bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron Chelation Improves Endothelial Function in Patients With Coronary Artery Disease
Authors: Duffy Stephen J. , Biegelsen Elizabeth S. , Holbrook Monika , Russell Judson D. , Gokce Noyan , Keaney John F. , Vita Joseph A.
Published: June 2012

Background
—Some epidemiological studies have shown that increased iron stores are associated with increased cardiovascular events. Redox-active iron may contribute to lipid peroxidation, endothelial cell activation, and generation of reactive oxygen species (especially hydroxyl radical, via Fenton chemistry). Increased oxidative stress is associated with impaired action of endothelium-derived nitric oxide in patients with atherosclerosis.

Methods and Results
—To test the hypothesis that reducing vascular iron stores would reverse endothelial dysfunction, we examined the effects of the iron chelator deferoxamine (500 mg intra-arterially over 1 hour) on vasomotor function in forearm resistance vessels of patients with coronary artery disease by venous occlusion plethysmography. Patients with coronary artery disease had impaired endothelium-dependent vasodilation in response to methacholine compared with healthy control subjects (
P
<0.001). Deferoxamine infusion decreased serum iron levels (
P
<0.001). Deferoxamine improved the blood flow response to methacholine in patients with coronary artery disease (
P
<0.01 by 2-way repeated-measures ANOVA) but had no effect on the response to sodium nitroprusside. In normal volunteers, deferoxamine had no effect on the response to methacholine. The nitric oxide synthase inhibitor
N
G
-monomethyl-
l
-arginine abolished augmentation of the methacholine response associated with deferoxamine. The hydroxyl radical scavenger mannitol had no effect on the methacholine response.

Conclusions
—Deferoxamine improved nitric oxide–mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.
Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol
Authors: Bloomfield Rubins Hanna , Davenport John , Babikian Viken , Brass Lawrence M. , Collins Dorothea , Wexler Laura , Wagner Stephen , Papademetriou Vassilios , Rutan Gale , Robins Sander J.
Published: June 2012

Background
—A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies.

Methods and Results
—Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%,
P
=0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol.

Conclusions
—In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.
Effects of Balloon Injury on Neointimal Hyperplasia in Streptozotocin-Induced Diabetes and in Hyperinsulinemic Nondiabetic Pancreatic Islet–Transplanted Rats
Authors: Indolfi Ciro , Torella Daniele , Cavuto Luigi , Davalli Alberto M. , Coppola Carmela , Esposito Giovanni , Carriero Mariolina V. , Rapacciuolo Antonio , Di Lorenzo Emilio , Stabile Eugenio , Perrino Cinzia , Chieffo Alaide , Pardo Francesco , Chiariello Massimo
Published: June 2012

Background
—The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown.

Methods and Results
—Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-
ras
–negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed.

Conclusions
—In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the
ras/MAPK
pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.
Critical Analysis of Dual-Chamber Implantable Cardioverter-Defibrillator Arrhythmia Detection
Authors: Wilkoff Bruce L. , Kühlkamp Volker , Volosin Kent , Ellenbogen Kenneth , Waldecker Bernd , Kacet Salem , Gillberg Jeffrey M. , DeSouza Cynthia M.
Published: June 2012

Background
—One of the perceived benefits of dual-chamber implantable cardioverter-defibrillators (ICDs) is the reduction in inappropriate therapy due to new detection algorithms. It was the purpose of the present investigation to propose methods to minimize bias during such comparisons and to report the arrhythmia detection clinical results of the PR Logic dual-chamber detection algorithm in the GEM DR ICD in the context of these methods.

Methods and Results
—Between November 1997 and October 1998, 933 patients received the GEM DR ICD in this prospective multicenter study. A total of 4856 sustained arrhythmia episodes (n=311) with stored electrogram and marker channel were classified by the investigators; 3488 episodes (n=232) were ventricular tachycardia (VT)/ventricular fibrillation (VF), and 1368 episodes (n=149) were supraventricular tachycardia (SVT). The overall detection results were corrected for multiple episodes within a patient with the generalized estimating equations (GEE) method with an exchangeable correlation structure between episodes. The relative sensitivity for detection of sustained VT and/or VF was 100.0% (3488 of 3488, n=232; 95% CI 98.3% to 100%), the VT/VF positive predictivity was 88.4% uncorrected (3488 of 3945, n=278) and 78.1% corrected (95% CI 73.3% to 82.3%) with the GEE method, and the SVT positive predictivity was 100.0% (911 of 911, n=101; 95% CI 96% to 100%).

Conclusions
—A structured approach to analysis limits the bias inherent in the evaluation of tachycardia discrimination algorithms through the use of relative VT/VF sensitivity, VT/VF positive predictivity, and SVT positive predictivity along with corrections for multiple tachycardia episodes in a single patient.
Growth Suppression of Human Coronary Vascular Smooth Muscle Cells by Gene Transfer of the Transcription Factor E2F-1
Authors: Shelat Harnath S. , Liu Ta-Jen , Hickman-Bick Diane L. , Barnhart Michael K. , Vida Thomas , Dillard Patricia M. , Willerson James T. , Zoldhelyi Pierre
Published: June 2012

Background
—The transcription factor E2F-1 promotes S-phase entry and death in transformed cells and primary cardiomyocytes. We tested the hypothesis that overexpression of E2F-1 forces growth-arrested human coronary vascular smooth muscle cells (VSMCs) to enter the S phase, undergo apoptosis, and thereby regulate VSMC growth.

Methods and Results
—Early-passage (≤5 passages) coronary VSMCs were transduced at an MOI of 100 with a recombinant adenovirus encoding human E2F-1. E2F-1 expression was observed by immunohistochemistry as early as 6 to 8 hours after exposure of the VSMCs to Ad.E2F-1 but not to the control vector Ad.RR. When cells were kept in growth-arrest medium, 40% of Ad.E2F-1–treated VSMCs entered the S phase by 96 hours, whereas the percentage remained <5% in Ad.RR-treated cells. Transition to the S phase in the E2F-1–transduced VSMCs was followed by apoptosis, as reflected by chromatin condensation, membrane blebbing, cell detachment, and loss of mitochondrial membrane integrity. E2F-1 overexpression resulted in positive dUTP nick end-labeling mediated by terminal deoxynucleotidyl transferase, associated with a robust increase in caspase 3–like activity. Four days after infection with Ad.E2F-1, the fraction of hypodiploid VSMCs in subG
1
increased to 75%. At 7 days, gene transfer of E2F-1 had completely suppressed the growth of VSMCs, whereas the number of Ad.RR-infected cells had increased >8 times.

Conclusions
—Overexpression of the transcription factor E2F-1 regulates growth of human coronary VSMCs by forcing the cells to enter the S phase and then to die. Cell death appears to involve caspase 3–like activity, which, in the VSMCs, is markedly increased by overexpression of E2F-1.
Adenoviral Expression of a Urokinase Receptor–Targeted Protease Inhibitor Inhibits Neointima Formation in Murine and Human Blood Vessels
Authors: Quax Paul H. A. , Lamfers Martine L. M. , Lardenoye JanWillem H. P. , Grimbergen Jos M. , de Vries Margreet R. , Slomp Jennichjen , de Ruiter Marco C. , Kockx Mark M. , Verheijen Jan H. , van Hinsbergh Victor W. M.
Published: June 2012

Background
—Smooth muscle cell migration, in addition to proliferation, contributes to a large extent to the neointima formed in humans after balloon angioplasty or bypass surgery. Plasminogen activator/plasmin–mediated proteolysis is an important mediator of this smooth muscle cell migration. Here, we report the construction of a novel hybrid protein designed to inhibit the activity of cell surface–bound plasmin, which cannot be inhibited by its natural inhibitors, such as α
2
-antiplasmin. This hybrid protein, consisting of the receptor-binding amino-terminal fragment of uPA (ATF), linked to the potent protease inhibitor bovine pancreas trypsin inhibitor (BPTI), can inhibit plasmin activity at the cell surface.

Methods and Results
—The effect of adenovirus-mediated ATF.BPTI expression on neointima formation was tested in human saphenous vein organ cultures. Infection of human saphenous vein segments with Ad.CMV.ATF.BPTI (5×10
9
pfu/mL) resulted in 87.5±3.8% (mean±SEM, n=10) inhibition of neointima formation after 5 weeks, whereas Ad.CMV.ATF or Ad.CMV.BPTI virus had only minimal or no effect on neointima formation. The efficacy of ATF.BPTI in vivo was demonstrated in a murine model for neointima formation. Neointima formation in the femoral artery of mice, induced by placement of a polyethylene cuff, was strongly inhibited (93.9±2%) after infection with Ad.CMV.mATF.BPTI, a variant of ATF.BPTI able to bind specifically to murine uPA receptor; Ad.CMV.mATF and Ad.CMV.BPTI had no significant effect.

Conclusions
—These data provide evidence that adenoviral transfer of a hybrid protein that binds selectively to the uPA receptor and inhibits plasmin activity directly on the cell surface is a powerful approach to inhibiting neointima formation and restenosis.
Increased Angiotensin-Converting Enzyme Activity in Coronary Artery Specimens From Patients With Acute Coronary Syndrome
Authors: Hoshida Shiro , Kato Junji , Nishino Masami , Egami Yasuyuki , Takeda Toshihiro , Kawabata Masayoshi , Tanouchi Jun , Yamada Yoshio , Kamada Takenobu
Published: June 2012

Background
—Angiotensin-converting enzyme (ACE) inhibitors are effective in the secondary prevention of ischemic heart disease, but they do not reduce the rate of restenosis. Vascular ACE activity in the culprit coronary lesions of these patients, however, has never been quantified.

Methods and Results
—We measured the ACE activity of vascular tissue obtained by directional coronary atherectomy in patients with acute coronary syndrome (n=17) and in patients with stable ischemic heart disease (n=36), with and without restenosis. The ACE activity of the culprit coronary lesions was significantly increased in patients with acute coronary syndrome (0.87±0.12 nmol · min
–1
· mg protein
–1
;
P
<0.01) but not in patients with ischemic heart disease with restenosis (n=11, 0.19±0.05 nmol · min
–1
· mg protein
–1
) when compared with those patients with ischemic heart disease without restenosis (n=25, 0.20±0.05 nmol · min
–1
· mg protein
–1
). There was no difference between the ACE activity of the coronary tissue of the in-stent (n=5) and stent-unrelated (n=6) restenosis patients (0.24±0.10 versus 0.15±0.04 nmol · min
–1
· mg protein
–1
). Serum ACE activity did not differ significantly among the patients.

Conclusions
—The present study demonstrates increased ACE activity in culprit lesions in acute coronary syndrome, indicating that enhanced ACE activity is related to the causative mechanism of active coronary lesions.
Quantitative Assessment of Severity of Ventricular Septal Defect by Three-Dimensional Reconstruction of Color Doppler–Imaged Vena Contracta and Flow Convergence Region
Authors: Ishii Masahiro , Hashino Kanoko , Eto Genjyu , Tsutsumi Takahiro , Himeno Wakako , Sugahara Yoko , Muta Hiromi , Furui Jun , Akagi Teiji , Ito Yuhei , Kato Hirohisa
Published: June 2012

Background
—The aim of the present study was to investigate the feasibility and potential value of the computer-controlled, 3D, echocardiographic reconstruction of the color Doppler–imaged vena contracta (CDVC) and the flow convergence (FC) region as a means of accurately and quantitatively estimating the severity of a ventricular septal defect (VSD).

Methods and Results
—We performed a 3D reconstruction of the CDVC and the FC region in 19 patients with an isolated VSD using an ultrasound system interfaced with a Tomtec computer. The variable asymmetric geometry of the CDVC and the FC region could be 3D-visualized in all patients. The 3D-measured areas of CDVC correlated well with volumetric measurements of the severity of VSD (
r
=0.97,
P
<0.001). Regression analysis between the shunt flow rate (calculated from the product of the area of CDVC and the continuous Doppler–derived velocity time integral) and the corresponding reference results (calculated by cardiac catheterization) demonstrated a close correlation (
r
=0.95,
P
<0.001). There was also a good correlation between shunt flow rates calculated using the conventional 2D, 1-axis measurement of the FC isovelocity surface area with the hemispheric assumption (
r
=0.95,
P
<0.001); shunt flow rates calculated using 3D, 3-axis measurements of the FC region (
r
=0.97,
P
<0.01); and reference results by cardiac catheterization. However, the 2D method substantially underestimated the actual shunt flow rate.

Conclusions
—The 3D reconstruction of the CDVC and the FC region may aid in quantifying the severity of VSD.
Key Role of the P2Y
1
Receptor in Tissue Factor–Induced Thrombin-Dependent Acute Thromboembolism
Authors: Léon Catherine , Freund Monique , Ravanat Catherine , Baurand Anthony , Cazenave Jean-Pierre , Gachet Christian
Published: June 2012

Background
—ADP plays a key role in hemostasis, acting through 2 platelet receptors: the P2Y
1
receptor and an unidentified P2 receptor, called P2cyc, coupled to adenylyl cyclase inhibition, which is the target of the antiplatelet drug clopidogrel. We showed that the P2Y
1
receptor is an essential cofactor in thrombotic states induced by intravenous infusion of collagen and epinephrine. The aim of the present study was to assess the role of this receptor in thrombin-dependent tissue factor–induced thromboembolism.

Methods and Results
—Human thromboplastin was injected intravenously into wild-type or P2Y
1
-deficient mice, and the effects on platelet count and mortality were determined and plasma thrombin–antithrombin III (TAT) complexes were quantified. P2Y
1
-deficient mice were resistant to the thromboembolism induced by injection of thromboplastin. Whereas the platelet count decreased sharply in wild-type mice, there was no significant drop in platelets in P2Y
1
-knockout mice. The platelet consumption in wild-type mice was probably due to thrombin generation, because it was abolished by hirudin. Thromboplastin also led to a rise in TAT complexes in plasma, again reflecting thrombin formation. This effect, however, was less important in P2Y
1
-knockout mice than in wild-type mice, indicating that less thrombin was generated in the absence of P2Y
1
. Similar results were obtained after intravenous administration of
N
6
-methyl-2′-deoxyadenosine-3′:5′-bisphosphate, a selective antagonist of the P2Y
1
receptor, to wild-type mice.

Conclusions
—Our results demonstrate a role of the P2Y
1
receptor in thrombotic states involving thrombin generation and provide further evidence for the potential relevance of this receptor as a target for antithrombotic drugs.
Allopurinol Enhances the Contractile Response to Dobutamine and Exercise in Dogs With Pacing-Induced Heart Failure
Authors: Ukai Tomohiko , Cheng Che-Ping , Tachibana Hideo , Igawa Akihiko , Zhang Zhu-Shan , Cheng Heng-Jie , Little William C.
Published: June 2012

Background
—Superoxide (O
2
−
) generated by enhanced xanthine oxidase (XO) activity may contribute to the increased myocardial oxidative stress in heart failure (CHF). Because blocking XO with allopurinol augments myofilament Ca
2+
sensitivity in reperfusion injury and CHF, we hypothesized that it may improve adrenergic inotropic responsiveness in CHF.

Methods and Results
—We studied the effect of allopurinol on the contractile response to dobutamine and exercise in 7 chronically instrumented conscious dogs before and after producing CHF by rapid pacing. Left ventricular (LV) contractile performance was measured by the slopes of the LV end-systolic pressure-volume relation (E
ES
) and stroke work–end-diastolic volume relation (M
SW
). Before CHF, allopurinol produced no change in LV contractile performance and did not alter the response to dobutamine or exercise. After CHF, allopurinol produced significant (
P
<0.05) increases in E
ES
(5.0±0.6 versus 3.3±0.6 mm Hg/mL) and M
SW
. Dobutamine and allopurinol produced greater increases in E
ES
(5.4±0.6 versus 7.4±0.6 mm Hg/mL) and M
SW
(60.1±7.4 versus 73.7±4.4 mm Hg) than did dobutamine alone. After allopurinol, dP/dt
max
, stroke volume, and M
SW
were higher during CHF exercise. LV diastolic pressures were lower during CHF exercise after allopurinol.

Conclusions
—Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.
Common Hepatic Lipase Gene Promoter Variant Determines Clinical Response to Intensive Lipid-Lowering Treatment
Authors: Zambon Alberto , Deeb Samir S. , Brown B. Greg , Hokanson John E. , Brunzell John D.
Published: June 2012

Background
—The common −514
C
→
T
polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The
C
allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL
2
cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the
CC
genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects.

Methods and Results
—Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by
14
C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the
CC
genotype had the greatest decrease in HL activity (
P
<0.005 versus
TC
and
TT
by ANOVA) and the greatest improvement in LDL density (
P
<0.005) and HDL
2
-C (
P
<0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of
TC
and none of the
TT
patients (
P
<0.001).

Conclusions
—In middle-aged men with established CAD and dyslipidemia, the HL gene −514
C
→
T
polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.
Diurnal Variation in Endothelium-Dependent Vasodilatation Is Not Apparent in Coronary Artery Disease
Authors: Shaw James A. , Chin-Dusting Jaye P. F. , Kingwell Bronwyn A. , Dart Anthony M.
Published: June 2012

Background
—Acute coronary syndromes present with an increased incidence from 6:00
am
to 12:00 noon. Whether endothelial function follows a diurnal rhythm and whether this rhythm is impaired in coronary artery disease (CAD) has not previously been studied.

Methods and Results
—Diurnal variation in endothelium-dependent vasodilatation was examined in 10 CAD patients and 10 control subjects. Forearm blood flow responses to acetylcholine, sodium nitroprusside, and
N
G
-monomethyl-
l
-arginine were determined by plethysmography at 8:00
am
, 2:00
pm
, and 8:00
pm
. Heart rate, blood pressure, plasma cortisol, and inflammatory markers were also determined. Heart rate and the low-frequency component of heart rate variability were greatest in the morning in control subjects, suggesting a diurnal variation in sympathetic activity. Basal forearm blood flows were significantly reduced in control subjects at 8:00
pm
compared with 8:00
am
and 2:00
pm
(1.2±0.2 versus 2.1±0.2 [8:00
am
] and 2.1±0.3 [2:00
pm
] mL · 100 mL
−1
· min
−1
;
P
<0.05) but unchanged in the CAD group. Acetylcholine (37 μg/min) responses were greater at 8:00
am
than at 8:00
pm
in control subjects (12.5±3.7 versus 19.6±2.9 mL · 100 mL
−1
· min
−1
, respectively;
P
<0.05), but these responses were not time dependent in the CAD group. Responses to sodium nitroprusside were similar at all time points and between those with and without CAD.

Conclusions
—Thus, normal volunteers have a diurnal variation in their endothelium-dependent vasodilatation that may counteract other, potentially adverse, diurnal variations in hemodynamic and other parameters. In contrast, CAD patients who had presented with acute coronary syndromes showed a loss of this protective mechanism.
Prospective Study of Fat and Protein Intake and Risk of Intraparenchymal Hemorrhage in Women
Authors: Iso Hiroyasu , Stampfer Meir J. , Manson JoAnn E. , Rexrode Kathryn , Hu Frank B. , Hennekens Charles H. , Colditz Graham A. , Speizer Frank E. , Willett Walter C.
Published: June 2012

Background
—Dietary animal fat and protein have been inversely associated with a risk of intraparenchymal hemorrhage in ecological studies.

Methods and Results
—In 1980, 85 764 women in the Nurses’ Health Study cohort, who were 34 to 59 years old and free of diagnosed cardiovascular disease and cancer, completed dietary questionnaires. From these questionnaires, we calculated fat and protein intake. By 1994, after 1.16 million person-years of follow-up, 690 incident strokes, including 74 intraparenchymal hemorrhages, had been documented. Multivariate-adjusted risk of intraparenchymal hemorrhage was higher among women in the lowest quintile of energy-adjusted saturated fat intake than at all higher levels of intake (relative risk [RR], 2.36; 95% CI, 1.10 to 5.09;
P
=0.03). For trans unsaturated fat, the corresponding RR was 2.50 (95% CI, 1.35 to 4.65;
P
=0.004). Animal protein intake was inversely associated with risk (RR in the highest versus lowest quintiles, 0.32; 95% CI, 0.10 to 1.00;
P
=0.04). The excess risk associated with low saturated fat intake was observed primarily among women with a history of hypertension (RR, 3.66; 95% CI, 1.09 to 12.3;
P
=0.04), but such an interaction was not seen for trans unsaturated fat or animal protein. These nutrients were not related to risk of other stroke subtypes. Dietary cholesterol and monounsaturated and polyunsaturated fat were not related to risk of any stroke subtype.

Conclusions
—Low intake of saturated fat and animal protein was associated with an increased risk of intraparenchymal hemorrhage, which may help to explain the high rate of this stroke subtype in Asian countries. The increased risk with low intake of saturated fat and trans unsaturated fat is compatible with the reported association between low serum total cholesterol and risk.
Effects of Ramipril and Vitamin E on Atherosclerosis
Authors: Lonn Eva M. , Yusuf Salim , Dzavik Vladimir , Doris C. Ian , Yi Qilong , Smith Sandra , Moore-Cox Anne , Bosch Jackie , Riley Ward A. , Teo Koon K.
Published: June 2012

Background
—Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3×2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients.

Methods and Results
—A total of 732 patients ≥55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-α-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (
P
=0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo.

Conclusions
—Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.
Effects of Endothelin A Receptor Blockade on Endothelial Function in Patients With Chronic Heart Failure
Authors: Berger Rudolf , Stanek Brigitte , Hülsmann Martin , Frey Bernhard , Heher Sandra , Pacher Richard , Neunteufl Thomas
Published: June 2012

Background
—Chronic heart failure (CHF) is associated with impaired endothelium-dependent vasodilation and increased basal vascular tone due, in part, to elevated endothelin-1 plasma levels. In the present study, we investigated whether a reduction of vascular tone using an endothelin A receptor blocker attenuates the impairment of endothelium-dependent, flow-mediated vasodilation (FMD).

Methods and Results
—Twenty-one patients with CHF randomly received either the endothelin A receptor blocker LU 135252 (30 mg/d, n=7; 300 mg/d, n=7) or a placebo (n=7). Using high-resolution ultrasound, FMD and endothelium-independent, nitroglycerin-induced dilation of the brachial artery were assessed at baseline in the 21 patients with CHF and in 11 controls and after 3 weeks treatment in the 21 patients with CHF. FMD at baseline was impaired in all 21 patients with CHF (3.2±2%) when compared with the 11 controls (9.7±4.9%;
P
=0.0005). In comparison with baseline, FMD significantly improved after 3 weeks of treatment with LU 135252 in all 14 patients receiving it (from 3.0±2.0% to 4.9±2.9%;
P
=0.04), but FMD remained unchanged with placebo. Subgroup analysis, according to different dosages, revealed a significant increase of FMD compared with baseline (from 2.4±1.5% to 5.5±2.4%;
P
=0.03) in the patients treated with the low-dose (30 mg/d), whereas a high dose of 300 mg/d failed to increase FMD significantly. Improvement in the high-dose group, however, may have been masked by reduced vasodilator capacity due to a significant increase in vessel size (from 4.8±0.4 to 5.1±0.7 mm;
P
=0.03).

Conclusions
—These results suggest that endothelin A receptor blockade improves FMD in CHF patients.
Bundle-Branch Reentry and the Postpacing Interval After Entrainment by Right Ventricular Apex Stimulation
Authors: Merino Jose L. , Peinado Rafael , Fernandez-Lozano Ignacio , Lopez-Gil Maria , Arribas Fernando , Ramirez Leonardo J. , Echeverria Ignacio J. , Sobrino Jose A.
Published: June 2012

Background
—Diagnosis of bundle-branch reentry ventricular tachycardia (BBR-VT) by the standard approach is challenging, and this may lead to nonrecognition of this tachycardia mechanism. Because the postpacing interval (PPI) after entrainment has been correlated with the distance from the pacing site to the reentrant circuit, BBR-VT entrainment by pacing from the right ventricular apex (RVA) should result in a PPI similar to the tachycardia cycle length (TCL). This factor may differentiate BBR-VT from other mechanisms of wide-QRS-complex tachycardia with AV dissociation, such as myocardial reentrant VT (MR-VT) or AV nodal reentrant tachycardia (AVNRT), in which the circuit is usually located away from the RVA.

Methods and Results
—Transient entrainment by RVA pacing was attempted in 18 consecutive BBR-VTs and finally achieved in 13. Results were compared with those found in 59 consecutive MR-VTs and 50 consecutive AVNRTs. The mean PPI−TCL difference was significantly (
P
<0.0001) shorter in the BBR-VT group (9±11 ms) than in the MR-VT (109±48 ms) and the AVNRT (150±29 ms) groups. No BBR-VT showed a PPI−TCL >30 ms (range −12 to 24 ms). Except for 2 MR-VTs, no MR-VT (range 21 to 211 ms) or AVNRT (range 100 to 215 ms) showed a PPI−TCL <30 ms.

Conclusions
—A PPI−TCL >30 ms, after entrainment by RVA stimulation, makes BBR-VT unlikely. Conversely, a PPI−TCL <30 ms is suggestive of BBR-VT but should lead to further investigation by use of conventional criteria.
Inducible Nitric Oxide Synthase Deficiency Does Not Affect the Susceptibility of Mice to Atherosclerosis but Increases Collagen Content in Lesions
Authors: Niu Xi-Lin , Yang Xia , Hoshiai Kiyotaka , Tanaka Kazuo , Sawamura Sadaaki , Koga Yasuhiro , Nakazawa Hiroe
Published: June 2012

Background
—Although endothelial nitric oxide synthase (NOS) is antiatherogenic, the role of inducible NOS (iNOS) in the development of atherosclerosis is not established.

Methods and Results
—We compared the susceptibility of iNOS knockout (iNOS
−/−
) and wild-type (iNOS
+/+
) mice to the development of atherosclerosis induced by feeding an atherogenic diet for 15 weeks. Plasma lipid level, atherosclerotic lesion size, and cellular density in the lesions were all similar in the 2 strains (lesion size: iNOS
+/+
285±73×10
3
μm
2
, iNOS
−/−
293±82×10
3
μm
2
, n=10). iNOS mRNA was detected in the lesions of iNOS
+/+
but not iNOS
−/−
mice through RT-PCR. Immunohistochemically, iNOS
+/+
mice showed iNOS staining in macrophages and medial smooth muscle cells in the lesions. Nitrotyrosine staining showed a similar distribution, whereas it was absent in iNOS
−/−
mice. There was no apparent difference in the intensity or distribution of vascular cell adhesion molecule-1 staining in the lesions of the 2 strains. However, the lesions of iNOS
+/+
mice showed a markedly decreased extracellular collagen content compared with those of iNOS
−/−
mice

Conclusions
—iNOS induction does not affect the development of atherosclerosis in mice fed an atherogenic diet, but the resulting lesions show decreased levels of extracellular collagen and may be more fragile.
Effect of Selective or Combined Inhibition of Integrins α
IIb
β
3
and α
v
β
3
on Thrombosis and Neointima After Oversized Porcine Coronary Angioplasty
Authors: Chico Timothy J. A. , Chamberlain Janet , Gunn Julian , Arnold Nadine , Bullens Sherron L. , Gadek Thomas R. , Francis Sheila E. , Bunting Stuart , Horton Michael , Shepherd Lynda , Lipari Michael T. , Quan Clifford , Knolle Jochen , Stilz Hans Ulrich , Peyman Anusch , Crossman David C.
Published: June 2012

Background
—Thrombosis and neointima formation limit the efficacy of coronary angioplasty (PTCA). Clinical trials have implicated the adhesion molecules integrin α
IIb
β
3
and integrin α
v
β
3
in these processes. The roles of these molecules in vascular smooth muscle cell adhesion, platelet aggregation, and the thrombotic and neointimal response to oversize porcine PTCA was investigated by use of a selective α
IIb
β
3
antagonist (lamifiban), a selective α
v
β
3
antagonist (VO514), and a combined α
IIb
β
3
/α
v
β
3
antagonist (G3580).

Methods and Results
—In vitro, both α
v
β
3
inhibitors caused dose-dependent inhibition of porcine vascular smooth muscle cell adhesion to vitronectin but not to collagen type IV, fibronectin, or laminin, whereas selective α
IIb
β
3
inhibition had no effect. Intravenous infusions of either α
IIb
β
3
inhibitor in swine profoundly inhibited ex vivo platelet aggregation to ADP, whereas selective α
v
β
3
inhibition had no effect. In a porcine PTCA model, intravenous infusions of the integrin antagonists were administered for 14 days after oversized balloon angioplasty injury. After PTCA, there was regional upregulation of integrin α
v
β
3
in the developing neointima, as assessed by immunohistochemistry. Six hours after PTCA, obstruction of lumen by thrombus was reduced significantly by α
IIb
β
3
inhibition compared with either control or α
v
β
3
inhibition (mean control, 18.7%; VO514, 18.5%; lamifiban, 6.4%; G3580, 7.9%). Twenty-eight days after PTCA, there was a significant reduction of neointima with inhibitors of either integrin (mean intima/media ratio: control, 3.08; VO514, 1.33; lamifiban, 0.97; G3580, 1.32).

Conclusions
—We conclude that both integrin α
IIb
β
3
and integrin α
v
β
3
participate in neointima development after experimental angioplasty.
Detection of Fibrous Cap in Atherosclerotic Plaque by Intravascular Ultrasound by Use of Color Mapping of Angle-Dependent Echo-Intensity Variation
Authors: Hiro Takafumi , Fujii Takashi , Yasumoto Kyounori , Murata Takashige , Murashige Akihiro , Matsuzaki Masunori
Published: June 2012

Background
—The thickness of the fibrous cap is a major determinant in the vulnerability of atherosclerotic plaque to rupture. It has been demonstrated that intravascular ultrasound (IVUS) backscatter from fibrous tissue is strongly dependent on the ultrasound beam angle of incidence. This study investigated the feasibility of using a new IVUS color mapping technique representing the angle-dependent echo-intensity variation to determine the thickness of the fibrous cap in atherosclerotic plaque.

Methods and Results
—Nineteen formalin-fixed noncalcified human atherosclerotic plaques from necropsy were imaged in vitro with a 30-MHz IVUS catheter. The IVUS catheter was moved coaxially relative to the plaque. The images showing maximum and minimum echo intensity of the plaque surface were selected to calculate the angle-dependent echo-intensity variation. A colorized representation of the echo-intensity variation in the plaque was obtained from the 2 IVUS images. A clearly bordered area with large variation in echo intensity was revealed for each plaque surface in the colorized IVUS image. The thickness (
x
, mm) of this area correlated significantly with that of fibrous cap (
y
, mm) measured from histologically prepared sections as
y
=1.05
x
−0.01 (
r
=0.81,
P
<0.0001). Bland-Altman analysis also supported the reliability of this method (mean difference, 0.00±0.10 mm).

Conclusions
—This novel technique for color mapping the echo-intensity variation in IVUS provided an accurate representation of the thickness of the fibrous cap in atherosclerotic plaque. This method may be useful in assessing plaque vulnerability to rupture in atherosclerosis.
Functional Significance of Hemodynamic Overload–Induced Expression of Leukemia-Inhibitory Factor in the Adult Mammalian Heart
Authors: Wang Feng , Seta Yukihiro , Baumgarten Georg , Engel David J. , Sivasubramanian Natarajan , Mann Douglas L.
Published: June 2012

Background
—Leukemia-inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines that utilize gp130 as a common signaling component. In the present study, we examined the mechanisms that govern LIF expression and functional effects in the adult heart.

Methods and Results
—LIF mRNA and protein biosynthesis were examined in the adult feline heart after hemodynamic overloading ex vivo. Both LIF mRNA and protein expression were detected within 60 to 90 minutes after hemodynamic overloading. Studies in isolated adult cardiac myocytes showed that these cells synthesized both LIF mRNA and protein. The functional effects of LIF in the heart were demonstrated by studies that showed that LIF stimulation led to a significant increase in general protein synthesis and an increase in sarcomeric protein synthesis. Pretreatment with LIF also protected the cells against hypoxia/reoxygenation-induced cardiac myocyte apoptosis and cellular injury. Finally, LIF had no effect on isolated cardiac myocyte cell motion.

Conclusions
—Hemodynamic overload is a sufficient stimulus for LIF expression in the adult mammalian heart. Given that LIF confers both hypertrophic and cytoprotective responses in adult cardiac myocytes, this study suggests that the expression of LIF within the heart may play an important role in mediating homeostatic responses within the myocardium.
Impaired Myofibrillar Energetics and Oxidative Injury During Human Atrial Fibrillation
Authors: Mihm Michael J. , Yu Fushun , Carnes Cynthia A. , Reiser Peter J. , McCarthy Patrick M. , Van Wagoner David R. , Bauer John Anthony
Published: June 2012

Background

—

Atrial fibrillation (AF) is associated with severe contractile dysfunction and structural and electrophysiological remodeling. Mechanisms responsible for impaired contractility are undefined, and current therapies do not address this dysfunction. We have found that myofibrillar creatine kinase (MM-CK), an important controller of myocyte contractility, is highly sensitive to oxidative injury, and we hypothesized that increased oxidative stress and energetic impairment during AF could contribute to contractile dysfunction.

Methods and Results

—

Right atrial appendages were obtained from AF patients undergoing the Maze procedure and from control patients who were in normal sinus rhythm and undergoing cardiac surgery. MM-CK activity was reduced in AF patients compared with controls (25.4±3.4 versus 18.2±3.8 μmol/mg of myofibrillar protein per minute; control versus AF;
P
<0.05). No reduction in total CK activity or myosin ATPase activity was detected. This selective reduction in MM-CK activity was associated with increased relative expression of the β-myosin isoform (25±6 versus 63±5%β, CTRL versus AF;
P
<0.05). Western blotting of AF myofibrillar isolates demonstrated no changes in protein composition but showed increased prevalence of protein oxidation as detected by Western blotting for 3-nitrotyrosine (peroxynitrite biomarker) and protein carbonyls (hydroxyl radical biomarker;
P
<0.05). Patterns of these oxidative markers were distinct, which suggests discrete chemical events and differential protein vulnerabilities in vivo. MM-CK inhibition was statistically correlated to extent of nitration (
P
<0.01) but not to carbonyl presence.

Conclusions

—

The present results provide novel evidence of oxidative damage in human AF that altered myofibrillar energetics may contribute to atrial contractile dysfunction and that protein nitration may be an important participant in this condition.
Polymorphism in the β
1
-Adrenergic Receptor Gene and Hypertension
Authors: Bengtsson Kristina , Melander Olle , Orho-Melander Marju , Lindblad Ulf , Ranstam Jonas , Råstam Lennart , Groop Leif
Published: June 2012

Background

—

The Arg389 variant of the β
1
-adrenergic receptor gene mediates a higher isoproterenol-stimulated adenylate cyclase activity than the Gly389 variant in vitro. We investigated whether the Arg389Gly or the Ser49Gly polymorphism is associated with hypertension in Scandinavians.

Methods and Results

—

A total of 292 unrelated, nondiabetic, hypertensive patients and 265 unrelated healthy control subjects were included in a case-control association study. From 118 families, 102 nondiabetic sibling pairs without antihypertensive medication who were discordant for the Arg389Gly polymorphism were selected for a sibling study. Allele and genotype frequencies of the Arg389Gly and Ser49Gly polymorphisms were compared between hypertensive patients and normotensive control subjects. Blood pressure and heart rate were compared between carriers of the different genotypes. In the case-control study, the age- and body mass index-adjusted odds ratio for hypertension in subjects homozygous for the Arg389 allele was 1.9 (95% confidence interval, 1.3 to 2.7;
P
=0.0005) when compared with carriers of 1 or 2 copies of the Gly389 allele. The genotype-discordant sibling pair analysis revealed that siblings homozygous for the Arg389 allele had significantly higher diastolic blood pressures (79.4±9.9 versus 76.0±10.1 mm Hg;
P
=0.003) and higher heart rates (68.3±11.0 versus 65.1±9.4 bpm;
P
=0.02) than siblings carrying 1 or 2 copies of the Gly389 allele. The Ser49Gly polymorphism was not associated with hypertension.

Conclusion

—

Our data suggest that individuals homozygous for the Arg389 allele of the β
1
-adrenergic receptor gene are at increased risk to develop hypertension.
Simultaneous Noncontact Mapping of Left Atrium in Patients With Paroxysmal Atrial Fibrillation
Authors: Hindricks Gerhard , Kottkamp Hans
Published: June 2012

Background

Catheter ablation of pulmonary vein ectopic foci is a potentially curative treatment strategy for patients with atrial fibrillation. However, identification of arrhythmogenic pulmonary veins with conventional mapping is difficult, especially in patients with rare focal activity, multiple active foci, or extrapulmonary foci. The present study was designed to investigate use of simultaneous noncontact mapping in this setting.

Methods and Results

In 17 consecutive patients with paroxysmal atrial fibrillation, a catheter-mounted noncontact multielectrode array positioned in the left atrium was used to reconstruct 3300 electrograms simultaneously from a single beat. Isopotential maps were generated during sinus rhythm and focal activity. After ectopic foci were identified, radiofrequency catheter ablation was performed in patients with 1 or 2 foci. However, in patients who had multiple foci, intraoperative ablation of atrial fibrillation was advised. A total of 28 ectopic foci (25 pulmonary vein foci and 3 extrapulmonary vein foci) were identified by use of isopotential maps generated from a single beat of focal activity. Radiofrequency catheter ablation guided by noncontact mapping was attempted in 12 patients with 1 or 2 ectopic foci. Successful ablation of atrial fibrillation was achieved in 9 of 12 patients (75%).

Conclusions

Noncontact mapping allows rapid and precise identification of arrhythmogenic pulmonary veins in addition to extrapulmonary vein foci. Thus, the present study shows that the technology may be used not only to guide radiofrequency catheter ablation, but also as a diagnostic tool to develop individual treatment strategies.
Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect
Authors: Aase Karin , von Euler Gabriel , Li Xuri , Pontén Annica , Thorén Peter , Cao Renhai , Cao Yihai , Olofsson Birgitta , Gebre-Medhin Samuel , Pekny Milos , Alitalo Kari , Betsholtz Christer , Eriksson Ulf
Published: June 2012

Background

Vascular endothelial growth factors (VEGFs) and their receptors are essential regulators of vasculogenesis and angiogenesis in both embryos and adults. One of the factors with a still unknown physiological function is VEGF-B, which is expressed in many tissues, including the heart.

Methods and Results

Mice carrying a targeted deletion in the VEGF-B gene were developed. In VEGF-B
−/−
animals, no gross abnormalities were observed in organs that normally show high expression of VEGF-B, such as the heart, muscle, and kidney. Analysis of heart function by ECG showed that adult VEGF-B
−/−
mice have an atrial conduction abnormality characterized by a prolonged PQ interval. VEGF- or basic fibroblast growth factor–induced corneal angiogenesis was similar in normal and VEGF-B
−/−
mice.

Conclusions

VEGF-B seems to be required for normal heart function in adult animals but is not required for proper development of the cardiovascular system either during development or for angiogenesis in adults.
Epicardial activation and repolarization patterns in patients with right ventricular hypertrophy.
Authors: Chen P S , Moser K M , Dembitsky W P , Auger W R , Daily P O , Calisi C M , Jamieson S W , Feld G K
Published: June 2012

To map global epicardial repolarization patterns and test the "SI" model of T wave generation, the patterns of epicardial activation and repolarization in patients with chronic pulmonary thromboembolism and right ventricular hypertrophy were studied by computerized mapping techniques and monophasic action potential (MAP) recording. The ventricular activation patterns were characterized by delayed right ventricular activation and the absence of normal early epicardial ventricular breakthrough in some cases. The repolarization patterns were characterized by nonuniform distribution of T wave morphologies. The T waves were predominantly positive over the left ventricular epicardium and negative or biphasic over the right ventricular epicardium. The activation-recovery (A-R) intervals were measured from the local activation to the maximal dV/dt of the upstroke of the T waves (Wyatt method). The difference between the A-R intervals and the MAP from onset of activation to 90% repolarization (MAP90) varies according to T wave morphology and could be as high as 96 msec with positive T waves, despite significant correlations (r = 0.56-0.90) between MAP90 and A-R intervals for each morphology. Better overall correlations were found if the minimal dV/dt on the downslope of the positive T waves was chosen to estimate the time of local repolarization (alternative method). Using this method, the mean A-R intervals were the same over the right and left ventricles. Cardiopulmonary bypass significantly prolonged the action potential duration equally at all parts of the epicardium. We conclude that in patients with right ventricular hypertrophy, the time of local repolarization can be estimated by our alternative method; the right ventricle completes activation and repolarization later than the left ventricle, and the distribution of T wave morphologies is nonuniform, with predominantly positive T waves observed over the left ventricle and negative or biphasic T waves observed over the right ventricle. These findings are compatible with the SI model of the generation of T waves.