beyond the initial 30 days.
Pharmacological Strategies for Improving Diastolic Dysfunction in the Setting of Chronic Pulmonary Hypertension
Authors: Chen Edward P. , Craig Damian M. , Bittner Hartmuth B. , Davis R. Duane , Van Trigt Peter
Published: June 2012

Background
—Right ventricular (RV) hypertrophy is an adaptive process that occurs in the setting of chronic pulmonary hypertension (CPH) and can lead to alterations in normal RV diastolic properties. This study was designed to investigate the effects of NO and milrinone on RV diastolic dysfunction in the setting of CPH and RV hypertrophy by use of a canine model of monocrotaline pyrrole (MCTP)–induced CPH.

Methods and Results
—Sixteen mongrel dogs (22 to 24 kg) were used. Animals underwent percutaneous pulmonary artery (PA) catheterization to measure pulmonary hemodynamics before and 8 weeks after injection of 3 mg/kg MCTP (n=8) or placebo (control, n=8). Eight weeks after injection, all hearts were instrumented with a PA flow probe, sonomicrometric dimension transducers, and micromanometers. Data were collected at baseline and after both NO and milrinone administration. Diastolic properties were quantified by use of the end-diastolic pressure-volume relationship and the time constant of ventricular isovolumic relaxation. Eight weeks after injection, significant increases in the PA pressure and pulmonary vascular resistance were observed in MCTP dogs. Significant worsening of RV diastolic function occurred in association with significant increases in the ratio of RV dry weight to LV+septal dry weight. NO and milrinone administration both led to significant improvements in RV diastolic properties.

Conclusions
—In the setting of MCTP-induced CPH, significant worsening of RV diastolic function was observed in association with significant increases in the ratio of RV dry weight to LV+septal dry weight, suggesting that these changes are partially due to RV hypertrophy. The significant improvement in RV diastolic properties after both NO and milrinone administration suggests that these agents may be effective forms of pharmacological therapy for improving RV diastolic dysfunction in the setting of CPH.
Angiotensin Blockade Inhibits Activation of Mitogen-Activated Protein Kinases in Rat Balloon-Injured Artery
Authors: Kim Shokei , Izumi Yasukatsu , Yano Masahiko , Hamaguchi Akinori , Miura Katsuyuki , Yamanaka Shinya , Miyazaki Hitoshi , Iwao Hiroshi
Published: June 2012

Background
—The effect of balloon injury on the arterial signal transduction pathway has not been examined. In vitro studies show that extracellular signal-regulated kinases (ERKs) and c-Jun NH
2
-terminal kinases (JNKs), belonging to the mitogen-activated protein kinase (MAPK) family, play a critical role in the activation of transcription factor activator protein-1 (AP-1) and cell proliferation or apoptosis. However, the activation and role of MAPKs in vascular diseases in vivo remain to be determined. Therefore, we examined the effect of balloon injury on arterial MAPKs and the possible role of angiotensin II.

Methods and Results
—Arterial JNK and ERK activities were measured by in-gel kinase assay. AP-1 DNA binding activity was determined by gel mobility shift analysis. After balloon injury of rat carotid artery, JNK (p46JNK and p55JNK) and ERK (p44ERK and p42ERK) activities were increased as early as 2 minutes, reached their peak (6- to 18-fold) at 5 minutes, and thereafter rapidly declined to control levels. JNK and ERK activations were followed by a 3.9-fold increase in arterial AP-1 DNA binding activity, which contained c-Jun and c-Fos proteins. Arterial JNK activation at 2 or 5 minutes was remarkably suppressed by E4177 (an angiotensin AT1 receptor antagonist) and cilazapril (an ACE inhibitor). E4177 also prevented activation of ERKs by suppressing their tyrosine phosphorylation, whereas cilazapril failed to prevent such activation. The increased AP-1 DNA binding activity was significantly inhibited by both E4177 and cilazapril.

Conclusions
—Arterial JNKs and ERKs are dramatically activated by balloon injury associated with the activation of the AP-1 complex. These MAPK activations, followed by AP-1 activation, are mediated at least in part by the AT1 receptor. Thus, activation of JNKs and ERKs may be responsible for balloon injury–induced neointima formation.