bluuebunny/crossref_metadata_2025 huggingface dataset:
Tamoxifen Effects on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis
Authors: Clarke Sarah C. , Schofield Peter M. , Grace Andrew A. , Metcalfe James C. , Kirschenlohr Heide L.
Published: June 2012

Background
—Tamoxifen and its analogues act as selective estrogen receptor modulators (SERMs) in women, with estrogen-like activities on some plasma cardiovascular risk factors (eg, lipoproteins). Effects of SERMs on men with coronary artery disease (CAD) have not been reported.

Methods and Results
—Thirty-one men with angiographically proven CAD were recruited; 16 were treated with tamoxifen (40 mg/d) for 56 days, and 15 were untreated. All the CAD patients were medicated with aspirin and an HMG-CoA reductase inhibitor for ≥6 weeks before entering the study. Ten men with angina-like symptoms but normal coronary arteries by angiography (NCA group) were also treated with tamoxifen. Blood samples were collected at days −7, 0, 7, 14, 21, 28, and 56 of treatment. Endothelium-dependent flow-mediated dilatation (ED-FMD) of the brachial artery was measured by high-resolution ultrasound at 5 visits. Tamoxifen caused an increase in %ED-FMD maximal at 28 days in the CAD group (2.1±0.3% to 7.5±0.7%;
P
<0.0001) and the NCA group (3.8±0.4% to 7.9±1.0%;
P
<0.0001), with no significant change in the untreated group. Tamoxifen also caused decreases in several plasma cardiovascular risk factors, including total cholesterol, triglycerides, lipoprotein(a), and fibrinogen. Except for the triglyceride response, these effects were similar to those reported for postmenopausal women treated with tamoxifen.

Conclusions
—Tamoxifen substantially increased ED-FMD in men with CAD who were taking conventional medication. Together with the effects on risk factors, the data strongly support clinical evaluation of SERMs for the treatment of men with CAD.
Molecular Fingerprint of Interferon-γ Signaling in Unstable Angina
Authors: Liuzzo Giovanna , Vallejo Abbe N. , Kopecky Stephen L. , Frye Robert L. , Holmes David R. , Goronzy Jörg J. , Weyand Cornelia M.
Published: June 2012

Background
—Activation of circulating monocytes in patients with acute coronary syndromes may reflect exposure to bacterial products or stimulation by cytokines such as IFN-γ. IFN-γ induces phosphorylation and nuclear translocation of transcription factor STAT-1, which initiates a specific program of gene induction. To explore whether monocyte activation is IFN-γ driven, patients with unstable (UA) or stable angina (SA) were compared for nuclear translocation of STAT-1 complexes and upregulation of IFN-γ–inducible genes CD64 and IP-10.

Methods and Results
—Peripheral blood mononuclear cells were stained for expression of CD64 on CD14
+
monocytes and analyzed by PCR for transcription of IP-10. Expression of CD64 was significantly increased in patients with UA. Monocytes from UA patients remained responsive to IFN-γ in vitro, with accelerated transcriptional competency of CD64. IP-10–specific sequences were spontaneously detectable in 82% of the UA patients and 15% of SA patients (
P
<0.001). Most importantly, STAT-1 complexes were found in nuclear extracts prepared from freshly isolated monocytes of patients with UA, which provides compelling evidence for IFN-γ signaling in vivo.

Conclusions
—Monocytes from UA patients exhibit a molecular fingerprint of recent IFN-γ triggering, such as nuclear translocation of STAT-1 complexes and upregulation of IFN-γ–inducible genes CD64 and IP-10, which suggests that monocytes are activated, at least in part, by IFN-γ. IFN-γ may derive from stimulated T lymphocytes, which implicates specific immune responses in the pathogenesis of acute coronary syndromes.
Serial Magnetic Resonance Imaging of Microvascular Remodeling in the Infarcted Rat Heart
Authors: Waller Christiane , Hiller Karl-Heinz , Kahler Elke , Hu Kai , Nahrendorf Matthias , Voll Sabine , Haase Axel , Ertl Georg , Bauer Wolfgang Rudolf
Published: June 2012

Background
—Alterations in the coronary circulation are important determinants of myocardial function. Few data are available, however, about microvascular changes in reactive hypertrophy. With MRI, serial determination of myocardial microcirculation after myocardial infarction (MI) is feasible.

Methods and Results
—We quantitatively determined myocardial perfusion and relative intracapillary blood volume using an MRI technique. Infarct size, myocardial mass, and left ventricular volumes were determined with cine MRI. Rats were investigated at 8, 12, and 16 weeks after MI (mean MI size 24.1±2.0%) or sham operation. Vasodilation was induced by adenosine. In the infarcted group, maximum perfusion decreased significantly from 8 to 16 weeks (5.6±0.3 versus 3.5±0.2 mL · g
−1
· min
−1
,
P
<0.01) compared with sham animals (5.5±0.3 versus 5.0±0.2 mL · g
−1
· min
−1
,
P
=0.17). Myocardial mass increased significantly (559.1±20.8 mg at 8 weeks versus 690.9±42.7 mg at 16 weeks,
P
<0.05) compared with sham-operated animals (516.3±41.7 versus 549.2±32.3 mg). Basal relative intracapillary blood volume increased significantly to 15.7±0.5 vol% at 8 weeks after MI and remained elevated (16.8±0.6 vol%) at 16 weeks compared with 12.1±0.3 vol% (
P
<0.01) in sham-operated rats.

Conclusions
—Our results indicate that significant microvascular changes occur during cardiac remodeling. Hypoperfusion in the hypertrophied myocardium is related to an increase in vascular capacity, suggesting a compensatory vasodilatory response at the capillary level. These microvascular changes may therefore contribute to the development of heart failure.
Endothelium-Derived Hyperpolarizing Factor
Authors: Coats Paul , Johnston Fiona , MacDonald John , McMurray John J. V. , Hillier Chris
Published: June 2012

Background
—Both a vascular endothelial cytochrome P450 (CYP450) product of arachidonic acid metabolism and the potassium ion (K
+
) have been identified as endothelium-derived hyperpolarizing factors (EDHFs) in animal vascular tissues. We studied the relative importance of EDHF, nitric oxide (NO), and prostacyclin (PGI
2
) as vasodilators in human subcutaneous arteries. We also examined the mechanisms underlying the vasodilator action of EDHF to elucidate its identity.

Methods and Results
—Subcutaneous resistance arteries were obtained from 41 healthy volunteers. The contribution of EDHF to the vasodilation induced by acetylcholine was assessed by inhibiting production of NO, PGI
2
, and membrane hyperpolarization. The mechanisms underlying the relaxation evoked by K
+
and EDHF were elucidated. EDHF was found to account for ≈80% of acetylcholine-mediated vasorelaxation. Its action was insensitive to the combination of barium and ouabain, whereas barium and ouabain reversed K
+
-mediated vasorelaxation. EDHF-mediated vasorelaxation, however, was sensitive to the phospholipase A
2
inhibitor oleyloxyethyl phosphorylcholine and the CYP450 inhibitor ketoconazole.

Conclusions
—EDHF is the major contributor to endothelium-dependent vasorelaxation in human subcutaneous resistance arteries. A product of phospholipase A
2
/CYP450–dependent metabolism of arachidonic acid and not K
+
is the likely identity of EDHF in human subcutaneous resistance arteries.
Differential Profile and Biochemical Effects of Antiautonomic Membrane Receptor Antibodies in Ventricular Arrhythmias and Sinus Node Dysfunction
Authors: Chiale Pablo A. , Ferrari Inés , Mahler Evelina , Vallazza Marina A. , Elizari Marcelo V. , Rosenbaum Mauricio B. , Levin Mariano J.
Published: June 2012

Background
—The relationship between anti-β-adrenergic (anti-βR) and anti-M
2
-cholinergic (anti-M2R) receptor antibodies (Abs) and cardiac arrhythmias and their biochemical effects have not been systematically investigated.

Methods and Results
—We studied 41 patients, 28 with ventricular arrhythmias (primary or due to Chagas’ heart disease or idiopathic dilated cardiomyopathy; group I), 13 with sinus node dysfunction (primary or caused by Chagas’ heart disease; group II), and 10 healthy controls (group III). The chronotropic effects of the IgG and immunopurified anti-β
1
RAbs or anti-M2RAbs were assessed on cultured cardiomyocytes before and after exposure to atropine and propranolol. The biochemical effects of the IgG from 9 patients from group I, 6 from group II, and 6 controls were evaluated on COS7 cells transfected with genes encoding for β
1
,β
2
-adrenergic receptors (cAMP increment) or M
2
-cholinergic receptors (phosphatidylinositol increment). The IgG from group I patients exerted a positive chronotropic action, with a high prevalence of anti-βRAbs (75%) and low prevalence of anti-M2RAbs (10.7%) and induced a clear-cut and long-lasting increment in cAMP. The IgG from group II patients depressed chronotropism, with a high prevalence of anti-M2RAbs (76.9%) and low prevalence of anti-βRAbs (15.4%) and evoked a marked augmentation of phosphatidylinositol.

Conclusions
—Our results demonstrate a strong correlation between anti-βRAbs and ventricular arrhythmias and anti-M2RAbs and sinus node dysfunction. Anti-βRAbs increase and anti-M2RAbs inhibit cAMP production. These findings offer new insight into the etiology and pathophysiology of cardiac arrhythmias, with therapeutic implications.
RANTES Deposition by Platelets Triggers Monocyte Arrest on Inflamed and Atherosclerotic Endothelium
Authors: von Hundelshausen Philipp , Weber Kim S. C. , Huo Yuqing , Proudfoot Amanda E. I. , Nelson Peter J. , Ley Klaus , Weber Christian
Published: June 2012

Background
—Circulating platelets and chemoattractant proteins, such as the CC chemokine RANTES, contribute to the activation and interaction of monocytes and endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease.

Methods and Results
—The binding of RANTES to human endothelial cells was detected by ELISA or immunofluorescence after perfusion with platelets or exposure to their supernatants. Monocyte arrest on endothelial monolayers or surface-adherent platelets was studied with a parallel-wall flow chamber and video microscopy. We show that RANTES secreted by thrombin-stimulated platelets is immobilized on the surface of inflamed microvascular or aortic endothelium and triggers shear-resistant monocyte arrest under flow conditions, as shown by inhibition with the RANTES receptor antagonist Met-RANTES or a blocking RANTES antibody. Deposition of RANTES and its effects requires endothelial activation, eg, by interleukin-1β, and is not supported by venous endothelium or adherent platelets. Immunohistochemistry revealed that RANTES is present on the luminal surface of carotid arteries of apolipoprotein E–deficient mice with early atherosclerotic lesions after wire-induced injury or cytokine exposure. In a mechanistic model of atherogenesis, monocyte adherence on endothelium covering such lesions was studied in murine carotid arteries perfused ex vivo, showing that the accumulation of monocytic cells in these carotid arteries involved RANTES receptors.

Conclusions
—The deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium. Delivery of RANTES by platelets may epitomize a novel principle relevant to inflammatory or atherogenic monocyte recruitment from the circulation.
Anti-Inflammatory, Antithrombotic, and Neuroprotective Effects of Activated Protein C in a Murine Model of Focal Ischemic Stroke
Authors: Shibata Masayoshi , Kumar S. Ram , Amar Arun , Fernandez Jose A. , Hofman Florence , Griffin John H. , Zlokovic Berislav V.
Published: June 2012

Background
—Activated protein C (APC) contributes to systemic anticoagulant and anti-inflammatory activities. APC may reduce organ damage by inhibiting thrombin generation and leukocyte activation. Neutrophils and cerebrovascular thrombosis contribute to ischemic neuronal injury, suggesting that APC may be a potential protective agent for stroke.

Methods and Results
—We examined the effects of APC in a murine model of focal ischemia. After middle cerebral artery occlusion/reperfusion, the average survival time in controls was 13.6 hours. Animals that received purified human plasma–derived APC 2 mg/kg IV either 15 minutes before or 10 minutes after stroke induction survived 24 hours and were killed for neuropathological analysis. APC 2 mg/kg given before or after onset of ischemia restored cerebral blood flow, reduced brain infarct volume (59% to 69%;
P
<0.003) and brain edema (50% to 61%;
P
<0.05), eliminated brain infiltration with neutrophils, and reduced the number of fibrin-positive cerebral vessels by 57% (
P
<0.05) and 25% (nonsignificant), respectively. The neuroprotective effect of APC was dose-dependent and associated with significant inhibition of ICAM-1 expression on ischemic cerebral blood vessels (eg, 61% inhibition with 2 mg/kg APC). Intracerebral bleeding was not observed with APC.

Conclusions
—APC exerts anti-inflammatory, antithrombotic, and neuroprotective effects in stroke. Central effects of APC are likely to be related to improved maintenance of the blood-brain barrier to neutrophils and to reduced microvascular obstructions and fibrin deposition.
High-Sensitivity C-Reactive Protein
Authors: Ridker Paul M.
Published: June 2012

Abstract
—Inflammation plays a major role in atherothrombosis, and measurement of inflammatory markers such as high-sensitivity C-reactive protein (HSCRP) may provide a novel method for detecting individuals at high risk of plaque rupture. Several large-scale prospective studies demonstrate that HSCRP is a strong independent predictor of future myocardial infarction and stroke among apparently healthy men and women and that the addition of HSCRP to standard lipid screening may improve global risk prediction among those with high as well as low cholesterol levels. Because agents such as aspirin and statins seem to attenuate inflammatory risk, HSCRP may also have utility in targeting proven therapies for primary prevention. Inexpensive commercial assays for HSCRP are now available; they have shown variability and classification accuracy similar to that of cholesterol screening. Risk prediction algorithms using a simple quintile approach to HSCRP evaluation have been developed for outpatient use. Thus, although limitations inherent to inflammatory screening remain, available data suggest that HSCRP has the potential to play an important role as an adjunct for global risk assessment in the primary prevention of cardiovascular disease.
Decreased Expression of Tumor Necrosis Factor-α and Regression of Hypertrophy After Nonsurgical Septal Reduction Therapy for Patients With Hypertrophic Obstructive Cardiomyopathy
Authors: Nagueh Sherif F. , Stetson Sonny J. , Lakkis Nasser M. , Killip Donna , Perez-Verdia Alex , Entman Mark L. , Spencer William H. , Torre-Amione Guillermo
Published: June 2012

Background
—Nonsurgical septal reduction therapy (NSRT) is a novel therapeutic strategy for patients with hypertrophic obstructive cardiomyopathy (HOCM). Although the clinical benefits of this technique appear to be clear, the structural and functional changes that lead to improvements in cardiac function are not completely defined. In these studies, we sought to define the effect of NSRT on myocardial function as well as various markers of hypertrophy including the expression of tumor necrosis factor (TNF)-α, a cytokine capable of producing fibrosis, left ventricular hypertrophy (LVH), and cardiomyopathy.

Methods and Results
—We performed endomyocardial biopsies of the RV side of the septum and echocardiograms on 15 HOCM patients at baseline and after successful NSRT. Comparative analysis on paired myocardial samples were performed to determine the effects of NSRT on LVH, end-diastolic volume and chamber stiffness, myocyte size, collagen content, and TNF-α levels. At baseline, myocardial TNF-α levels were increased in all patients. After NSRT, myocyte size, collagen content, and TNF-α were significantly decreased. These changes were accompanied by an increase in left ventricular volumes and a reduction in LVH and chamber stiffness.

Conclusions
—We suggest that pressure overload in HOCM patients contributes to the development of hypertrophy. These data provide the initial experimental evidence to suggest that TNF-α may play a pathogenetic role in the hypertrophy of pressure overload.
Elevated Urinary Albumin Excretion Is Associated With Impaired Arterial Dilatory Capacity in Clinically Healthy Subjects
Authors: Clausen P. , Jensen J. S. , Jensen G. , Borch-Johnsen K. , Feldt-Rasmussen B.
Published: June 2012

Background
—Elevated urinary albumin excretion (UAE) predicts atherosclerotic cardiovascular disease. It is hypothesized that elevated UAE is associated with a generalized vascular dysfunction. This study tested this hypothesis for conduit arteries.

Methods and Results
—Clinically healthy subjects were selected: 19 with UAE >90th percentile in the background population (6.6 μg/min<UAE<150 μg/min) and 41 with normoalbuminuria (UAE <6.6 μg/min). External ultrasound was used to measure the dilatory response of the brachial artery to postischemic increased blood flow (endothelium-dependent, flow-associated dilation) and to nitroglycerin (endothelium-independent, nitroglycerin-induced dilation). Plasma concentrations of the endothelial markers nitrate/nitrite, thrombomodulin, and von Willebrand factor antigen were also measured. Both flow-associated and nitroglycerin-induced dilations were significantly impaired in subjects with elevated UAE as compared with normoalbuminuric control subjects: 102.0±1.0% (mean±SEM) versus 104.3±0.6% (
P
<0.05) and 120.1±1.5% versus 123.8±1.0% (
P
<0.05). No differences in the plasma concentrations of endothelial markers were found.

Conclusions
—Slightly elevated UAE is associated with impaired conduit arterial dilatory capacity in clinically healthy subjects, and this impairment may be explained by a reduced dilatory response to nitric oxide of both endogenous and exogenous origin. Impaired arterial dilatory capacity may contribute to the increased cardiovascular risk in subjects with elevated UAE.
Myocardial Efficiency and Sympathetic Reinnervation After Orthotopic Heart Transplantation
Authors: Bengel Frank M. , Ueberfuhr Peter , Schiepel Nina , Nekolla Stephan G. , Reichart Bruno , Schwaiger Markus
Published: June 2012

Background
—The lack of cardiac catecholamine uptake and storage caused by sympathetic denervation may influence performance of the transplanted heart. Reinnervation, occurring late after transplantation, may partially resolve these effects. In this study, oxidative metabolism and its relation to cardiac work were compared in allografts and normal and failing hearts, and the effects of sympathetic reinnervation were evaluated.

Methods and Results
—Twenty-seven nonrejecting, symptom-free transplant recipients, 11 healthy control subjects, and 10 patients with severe dilated cardiomyopathy underwent PET with
11
C acetate for assessment of oxidative metabolism by the clearance constant
k(mono)
and radionuclide angiography or MRI for measurement of ventricular function, geometry, and work. Efficiency was estimated noninvasively by a work-metabolic index [WMI=(stroke volume×heart rate×systolic pressure)/
k(mono)
]. In 14 of 27 transplants, presence of regional reinnervation was identified with PET and the catecholamine analogue
11
C hydroxyephedrine (extent, 24±14% of left ventricle). The WMI was comparable in normal subjects and reinnervated and denervated transplants (6.2±2.3 versus 4.9±2.0 versus 4.9±1.2 · 10
6
mm Hg · mL;
P
=NS) and significantly lower in cardiomyopathy patients (3.0±1.3 · 10
6
mm Hg · mL;
P
<0.001). For normal subjects and transplant recipients, the WMI was significantly correlated with afterload (peripheral vascular resistance;
r
=−0.65,
P
<0.01), preload (end-diastolic volume;
r
=0.78,
P
<0.01), and stroke volume (
r
=0.81,
P
<0.01) but not with hydroxyephedrine retention (transplants only;
r
=0.09,
P
=NS).

Conclusions
—After transplantation, cardiac efficiency is improved compared with failing hearts and comparable to normal hearts. Differences between denervated and reinnervated allografts were not surveyed. Additionally, the dependency on loading conditions and contractility was preserved, suggesting that normal regulatory interactions for efficiency are intact and that sympathetic tone does not play a role under resting conditions.
Effect of Hydroxymethyl Glutaryl Coenzyme A Reductase Inhibitor Therapy on High Sensitive C-Reactive Protein Levels
Authors: Jialal I. , Stein D. , Balis D. , Grundy S. M. , Adams-Huet B. , Devaraj S.
Published: June 2012

Background
—Prospective studies indicate that baseline levels of C-reactive protein (CRP), the prototypic marker of inflammation, are associated with an increased risk for cardiovascular events. Limited studies have examined therapies that influence high-sensitive CRP (hs-CRP) levels, especially in hyperlipidemic patients. Thus, we tested the effects of 3 hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), simvastatin (20 mg/d), pravastatin (40 mg/d), and atorvastatin (10 mg/d), on levels of hs-CRP in a randomized, double-blind, crossover trial of 22 patients with combined hyperlipidemia (LDL cholesterol >130 mg/dL and triglycerides of 200 to 600 mg/dL).

Methods and Results
—After 6 weeks of an American Heart Association Step 1 diet, fasting blood samples were drawn at baseline and after 6 weeks of therapy with each drug. hs-CRP levels were significantly decreased after treatment with all 3 statins compared with baseline (median values: baseline, 2.6 mg/L; atorvastatin, 1.7 mg/L; simvastatin, 1.7 mg/L; and pravastatin, 1.9 mg/L;
P
<0.025). The reductions obtained with the 3 statins were similar. In addition, there was no significant effect on either plasma interleukin-6 or interleukin-6 soluble receptor levels. There was no relationship between reductions in hs-CRP and LDL cholesterol.

Conclusions
—Pravastatin, simvastatin, and atorvastatin significantly decreased levels of hs-CRP. These data support an anti-inflammatory effect of these drugs.
Oral Anticoagulant Therapy During and After Coronary Angioplasty
Authors: Berg Jurriën M. ten , Hutten Barbara A. , Kelder Johannes C. , Verheugt Freek W. A. , Plokker H. W. Thijs
Published: June 2012

Background
—In the randomized Balloon Angioplasty and Anticoagulation Study (BAAS), the addition of oral anticoagulants to aspirin significantly reduced early and late events after coronary angioplasty. However, bleeding episodes were increased. The present report studied the intensity and the duration of anticoagulation as predictors of thrombotic and bleeding events.

Methods and Results
—A total of 530 patients, 34% of whom received a stent, were treated with aspirin plus coumarins. Half of the patients were randomized to angiographic follow-up. The target international normalized ratio (INR) was 2.1 to 4.8 during angioplasty and 6-month follow-up. Thrombotic events were death, myocardial infarction, target lesion revascularization, and thrombotic stroke. Bleeding complications were hemorrhagic stroke, major extracranial bleeding, and false aneurysm. “Optimal” anticoagulation was defined as an INR in the target range for at least 70% of the follow-up time. There were 17 early thrombotic events (3.2%), 7 early bleeding episodes (1.3%), and 10 false aneurysms (1.9%). The incidence rate for both early thrombotic and bleeding events was lowest in patients in the target range. A total of 61 late thrombotic events occurred (11.6%). Optimal anticoagulation was an independent predictor of late thrombotic events (relative risk, 0.33; 95% CI, 0.19 to 0.57) and was associated with a 0.21 mm (95% CI, 0.17 to 0.42) larger vessel lumen at 6 months. Late bleeding episodes (1.4%) were lowest in patients in the target range.

Conclusions
—Coumarins started before coronary angioplasty with a target INR of 2.1 to 4.8 led to the lowest procedural event rate, without an increase in bleeding episodes. During follow-up, optimal anticoagulation was associated with a decrease in the incidence of late events by 67% and a significant improvement in 6-month angiographic outcome.
Relation of a Common Methylenetetrahydrofolate Reductase Mutation and Plasma Homocysteine With Intimal Hyperplasia After Coronary Stenting
Authors: Kosokabe Tai , Okumura Kenji , Sone Takahito , Kondo Junichiro , Tsuboi Hideyuki , Mukawa Hiroaki , Tomida Takahito , Suzuki Tomomichi , Kamiya Hiroki , Matsui Hideo , Hayakawa Tetsuo
Published: June 2012

Background
—Hyperhomocysteinemia has been identified as an independent risk factor for coronary artery disease. Recent studies have shown that a common mutation (nucleotide 677 C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene may contribute to mild hyperhomocysteinemia and, therefore, to the incidence of coronary artery disease. No information exists, however, regarding the association between the mutation of the MTHFR gene or plasma homocysteine levels and morphological analysis of coronary atherosclerosis using intravascular ultrasound.

Methods and Results
—To examine the potential influence of MTHFR genotype and homocysteine on coronary arteries morphologically, we screened 62 patients with 65 lesions that were treated with 93 Palmaz-Schatz stents. The plasma homocysteine levels in the patients with the TT genotype were not significantly higher than those in the patients with non-TT (CC+CT) genotypes (13.1±5.5 versus 11.5±3.1 mmol/L,
P
=0.16). Angiographic analysis showed that the percent diameter stenosis in the patients with the TT genotype was significantly greater than that in those with non-TT genotypes (43.7±17.8% versus 29.0±22.0%,
P
=0.015). Intravascular ultrasound analysis showed that the TT genotype was significantly associated with greater intimal hyperplasia area (5.70±1.94 versus 3.72±1.38 mm
2
,
P
=0.001). In multiple stepwise regression analysis, the number of the T alleles was the only independent predictor of intimal hyperplasia after intervention (
r
2
=0.21,
P
=0.004).

Conclusions
—The homozygous mutant genotype of the MTHFR gene may increase the risk of in-stent restenosis more than does the normal homozygous or heterozygous genotype.
Long-Term Effects of Intracoronary β-Radiation in Balloon- and Stent-Injured Porcine Coronary Arteries
Authors: Kałuża Grzegorz L. , Raizner Albert E. , Mazur Wojciech , Schulz Daryl G. , Buergler John M. , Fajardo Luis F. , Tio Fermin O. , Ali Nadir M.
Published: June 2012

Background
—The data on the long-term safety and efficacy of intracoronary β-radiation in animal models are limited.

Methods and Results
—A total of 30 coronary arteries in 15 swine were subjected to balloon or stent injury followed by β-radiation from a centered
32
P source (2000 cGy to 1 mm beyond lumen surface) or a sham radiation procedure. The animals received aspirin for 6 months and ticlopidine for 30 days. Five of the 10 animals subjected to radiation died (at 5 days, 7 days, 3 months [n=2], and 4 months) as a result of layered, occlusive thrombus at the intervention site (3 stent and 2 balloon injury sites). No deaths occurred in the control group. In the surviving animals, balloon-injured and irradiated vessels showed a trend toward larger lumens than controls (2.15±0.17 versus 1.80±0.08 mm
2
,
P
=0.06) and larger external elastic lamina areas (3.32±0.21 versus 2.62±0.10 mm
2
,
P
=0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58±0.33, 3.16±0.35, and 8.12±0.42 mm
2
for irradiated vessel segments; these values were not different from those in controls (3.21±0.15, 2.84±0.27, and 7.76±0.28 mm
2
, respectively). Histologically, healing was complete in most survivors, although intramural fibrin and hemorrhage were occasionally seen.

Conclusion
—In the long-term (6 month) porcine model of restenosis, the inhibition by intracoronary β-radiotherapy of the neointimal formation that is known to be present at 1 month is not sustained. This lack of effect on neointimal formation after balloon and stent arterial injury is accompanied by subacute and late thrombosis that leads to cardiac death on a background of continuous aspirin but relatively brief ticlopidine treatment.
Implantation of Cardioverter Defibrillators Without Induction of Ventricular Fibrillation
Authors: Swerdlow Charles D.
Published: June 2012

Background
—The upper limit of vulnerability (ULV) is the weakest shock at which ventricular fibrillation (VF) is not induced by a T-wave shock. This study tested the hypothesis that a vulnerability safety margin based on the ULV can be used as an implantable cardioverter-defibrillator implantation criterion.

Methods and Results
—Implantable cardioverter-defibrillators were implanted in 80 patients if T-wave shocks did not induce VF and the baseline-rhythm R wave was ≥7 mV. The T-wave shock was 10 J in the first 45 patients (group A) and 15 J in the last 35 patients (group B). After inductionless implantations, the first VF shock was programmed to the T-wave shock plus 5 J. If T-wave shocks induced VF, the ULV was measured and the first shock was programmed to the ULV+5 J. Inductionless implantations were performed in 58 patients (72%), 28 in group A (62%) and 30 in group B (86%;
P
=0.04). If T-wave scanning had been done at 15 J in group A patients, inductionless implantations could have been performed in 84% of them. At 3 months, VF was induced twice during electrophysiological study in 75 patients (94%). All VFs were detected in ≤4.7 s and were terminated by the first shock. During follow-up, 197 of 198 appropriate first shocks for rapid ventricular tachycardia or VF (99%) were successful in patients who had inductionless implantations (95% confidence intervals, 97% to 100%).

Conclusion
—Inductionless implantations can be performed in >80% of implantable cardioverter-defibrillator recipients using a vulnerability safety margin based on a T-wave scan at 15 J.
Prolonged Antiplatelet Therapy to Prevent Late Thrombosis After Intracoronary γ-Radiation in Patients With In-Stent Restenosis
Authors: Waksman Ron , Ajani Andrew E. , White R. Larry , Pinnow Ellen , Dieble Regina , Bui Anh B. , Taaffe Maeve , Gruberg Luis , Mintz Gary S. , Satler Lowell F. , Pichard Augusto D. , Kent Kenneth K. , Lindsay Joseph
Published: June 2012

Background
—Intracoronary γ-radiation reduces recurrent in-stent restenosis. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. The Washington Radiation for In-Stent Restenosis Trial (WRIST) PLUS, which involved 6 months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis.

Methods and Results
—A total of 120 consecutive patients with diffuse in-stent restenosis in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive
192
Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 6 months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the γ-radiation–treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only 1 month of antiplatelet therapy). At 6 months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active γ-radiation group and similar to those in the placebo historical control group.

Conclusions
—Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with in-stent restenosis treated with γ-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only 1 month of clopidogrel and aspirin.
Echocardiographic and Electrocardiographic Diagnoses of Left Ventricular Hypertrophy Predict Mortality Independently of Each Other in a Population of Elderly Men
Authors: Sundström Johan , Lind Lars , Ärnlöv Johan , Zethelius Björn , Andrén Bertil , Lithell Hans O.
Published: June 2012

Background
—The increased risk associated with left ventricular hypertrophy (LVH) diagnosed echocardiographically (Echo-LVH) or electrocardiographically (ECG-LVH) is well known, but the clinically relevant question of how much additional prognostic information would be provided by echocardiographically assessing LVH if a subject’s ECG-LVH and hypertension status are known has not been addressed.

Methods and Results
—We investigated whether Echo-LVH and ECG-LVH predicted total and cardiovascular mortality and morbidity independently of each other and of other cardiovascular risk factors by using a population-based sample of 475 men investigated at age 70 with a median follow-up time of 5.2 years. Echocardiographic left ventricular mass index (LVMI) predicted total mortality (hazards ratio [HR] 1.44, 95% CI 1.09 to 1.92, for a 1-SD increase in LVMI) and cardiovascular mortality (HR 2.38, 95% CI 1.52 to 3.73) independently of ECG-LVH and other cardiovascular risk factors. ECG-LVH, defined as Cornell product >244 μV · s, predicted total mortality (HR 2.89, 95% CI 1.41 to 5.96) independently of LVMI and other cardiovascular risk factors. Thus, Echo-LVH and ECG-LVH provided complementary prognostic information, especially in hypertensive subjects.

Conclusions
—Echo-LVH and ECG-LVH predict mortality independently of each other and of other cardiovascular risk factors, implying that Echo-LVH and ECG-LVH in part carry different prognostic information. Therefore, to fully assess the increased risk associated with these conditions, both ECG and echocardiography should be performed.
Chemical Cardioversion of Atrial Fibrillation or Flutter With Ibutilide in Patients Receiving Amiodarone Therapy
Authors: Glatter Kathy , Yang Yanfei , Chatterjee Kanu , Modin Gunnard , Cheng Jie , Kayser Steve , Scheinman Melvin M.
Published: June 2012

Background
—Ibutilide is a class III drug that is used for the cardioversion of atrial arrhythmias, but it can cause torsade de pointes. Amiodarone also prolongs the QT interval but rarely causes torsade de pointes. There are no studies in which the concomitant use of the 2 agents was examined. The purpose of the present study was to assess the efficacy and safety of cardioversion with combination therapy in patients with atrial fibrillation or flutter.

Methods and Results
—The study included 70 patients who were treated with long-term oral amiodarone and were referred for elective cardioversion of atrial fibrillation (57 of 70, 81%) or flutter (13 of 70, 19%). Patients were taking amiodarone (153±259 days, mean±SD) and were administered 2 mg intravenous ibutilide. Left ventricular ejection fraction was measured with echocardiography. The QT intervals were measured on 12-lead ECG. Fifty-five patients (79%) had structural heart disease. Patients were in arrhythmia for 196±508 days before cardioversion, with a left ventricular ejection fraction of 50±11%. In patients with atrial fibrillation, 22 (39%) of 57 and 7 (54%) of 13 patients with flutter converted within 30 minutes of infusion. Thirty-nine patients who did not convert after ibutilide were treated with electrical cardioversion, and 35 (90%) of 39 patients were successfully converted. The QT intervals were further prolonged after ibutilide for the group from 371±61 to 479±92 ms (
P
<0.001). There was 1 episode of nonsustained torsade de pointes (1 of 70, 1.4%) after ibutilide.

Conclusions
—The use of ibutilide converted 54% of patients with atrial flutter and 39% of patients with atrial fibrillation who were treated with long-term amiodarone. Despite QT-interval prolongation after ibutilide, only 1 episode of torsade de pointes occurred. Our observations suggest that combination therapy may be a useful cardioversion method for chronic atrial fibrillation or flutter.
G20210A Prothrombin Gene Polymorphism and Prothrombin Activity in Subjects With or Without Angiographically Documented Coronary Artery Disease
Authors: Russo Carla , Girelli Domenico , Olivieri Oliviero , Guarini Patrizia , Manzato Franco , Pizzolo Francesca , Zaia Barbara , Mazzucco Alessandro , Corrocher Roberto
Published: June 2012

Background
—G20210A prothrombin mutation has been associated with high prothrombin levels and an increased risk of venous thrombosis. The role of this common polymorphism, as well as that of prothrombin levels, in determining the risk of arterial disease is still somewhat controversial.

Methods and Results
—We determined the prevalence of the G20210A mutation and prothrombin activity in 660 individuals, of whom 436 had angiographically documented severe coronary artery disease (CAD patients) and 224 had normal coronary angiography (CAD-free control subjects). Heterozygosity for the 20210A allele was found in 5.3% of the CAD patients versus 3.1% of the CAD-free subjects (
P
=0.21). Similarly, no statistically significant difference was found between CAD patients with or without previous myocardial infarction (4.5% versus 5.3%, respectively;
P
=0.73). The genotype-phenotype correlation study showed a significant influence of the 20210A allele on prothrombin activity, with higher levels in carriers compared with noncarriers (153.2% versus 122.2%, respectively;
P
<0.001). Prothrombin activity was significantly higher in CAD patients than in CAD-free subjects (132.8% versus 123.3%, respectively;
P
<0.005). By multiple logistic regression, prothrombin activity in the upper tertile of the control distribution was significantly associated with CAD compared with prothrombin activity in the lower tertile (adjusted odds ratio 1.86, 95% CI 1.01 to 3.4).

Conclusions
—In a population with a clear-cut definition of the phenotype, the G20210A prothrombin mutation was not significantly associated, per se, with either angiographically documented CAD or myocardial infarction, whereas it significantly influenced prothrombin activity. In our population, high prothrombin activity itself was independently associated with CAD but not with the presence or absence of previous myocardial infarction.
Comparison of 3 and 6 Months of Oral Anticoagulant Therapy After a First Episode of Proximal Deep Vein Thrombosis or Pulmonary Embolism and Comparison of 6 and 12 Weeks of Therapy After Isolated Calf Deep Vein Thrombosis
Authors: Pinede Laurent , Ninet Jacques , Duhaut Pierre , Chabaud Sylvie , Demolombe-Rague Sylvie , Durieu Isabelle , Nony Patrice , Sanson Christian , Boissel Jean-Pierre
Published: June 2012

Background
—The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism remains controversial.

Methods and Results
—We performed an open-label, randomized trial comparing a short oral anticoagulant course (3 months for proximal deep vein thrombosis [P-DVT] and/or pulmonary embolism [PE]; 6 weeks for isolated calf DVT [C-DVT]) with a long course of therapy (6 months for P-DVT/PE; 12 weeks for C-DVT). The outcome events were recurrences and major, minor, or fatal bleeding complications. A total of 736 patients were enrolled. There were 23 recurrences of venous thromboembolism in the short treatment group (6.4%) and 26 in the long treatment group (7.4%); the 2 treatment regimens had an equivalent effect. For the hemorrhage end point, the difference between the short and the long treatment groups was not significant: 15.5% versus 18.4% for all events (
P
=0.302), 1.7% versus 2.8% (
P
=0.291) for major events, and 13.9% versus 15.3% for minor bleeding. Subgroup analysis demonstrated that the rate of recurrence was lower for C-DVT than for P-DVT or PE.

Conclusions
—After isolated C-DVT, 6 weeks of oral anticoagulation is sufficient. For P-DVT or PE, we demonstrated an equivalence between 3 and 6 months of anticoagulant therapy. For patients with temporary risk factors who have a low risk of recurrence, 3 months of treatment seems to be sufficient. For patients with idiopathic venous thromboembolism or permanent risk factors who have a high risk of recurrence, other trials are necessary to assess prolonged therapy beyond 6 months.
Is Arrhythmia Detection by Automatic External Defibrillator Accurate for Children?
Authors: Cecchin Frank , Jorgenson Dawn B. , Berul Charles I. , Perry James C. , Zimmerman A. Andrew , Duncan Brian W. , Lupinetti Flavian M. , Snyder David , Lyster Thomas D. , Rosenthal Geoffrey L. , Cross Brett , Atkins Dianne L.
Published: June 2012

Background
—Use of automatic external defibrillators (AEDs) in children aged <8 years is not recommended. The purpose of this study was to develop an ECG database of shockable and nonshockable rhythms from a broad age range of pediatric patients and to test the accuracy of the Agilent Heartstream FR2 Patient Analysis System for sensitivity and specificity.

Methods and Results
—Children aged ≤12 years who either developed arrhythmias or were at risk for developing arrhythmias were studied. Two sources were used for the database: children whose rhythms were recorded prospectively via a modified AED and children who had arrhythmias captured on paper and digitized for subsequent analysis. The rhythms were divided into 5-second strips, classified by 3 reviewers, and then assessed by the AED analysis algorithm. A total of 696 five-second rhythm strips from 191 children (81 female and 110 male) aged 1 day to 12 years (median 3.0 years) were analyzed. There was 100% specificity for nonshockable rhythms. Sensitivity for ventricular fibrillation was 96%.

Conclusions
—There was excellent AED rhythm analysis sensitivity and specificity in all age groups for ventricular fibrillation and nonshockable rhythms. The high specificity and sensitivity indicate that there is a very low risk of an inappropriate shock and that the AED correctly identifies shockable rhythms, making the algorithm both safe and effective for children.
T Helper–Cell Phenotype Regulates Atherosclerosis in Mice Under Conditions of Mild Hypercholesterolemia
Authors: Huber S. A. , Sakkinen P. , David C. , Newell M. K. , Tracy R. P.
Published: June 2012

Background
—T cells are implicated in atherosclerosis, but little is known about the genetic control or molecular pathways, especially under conditions of mild hypercholesterolemia.

Methods and Results
—BALB/c mice, making a CD4+ Th2 (IL-4+) cell response, express both MHC class II antigens (IA
d
, IE
d
) and are atherosclerosis-resistant. C57Bl/6 mice produce a CD4+ Th1 (interferon [IFN]γ+) response, express IA
b
but no IE, and are atherosclerosis-prone. To evaluate T helper–cell phenotype in fatty streak formation, wild-type C57Bl/6 mice (IA
b
+IE−) and transgenic mice, either AB
o
, IA
b
−IE−; ABEα, IA−IE
k
+; or Bl.Tg.Eα, IA
b
+IE
k
+, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in AB
o
, ABEα, and Bl.Tg.Eα strains was decreased by 54%, 79%, and 82%, respectively, compared with wild-type, correlating with decreased Th1 and increased Th2 expression and suggesting that T helper–cell phenotype is important in fatty lesion development. Decreasing Th1 cells by antibodies (α-CD4) or cytokines (IL-4) also caused ≥80% reductions in lesion size. Immunohistology revealed IFN-γ, but not IL-4, colocalized with activated macrophages. Confirming these findings in a different mouse strain, BALB/c Stat 6 knockout mice (Th2 cell–deficient) developed aortic lesions comparable to C57Bl/6 mice on the same diet.

Conclusions
—In mildly hypercholesterolemic C57Bl/6 mice, presence of IA
b
and absence of IE regulated CD4+ T helper–cell phenotype; fatty lesions were proportional to IFNγ+ Th1 cells in both C57Bl/6 and BALB/c strains. IFN-γ may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.
Low Dietary Folate Intake Is Associated With an Excess Incidence of Acute Coronary Events
Authors: Voutilainen Sari , Rissanen Tiina H. , Virtanen Jyrki , Lakka Timo A. , Salonen Jukka T.
Published: June 2012

Background
—Although several prospective studies have shown that low folate intake and low circulating folate are associated with increased risk of coronary heart disease (CHD), the findings are inconsistent.

Methods and Results
—We studied the associations of dietary intake of folate, vitamin B
6
, and vitamin B
12
with the risk of acute coronary events in a prospective cohort study of 1980 Finnish men 42 to 60 years old examined in 1984 to 1989 in the Kuopio Ischemic Heart Disease Risk Factor Study. Nutrient intakes were assessed by 4-day food record. During an average follow-up time of 10 years, 199 acute coronary events occurred. In a Cox proportional hazards model adjusted for 21 conventional and nutritional CHD risk factors, men in the highest fifth of folate intake had a relative risk of acute coronary events of 0.45 (95% CI 0.25 to 0.81,
P
=0.008) compared with men in the lowest fifth. This association was stronger in nonsmokers and light alcohol users than in smokers and alcohol users. A high dietary intake of vitamin B
6
had no significant association and that of vitamin B
12
a weak association with a reduced risk of acute coronary events.

Conclusions
—The present work in CHD-free middle-aged men is the first prospective cohort study to observe a significant inverse association between quantitatively assessed moderate-to-high folate intakes and incidence of acute coronary events in men. Our findings provide further support in favor of a role of folate in the promotion of good cardiovascular health.
Immunohistological Changes in Dilated Cardiomyopathy Induced by Immunoadsorption Therapy and Subsequent Immunoglobulin Substitution
Authors: Staudt Alexander , Schäper Frank , Stangl Verena , Plagemann Andreas , Böhm Marco , Merkel Kurt , Wallukat Gerd , Wernecke Klaus D. , Stangl Karl , Baumann Gert , Felix Stephan B.
Published: June 2012

Background
—Immunoadsorption (IA) and subsequent immunoglobulin (Ig) G substitution represent an additional therapeutic approach in dilated cardiomyopathy (DCM). It remains to be elucidated whether this treatment modulates myocardial inflammation, which is possibly a causal factor of ventricular dysfunction.

Methods and Results
—From 25 DCM patients (EF <30%), 12 patients were randomized for IA therapy and subsequent IgG substitution at 1-month intervals until month 3. Before (<7 days) and after IA therapy, right ventricular biopsies were obtained from all patients. Biopsies were also obtained at intervals of 3 months from 13 patients without IA/IgG treatment (controls). IA/IgG treatment induced improvement in left ventricular ejection fraction from 21.3±1.7% (±SEM) to 27.0±1.3% (
P
<0.01 versus baseline/controls) and reduction of the β-receptor autoantibody serum levels (
P
<0.01 versus baseline/controls). The number of CD3 cells decreased from 5.7±0.8 to 2.9±0.5 cells/mm
2
(
P
<0.01 versus baseline/controls). This decline was paralleled by a decrease in CD4 (
P
<0.01 versus baseline/controls) and CD8 (
P
<0.05 versus baseline/controls) lymphocytes. The number of leukocyte common antigen–positive cells (leukocytes) was reduced from 20.0±3.2 to 9.9±2.8 cells/mm
2
(
P
<0.01 versus baseline/
P
<0.05 versus controls). HLA class II expression decreased from 2.1±0.7% to 1.1±0.4% (
P
<0.05 versus controls/baseline). The number of immunopositive cells and the expression of HLA class II in controls remained stable. In both groups, the degree of fibrosis remained unchanged.

Conclusions
—IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.