bluuebunny/crossref_metadata_2025 huggingface dataset:
Ischemic Mitral Regurgitation
Authors: Grigioni Francesco , Enriquez-Sarano Maurice , Zehr Kenton J. , Bailey Kent R. , Tajik A. Jamil
Published: June 2012

Background
—Myocardial infarction (MI) can directly cause ischemic mitral regurgitation (IMR), which has been touted as an indicator of poor prognosis in acute and early phases after MI. However, in the chronic post-MI phase, prognostic implications of IMR presence and degree are poorly defined.

Methods and Results
—We analyzed 303 patients with previous (>16 days) Q-wave MI by ECG who underwent transthoracic echocardiography: 194 with IMR quantitatively assessed in routine practice and 109 without IMR matched for baseline age (71±11 versus 70±9 years,
P
=0.20), sex, and ejection fraction (EF, 33±14% versus 34±11%,
P
=0.14). In IMR patients, regurgitant volume (RVol) and effective regurgitant orifice (ERO) area were 36±24 mL/beat and 21±12 mm
2
, respectively. After 5 years, total mortality and cardiac mortality for patients with IMR (62±5% and 50±6%, respectively) were higher than for those without IMR (39±6% and 30±5%, respectively) (both
P
<0.001). In multivariate analysis, independently of all baseline characteristics, particularly age and EF, the adjusted relative risks of total and cardiac mortality associated with the presence of IMR (1.88,
P
=0.003 and 1.83,
P
=0.014, respectively) and quantified degree of IMR defined by RVol ≥30 mL (2.05,
P
=0.002 and 2.01,
P
=0.009) and by ERO ≥20 mm
2
(2.23,
P
=0.003 and 2.38,
P
=0.004) were high.

Conclusions
—In the chronic phase after MI, IMR presence is associated with excess mortality independently of baseline characteristics and degree of ventricular dysfunction. The mortality risk is related directly to the degree of IMR as defined by ERO and RVol. Therefore, IMR detection and quantification provide major information for risk stratification and clinical decision making in the chronic post-MI phase.
Combined and Individual Mitochondrial HSP60 and HSP10 Expression in Cardiac Myocytes Protects Mitochondrial Function and Prevents Apoptotic Cell Deaths Induced by Simulated Ischemia-Reoxygenation
Authors: Lin Kurt M. , Lin Brian , Lian Ian Y. , Mestril Ruben , Scheffler Immo E. , Dillmann Wolfgang H.
Published: June 2012

Background
—The mitochondrial heat-shock proteins HSP60 and HSP10 form a mitochondrial chaperonin complex, and previous studies have shown that their increased expression exerts a protective effect against ischemic injury when cardiac myocytes are submitted to simulated ischemia. The more detailed mechanisms by which such a protective effect occurs are currently unclear. We wanted to determine whether HSP60 and HSP10 could exert a protection against simulated ischemia and reoxygenation (SI/RO)–induced apoptotic cell death and whether such protection results from decreased mitochondrial cytochrome
c
release and caspase-3 activation and from the preservation of ATP levels by preservation of the electron transport chain complexes. In addition, we explored whether increased expression of HSP60 or HSP10 by itself exerts a protective effect.

Methods and Results
—We overexpressed HSP60 and HSP10 together or separately in rat neonatal cardiac myocytes using an adenoviral vector and then subjected the myocytes to SI/RO. Cell death and apoptosis in myocytes were quantified by parameters such as enzyme release, DNA fragmentation, and caspase-3 activation. Overexpression of the combination of HSP60 and HSP10 and of HSP60 or HSP10 individually protected myocytes against apoptosis. This protection is accompanied by decreases in mitochondrial cytochrome
c
release and in caspase-3 activity and increases in ATP recovery and activities of complex III and IV in mitochondria after SI/RO.

Conclusions
—These results suggest that mitochondrial chaperonins HSP60 and HSP10 in combination or individually play an important role in maintaining mitochondrial integrity and capacity for ATP generation, which are the crucial factors in determining survival of cardiac myocytes undergoing ischemia/reperfusion injury.
In Utero Remodeling of the Fetal Lamb Ductus Arteriosus
Authors: Clyman Ronald I. , Chen Yao Qi , Chemtob Sylvain , Mauray Françoise , Kohl Thomas , Varma Daya R. , Roman Christine
Published: June 2012

Background
—The ductus arteriosus (DA) of newborn infants exposed in utero to indomethacin is resistant to postnatal indomethacin; we hypothesized that this is due to ductus constriction in utero, with subsequent remodeling of the vessel.

Methods and Results
—Infusion of fetal lambs with indomethacin for 48 hours constricted the DA and increased the thickness of the avascular zone of the DA, which in turn induced the expression of vascular endothelial growth factor, endothelial nitric oxide synthase (due to ingrowth of vasa vasorum), neointima formation, and loss of smooth muscle cells; moderate degrees of DA constriction in utero increased NO production, which inhibited DA contractility. Marked degrees of DA constriction decreased tissue distensibility and contractile capacity.

Conclusions
—DA patency is no longer controlled primarily by prostaglandins once it has been exposed to indomethacin in utero.
Stent Thrombosis in the Modern Era
Authors: Cutlip Donald E. , Baim Donald S. , Ho Kalon K. L. , Popma Jeffrey J. , Lansky Alexandra J. , Cohen David J. , Carrozza Joseph P. , Chauhan Manish S. , Rodriguez Orlando , Kuntz Richard E.
Published: June 2012

Background
—There are limited studies of stent thrombosis in the modern era of second-generation stents, high-pressure deployment, and current antithrombotic regimens.

Methods and Results
—Six recently completed coronary stent trials and associated nonrandomized registries that enrolled 6186 patients (6219 treated vessels) treated with ≥1 coronary stent followed by antiplatelet therapy with aspirin and ticlopidine were pooled for this analysis. Within 30 days, clinical stent thrombosis developed in 53 patients (0.9%). The variables most significantly associated with the probability of stent thrombosis were persistent dissection NHLBI grade B or higher after stenting (OR, 3.7; 95% CI, 1.9 to 7.7), total stent length (OR, 1.3; 95% CI, 1.2 to 1.5 per 10 mm), and final minimal lumen diameter within the stent (OR, 0.4; 95% CI, 0.2 to 0.7 per 1 mm). Stent thrombosis was documented by angiography in 45 patients (0.7%). Clinical consequences of angiographic stent thrombosis included 64.4% incidence of death or myocardial infarction at the time of stent thrombosis and 8.9% 6-month mortality.

Conclusions
—Stent thrombosis occurred in <1.0% of patients undergoing stenting of native coronary artery lesions and receiving routine antiplatelet therapy with aspirin plus ticlopidine. Procedure-related variables of persistent dissection, total stent length, and final lumen diameter were significantly associated with the probability of stent thrombosis. Continued efforts to eliminate this complication are warranted given the serious clinical consequences.
Flow-Induced Dilation of Human Coronary Arterioles
Authors: Miura Hiroto , Wachtel Ruth E. , Liu Yanping , Loberiza Fausto R. , Saito Takashi , Miura Mamoru , Gutterman David D.
Published: June 2012

Background
—Flow-induced vasodilation (FID) is a physiological mechanism for regulating coronary flow and is mediated largely by nitric oxide (NO) in animals. Because hyperpolarizing mechanisms may play a greater role than NO in the microcirculation, we hypothesized that hyperpolarization contributes importantly to FID of human coronary arterioles.

Methods and Results
—Arterioles from atria or ventricles were cannulated for videomicroscopy. Membrane potential of vascular smooth muscle cells (VSMCs) was measured simultaneously. After constriction with endothelin-1, increases in flow induced an endothelium-dependent vasodilation.
Nω
-Nitro-
l
-arginine methyl ester 10
−
4
mol/L modestly impaired FID of arterioles from patients without coronary artery disease (CAD), whereas no inhibition was seen in arterioles from patients with CAD. Indomethacin 10
−
5
mol/L was without effect, but 40 mmol/L KCl attenuated maximal FID. Tetraethylammonium 10
−
3
mol/L but not glibenclamide 10
−
6
mol/L reduced FID. Charybdotoxin 10
−
8
mol/L impaired both FID (15±3% versus 75±12%,
P
<0.05) and hyperpolarization (−32±2 mV [from −28±2 mV after endothelin-1] versus −42±2 mV [−27±2 mV],
P
<0.05). Miconazole 10
−
6
mol/L or 17-octadecynoic acid 10
−
5
mol/L reduced FID. By multivariate analysis, age was an independent predictor for the reduced FID.

Conclusions
—We conclude that shear stress induces endothelium-dependent vasodilation, hyperpolarizing VSMCs through opening Ca
2+
-activated K
+
channels in human coronary arterioles. In subjects without CAD, NO contributes to FID. NO and prostaglandins play no role in patients with CAD; rather, cytochrome P450 metabolites are involved. This is consistent with a role for endothelium-derived hyperpolarizing factor in FID of the human coronary microcirculation.
Electroanatomic Mapping of Entrained and Exit Zones in Patients With Repaired Congenital Heart Disease and Intra-Atrial Reentrant Tachycardia
Authors: Triedman John K. , Alexander Mark E. , Berul Charles I. , Bevilacqua Laura M. , Walsh Edward P.
Published: June 2012

Background
—Characterization of reentrant circuits and targeting ablation sites remains difficult for intra-atrial reentrant tachycardias (IART) in congenital heart disease (CHD).

Methods and Results
—Electroanatomic mapping and entrainment pacing were performed before successful ablation of 18 IART circuits in 15 patients with CHD. Principal features of IART circuits were atrial septal defect (4 patients), atriotomy (3 patients), other atrial scar (3 patients), crista terminalis (3 patients), and right atrioventricular valve (5 patients). A median of 176 sites (range, 96 to 317 sites) was mapped for activation and 13 sites (range, 9 to 28 sites) for entrainment response. Postpacing intervals within 20 ms of tachycardia cycle length and stimulus–to–P-wave intervals of 0 to 90 ms (exit zones) were mapped to atrial surfaces generated by electroanatomic mapping. Criteria for entrainment were met over a median of 21 cm
2
of atrial surface (range, 2 to 75 cm
2
), 19% (range, 1% to 81%) of total area tested. Using integrated data, relations between activation sequence and protected corridor of conduction could be inferred for 16 of 17 IARTs. Successful ablation was achieved at a site distant from the putative protected corridor in 9 of 18 (50%) circuits.

Conclusions
—The right atrium in CHD supports a variety of IART mechanisms. Fusion of activation and entrainment data provided insight into specific IART mechanisms relevant to ablation.
Baroreflex Sensitivity and Heart Rate Variability in the Identification of Patients at Risk for Life-Threatening Arrhythmias
Authors: La Rovere Maria Teresa , Pinna Gian Domenico , Hohnloser Stefan H. , Marcus Frank I. , Mortara Andrea , Nohara Ryuji , Bigger J. Thomas , Camm A. John , Schwartz Peter J.
Published: June 2012

Background
—The need for accurate risk stratification is heightened by the expanding indications for the implantable cardioverter defibrillator. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) focused interest on patients with both depressed left ventricular ejection fraction (LVEF) and the presence of nonsustained ventricular tachycardia (NSVT). Meanwhile, the prospective study Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) demonstrated that markers of reduced vagal activity, such as depressed baroreflex sensitivity (BRS) and heart rate variability (HRV), are strong predictors of cardiac mortality after myocardial infarction.

Methods and Results
—We analyzed 1071 ATRAMI patients after myocardial infarction who had data on LVEF, 24-hour ECG recording, and BRS. During follow-up (21±8 months), 43 patients experienced cardiac death, 5 patients had episodes of sustained VT, and 30 patients experienced sudden death and/or sustained VT. NSVT, depressed BRS, or HRV were all significantly and independently associated with increased mortality. The combination of all 3 risk factors increased the risk of death by 22×. Among patients with LVEF<35%, despite the absence of NSVT, depressed BRS predicted higher mortality (18% versus 4.6%,
P
=0.01). This is a clinically important finding because this group constitutes 25% of all patients with depressed LVEF. For both cardiac and arrhythmic mortality, the sensitivity of low BRS was higher than that of NSVT and HRV.

Conclusions
—BRS and HRV contribute importantly and additionally to risk stratification. Particularly when LVEF is depressed, the analysis of BRS identifies a large number of patients at high risk for cardiac and arrhythmic mortality who might benefit from implantable cardioverter defibrillator therapy without disproportionately increasing the number of false-positives.
Peripheral Arterial Responses to Treadmill Exercise Among Healthy Subjects and Atherosclerotic Patients
Authors: Rozanski Alan , Qureshi Ehtasham , Bauman Mara , Reed George , Pillar Giora , Diamond George A.
Published: June 2012

Background
—Peripheral cutaneous vascular beds, such as the fingertips, contain a high concentration of arteriovenous anastomoses, richly innervated by α-adrenergic nerve fibers, to control heat regulation. Nevertheless, for a variety of technical reasons, finger blood flow responses to exercise have not been well studied in health and disease. Hence, we compared finger pulse-wave amplitude (PWA) responses to exercise among 50 normal volunteers and 57 patients with atherosclerotic coronary artery disease (CAD) using a robust, modified form of volume plethysmography.

Methods and Results
—PWA was quantified for each minute of exercise as a ratio relative to baseline. Exercise PWA responses were compared with clinical, hemodynamic, ECG, and myocardial single photon emission computed tomography parameters. Among normal subjects, 38 (76%) manifested vasodilation throughout exercise and 12 (24%) manifested initial vasodilation followed by vasoconstriction at high heart rate thresholds. None manifested vasoconstriction throughout exercise. By contrast, 20 CAD patients (35%) manifested progressive vasoconstriction from the onset of exercise, and 10 others (18%) manifested vasoconstriction at low heart rate thresholds (
P
<0.001 versus normals) after initial vasodilation with exercise. Patients exhibiting vasodilation versus vasoconstriction during exercise had similar clinical and exercise profiles, except for a greater use of ACE inhibitors and a greater level of achieved metabolic equivalents among the former (
P
<0.05 for both).

Conclusions
—Half of our CAD patients manifested diminution in PWA that was consistent with peripheral arterial vasoconstriction during the early phases of treadmill exercise. Such paradoxical vasoconstrictive responses were not observed in normal subjects and, therefore, they may represent generalized vascular pathology secondary to atherosclerosis.
New Anti–Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Atherosclerosis in Apolipoprotein E–Knockout Mice
Authors: Ni Weihua , Egashira Kensuke , Kitamoto Shiro , Kataoka Chu , Koyanagi Masamichi , Inoue Shujiro , Imaizumi Katsumi , Akiyama Chiyuki , Nishida Ken-ichi , Takeshita Akira
Published: June 2012

Background
—Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy.

Methods and Results
—We devised a new strategy for anti–MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E–knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content.

Conclusions
—We conclude that this anti–MCP-1 gene therapy may serve not only to reduce atherogenesis but also to stabilize vulnerable atheromatous plaques. This strategy may be a useful and feasible form of gene therapy against atherosclerosis in humans.
Balloon Dilation Angioplasty of Peripheral Pulmonary Stenosis Associated With Williams Syndrome
Authors: Geggel Robert L. , Gauvreau Kimberlee , Lock James E.
Published: June 2012

Background
—Experience of balloon dilation of peripheral pulmonary stenosis (PPS) in Williams syndrome (WS) is limited.

Methods and Results
—Catheterizations in all patients with WS undergoing therapy for PPS from 1984 to 1999 were reviewed. Criteria for successful dilation included an increase >50% in predilation diameter and a decrease >20% in ratio of right ventricular (RV) to aortic (Ao) systolic pressure. Median age and weight were 1.5 years and 9.5 kg. There were 134 dilations during 39 procedures in 25 patients. The success rate for initial dilations was 51%. In multivariate analysis, successful dilation was more likely (1) in distal than in central pulmonary arteries (
P
=0.02), (2) if the balloon waist resolved with inflation (
P
=0.001), and (3) with larger balloon/stenosis ratio (
P
<0.001). RV pressure was unchanged after dilation (96±30 versus 97±31 mm Hg), primarily because of failure to enlarge central pulmonary arteries. The Ao pressure increased (102±14 versus 109±19 mm Hg,
P
=0.03), and the RV/Ao pressure ratio decreased (0.97±0.34 versus 0.91±0.30,
P
=0.05). Aneurysms developed after 24 dilations (18%) and were not related to balloon/stenosis ratio. Balloon rupture in 12 dilations produced an aneurysm in all 7 cases when rupture was in a hypoplastic segment. Three patients died, none from pulmonary artery trauma, and all before 1994.

Conclusions
—Mortality occurred early in our experience. Despite successful dilation of distal pulmonary arteries, there was modest initial hemodynamic improvement, mainly because of persistent central pulmonary artery obstruction. A serial approach of distal dilations followed by surgical repair of proximal obstruction may be a rational and successful therapy.
Increased Myocardial GRP94 Amounts During Sustained Atrial Fibrillation
Authors: Vitadello Maurizio , Ausma Jannie , Borgers Marcel , Gambino Antonio , Casarotto Dino C. , Gorza Luisa
Published: June 2012

Background
—Structural and phenotypic changes of cardiomyocytes characterize atrial fibrillation. We investigated whether changes in the glucose-regulated protein GRP94, which is essential for cell viability, occur in the presence of chronic atrial fibrillation.

Methods and Results
—Samples of fibrillating atrial myocardium obtained from both goat and human hearts were analyzed for GRP94 expression by an immunologic approach. In goats, atrial fibrillation was induced and maintained for 2, 4, 8, and 16 weeks. After 16 weeks of atrial fibrillation, cardioversion was applied and followed by 8 weeks of sinus rhythm. GRP94 levels doubled in goat atrial myocytes after 4 to 16 weeks of fibrillation with respect to normal atria and returned to control levels in atrial myocardium of cardioverted goats. Immunohistochemical analyses confirm that GRP94 increase occurred within cardiomyocytes. Significantly, increased levels of GRP94 were also observed in samples from human fibrillating atria. In the absence of signs of myocyte irreversible damage, the GRP94 increase in fibrillating atria is comparable to GRP94 levels observed in perinatal goat myocardium. However, calreticulin, another endoplasmic reticulum protein highly expressed in perinatal hearts, does not increase in fibrillating atria, whereas inducible HSP70, a cytoplasm stress protein that is expressed in perinatal goat hearts at levels comparable to those observed in the adult heart, shows a significant increase in chronic fibrillating atria.

Conclusions
—Our data demonstrate a large, reversible increase in GRP94 in fibrillating atrial myocytes, which may be related to the appearance of a protective phenotype.
Simvastatin Depresses Blood Clotting by Inhibiting Activation of Prothrombin, Factor V, and Factor XIII and by Enhancing Factor Va Inactivation
Authors: Undas Anetta , Brummel Kathleen E. , Musial Jacek , Mann Kenneth G. , Szczeklik Andrew
Published: June 2012

Background
—The mechanism of the antithrombotic action of statins is unclear. The aim of this study was to evaluate the effects of simvastatin on the coagulation process at sites of microvascular injury.

Methods and Results
—Tissue factor–initiated coagulation was assessed in blood samples collected every 30 seconds from bleeding-time wounds of 17 patients who had advanced coronary artery disease and total cholesterol levels of 224.6±11.8 mg/dL (mean±SEM). Quantitative Western blotting for time courses of fibrinogen depletion and activation of prothrombin, factor V, and factor XIII was performed before and after 3 months of simvastatin treatment (20 mg/d). Simvastatin induced reductions in total cholesterol (23%) and LDL-cholesterol (36%), which were accompanied by significant decreases in the rates of prothrombin activation (16.2±2.1%;
P
=0.004), formation of α-thrombin B-chain (27.4±1.8%;
P
=0.001), generation of factor Va heavy chain (29.7±3.1%;
P
=0.007) and factor Va light chain (18.9±1.2%;
P
=0.02), factor XIII activation (19.8±1.3%;
P
=0.001), and fibrinogen conversion to fibrin (72.2±3%;
P
=0.002). Posttreatment fibrinopeptides A and B concentrations, determined by using high-performance liquid chromatography, were reduced within the last 30 seconds of bleeding. The 30-kDa fragment of the factor Va heavy chain (residues 307 to 506), produced by activated protein C, and the 97-kDa fragment of the factor Va heavy chain (residues 1 to 643) were released more rapidly after simvastatin treatment. The antithrombotic actions of simvastatin showed no relationship to its cholesterol-lowering action.

Conclusions
—Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.
Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease
Authors: Ferreiro Carlos Regenga , Chagas Antonio Carlos Palandri , Carvalho Maria Helena Catelli , Dantas Ana Paula , Jatene Marcelo Biscegli , Bento de Souza Luiz Carlos , Lemos da Luz Protásio
Published: June 2012

Background
—Chronic hypoxia has been shown to modulate nitric oxide (NO) responses in different cell models, but the relationship between hypoxia and NO synthase (NOS) regulation in humans was not studied. We studied the relationship between endothelial and inducible NOS (eNOS and iNOS) activities and expression and chronic hypoxia in children with cyanotic and acyanotic congenital heart defects.

Methods and Results
—Right atrial tissue was excised from 18 patients during cardiac surgery. eNOS and iNOS activities were measured by conversion of
l
-[H
3
]arginine to
l
-[H
3
]citrulline. Gene expression of eNOS and iNOS was quantified by competitive reverse transcription–polymerase chain reaction. The eNOS activity and expression were significantly reduced in cyanotic hearts compared with acyanotic hearts: 0.38±0.14 versus 1.06±0.11 pmol · mg
−1
· min
−1
(
P
<0.0001) and 0.54±0.08 versus 0.80±0.10 relative optical density (ROD) of cDNA (
P
<0.0001), respectively. In contrast, iNOS activity and expression were significantly higher in cyanotic than in acyanotic children: 7.04±1.20 versus 4.17±1.10 pmol · mg
−1
· min
−1
(
P
<0.0001) and 2.55±0.11 versus 1.91±0.18 ROD of cDNA (
P
<0.0001), respectively.

Conclusions
—Hypoxia downregulates eNOS activity and gene expression in cardiac tissue from patients with cyanotic congenital heart defects. By contrast, iNOS activity and expression are increased in cyanotic children and may represent an alternative mechanism to counteract the effects of hypoxia in the cardiovascular system. Therefore, a novel adaptive mechanism during hypoxia is suggested.
Ischemia-Reperfusion of Rat Myocardium Activates Nuclear Factor-κB and Induces Neutrophil Infiltration Via Lipopolysaccharide-Induced CXC Chemokine
Authors: Chandrasekar Bysani , Smith Jeffrey B. , Freeman Gregory L.
Published: June 2012

Background
—Mechanisms by which neutrophils are attracted to the myocardium in ischemia/reperfusion are not fully defined. Lipopolysaccharide-induced CXC chemokine (LIX), cytokine-induced neutrophil chemoattractant (KC), and macrophage inflammatory protein-2 (MIP-2) are rodent chemokines with potent neutrophil-chemotactic activity. The goals of the present study were to evaluate the roles of these chemokines in a rat model of ischemia/reperfusion and to examine the mechanisms of chemokine induction by oxidative stress and cytokines in cultured cardiomyocytes.

Methods and Results
—Male Wistar-Kyoto rats underwent 45 minutes of ligation of the left anterior descending coronary artery, followed by reperfusion for various periods. Compared with sham-operated controls, myocardium from reperfused animals had higher levels of free radicals, increased neutrophil infiltration evidenced histologically and by elevated myeloperoxidase activity, and increased nuclear factor (NF)-κB DNA binding activity. Ischemia-reperfusion also induced the expression of interleukin-1β, tumor necrosis factor (TNF)-α, LIX, KC, and MIP-2 mRNA and protein. LIX expression was localized to resident myocardial cells, whereas KC and MIP-2 were expressed only in infiltrating inflammatory cells. Neutralization of LIX inhibited 79% of neutrophil infiltration into previously ischemic myocardium. In contrast, neutralization of KC and MIP-2 reduced neutrophil infiltration by only 28% and 37%, respectively. In cultured cardiomyocytes, LIX expression was induced by oxidative stress or TNF-α and was blocked by the NF-κB inhibitor pyrrolidinedithiocarbamate.

Conclusions
—LIX is expressed by resident myocardial cells during ischemia-reperfusion and is induced in cultured cardiomyocytes by oxidative stress or TNF-α via NF-κB activation. Although KC and MIP-2 are expressed by inflammatory cells infiltrating the myocardium during reperfusion after ischemia, neutrophil recruitment to reperfused rat myocardium is mainly due to cardiomyocyte expression of LIX.
New-Onset Atrial Fibrillation
Authors: Humphries Karin H. , Kerr Charles R. , Connolly Stuart J. , Klein George , Boone John A. , Green Martin , Sheldon Robert , Talajic Mario , Dorian Paul , Newman David
Published: June 2012

Background
—Although sex differences in coronary artery disease have received considerable attention, few studies have dealt with sex differences in the most common sustained cardiac arrhythmia, atrial fibrillation (AF). Differences in presentation and clinical course may dictate different approaches to detection and management. We sought to examine sex-related differences in presentation, treatment, and outcome in patients presenting with new-onset AF.

Methods and Results
—The Canadian Registry of Atrial Fibrillation (CARAF) enrolled subjects at the time of first ECG-confirmed diagnosis of AF. Participants were followed at 3 months, at 1 year, and annually thereafter. Treatment was at the discretion of the patients’ physicians and was not directed by CARAF investigators. Baseline and follow-up data collection included a detailed medical history, clinical, ECG, and echocardiographic measures, medication history, and therapeutic interventions. Three hundred thirty-nine women and 560 men were followed for 4.14±1.39 years. Compared with men, women were older at the time of presentation, more likely to seek medical advice because of symptoms, and experienced significantly higher heart rates during AF. Compared with older men, older women were half as likely to receive warfarin and twice as likely to receive acetylsalicylic acid. Compared with men on warfarin, women on warfarin were 3.35 times more likely to experience a major bleed.

Conclusions
—Anticoagulants are underused in older women with AF relative to older men with AF, despite comparable risk profiles. Women receiving warfarin have a significantly higher risk of major bleeding, suggesting the need for careful monitoring of anticoagulant intensity in women.
Novel Molecular Mechanism of Increased Myocardial Endothelin-1 Expression in the Failing Heart Involving the Transcriptional Factor Hypoxia-Inducible Factor-1α Induced for Impaired Myocardial Energy Metabolism
Authors: Kakinuma Yoshihiko , Miyauchi Takashi , Yuki Koichi , Murakoshi Nobuyuki , Goto Katsutoshi , Yamaguchi Iwao
Published: June 2012

Background
—Hypoxia-inducible factor (HIF)-1α is an important transcriptional factor that activates the gene expression of glycolytic enzymes, which are activated as compensation for impaired β-oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expression is markedly increased in heart failure. The mechanism, however, is unknown. Because we found an HIF-1α binding site in the 5′-promoter region of the ET-1 gene, we hypothesized that HIF-1α is involved in this mechanism.

Methods and Results
—In rat cardiomyocytes, luciferase assay and electrophoretic mobility shift assay showed that HIF-1α transcriptionally activates ET-1 gene expression by direct interaction with the predicted DNA binding site in the 5′-promoter region. HIF-1α mRNA and ET-1 mRNA in the failing heart increased during the aggravation of heart failure in vivo in animal models, ie, rats with myocardial infarction and hamsters with cardiomyopathy. In cultured cardiomyocytes treated with a mitochondrial inhibitor, HIF-1α mRNA and ET-1 mRNA were markedly increased with activated glycolysis, and antisense oligonucleotide for HIF-1α largely inhibited the increased gene expression of ET-1.

Conclusions
—The present study revealed a novel molecular mechanism of upregulation of myocardial ET-1 in heart failure, indicating that induction of HIF-1α to stimulate glycolysis as an adaptation in heart failure against impaired energy metabolism alternatively causes an elevation of cardiac ET-1 gene expression as a maladaptation.
Increased Mortality With Oral Platelet Glycoprotein IIb/IIIa Antagonists
Authors: Chew Derek P. , Bhatt Deepak L. , Sapp Shelly , Topol Eric J.
Published: June 2012

Background
—Numerous clinical trials have established the benefits of intravenous glycoprotein IIb/IIIa inhibition in the management of coronary artery disease. In contrast, the recent large-scale, placebo-controlled, randomized trials of the oral glycoprotein IIb/IIIa antagonists have failed to provide commensurate reductions in late composite ischemic end points despite potent inhibition of platelet aggregation.

Methods and Results
—The ORs for death, myocardial infarction, urgent revascularization, and major bleeding from the 4 large-scale, placebo-controlled, randomized trials with oral glycoprotein IIb/IIIa inhibitors were calculated and combined. Stratification by low-dose or high-dose therapy and the use of concurrent aspirin was also undertaken. In 33 326 patients followed for >30 days, a consistent and statistically significant increase in mortality was observed with oral glycoprotein IIb/IIIa therapy (OR, 1.37; 95% CI, 1.13 to 1.66;
P
=0.001). This effect was evident regardless of aspirin coadministration and treatment with either low-dose or high-dose therapy. Although a reduction in urgent revascularization was observed with oral glycoprotein IIb/IIIa inhibition, pooled analysis favored an increase in myocardial infarction that did not demonstrate statistical significance.

Conclusions
—Although we found a highly significant excess in mortality consistent across 4 trials with 3 different oral glycoprotein IIb/IIIa inhibitor agents, this was associated with a reduction in the need for urgent revascularization and no increase in myocardial infarction. These findings suggest the potential for a direct toxic effect with these agents and argue against a prothrombotic mechanism. Further investigation to elucidate the cause of this increased fatality risk is warranted.
PPARα Agonists Inhibit Tissue Factor Expression in Human Monocytes and Macrophages
Authors: Neve Bernadette P. , Corseaux Delphine , Chinetti Giulia , Zawadzki Christophe , Fruchart Jean-Charles , Duriez Patrick , Staels Bart , Jude Brigitte
Published: June 2012

Background
—Monocytic tissue factor (TF) expression may contribute to thrombogenicity associated with plaque rupture and may propagate thrombus formation at the site of vascular lesions. Induction of monocytic TF expression by endotoxin is mediated by the activation of transcription factors such as AP-1 and NF-κB. Both these signaling pathways are modulated by peroxisome proliferator–activated receptor-α (PPARα). Therefore, we have studied the effects of fibrates and other PPARα agonists on the expression of TF.

Methods and Results
—We show that PPARα protein, like primary human monocytes, is also expressed in the human monocytic THP-1 cell line. Fenofibric acid, WY14643, and GW2331 inhibited TF mRNA upregulation after stimulation of THP-1 cells with lipopolysaccharide or interleukin-1β. In primary human monocytes and macrophages, the lipopolysaccharide- or interleukin-1β–mediated induction of TF activity was also inhibited by fenofibric acid, WY14643, or GW2331.

Conclusions
—These data indicate that activation of PPARα results in the downregulation of the TF gene. Our results suggest a novel role for PPARα in the control of atherosclerotic plaque thrombogenicity through its effects on TF expression in monocytes and macrophages.
Immunomodulating Therapy With Intravenous Immunoglobulin in Patients With Chronic Heart Failure
Authors: Gullestad Lars , Aass Halfdan , Fjeld Jan G. , Wikeby Lisbeth , Andreassen Arne K. , Ihlen Halfdan , Simonsen Svein , Kjekshus John , Nitter-Hauge Sigurd , Ueland Thor , Lien Egil , Frøland Stig S. , Aukrust Pål
Published: June 2012

Background
—Congestive heart failure (CHF) is characterized by enhanced immune activation, and immune-mediated mechanisms may play a pathogenic role in this disorder. Based on the immunomodulatory effects of intravenous immunoglobulin (IVIG), we hypothesized that IVIG could downregulate inflammatory responses in CHF patients and have potential beneficial effects on the left ventricular ejection fraction (LVEF).

Methods and Results
—Forty patients with chronic symptomatic CHF and LVEF of <40%, stratified according to cause (ie, ischemic and idiopathic dilated cardiomyopathy), were randomized in a double-blind fashion to receive therapy with IVIG or placebo for a total period of 26 weeks. Our main findings were that (1) IVIG, but not placebo, induced a marked rise in plasma levels of the anti-inflammatory mediators interleukin (IL)-10, IL-1 receptor antagonist, and soluble tumor necrosis factor receptors; (2) significantly correlated with these anti-inflammatory effects, IVIG, but not placebo, induced a significant increase in LVEF from 26±2% to 31±3% (
P
<0.01), and this was found independent of the cause of heart failure; and (3) N-terminal pro–atrial natriuretic peptide decreased significantly after induction therapy and continued to decrease toward the end of study during IVIG therapy (
P
<0.001) but remained unchanged during placebo.

Conclusions
—We demonstrated an IVIG-induced change in the balance between inflammatory and anti-inflammatory cytokines that favored an anti-inflammatory net effect in CHF. This effect was significantly correlated with an improvement in LVEF, suggesting a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in CHF patients.
An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro
Authors: Aikawa Masanori , Rabkin Elena , Sugiyama Seigo , Voglic Sami J. , Fukumoto Yoshihiro , Furukawa Yutaka , Shiomi Masashi , Schoen Frederick J. , Libby Peter
Published: June 2012

Background
—Unstable atherosclerotic plaques that cause acute coronary events usually contain abundant macrophages expressing matrix metalloproteinases (MMPs) and tissue factor (TF), molecules that probably contribute to plaque rupture and subsequent thrombus formation. Lipid lowering with HMG-CoA reductase inhibitors reduces acute coronary events.

Methods and Results
—To test whether lipid lowering with an HMG-CoA reductase inhibitor retards macrophage accumulation in rabbit atheroma, we administered cerivastatin to immature Watanabe heritable hyperlipidemic rabbits (cerivastatin group, n=10, cerivastatin 0.6 mg · kg
−1
· d
−1
; control group, n=9, saline 0.6 mL · kg
−1
· d
−1
) for 32 weeks and measured macrophage accumulation and expression of MMPs and TF. Serum cholesterol levels after 32 weeks were 809±40 mg/dL (control group) and 481±24 mg/dL (treated group). Cerivastatin diminished accumulation of macrophages in aortic atheroma. Macrophage expression of MMP-1, MMP-3, MMP-9, and TF also decreased with cerivastatin treatment. Cerivastatin reduced the number of macrophages expressing histone mRNA (a sensitive marker of cell proliferation) detected by in situ hybridization but did not alter macrophages bearing a marker of death (TUNEL staining). Cerivastatin treatment (≥0.01 μmol/L) also reduced growth, proteolytic activity due to MMP-9, and TF expression in cultured human monocyte/macrophages.

Conclusions
—These results suggest that lipid lowering with HMG-CoA reductase inhibitors alters plaque biology by reducing proliferation and activation of macrophages, prominent sources of molecules responsible for plaque instability and thrombogenicity.
Morphine Mimics Preconditioning via Free Radical Signals and Mitochondrial K
ATP
Channels in Myocytes
Authors: McPherson Bradley C. , Yao Zhenhai
Published: June 2012

Background
—We tried to determine whether morphine mimics preconditioning (PC) to reduce cell death in cultured cardiomyocytes and whether opioid δ
1
receptors, free radicals, and K
ATP
channels mediate this effect.

Methods and Results
—Chick embryonic ventricular myocytes were studied in a flow-through chamber while flow rate, pH, and O
2
and CO
2
tension were controlled. Cardiomyocyte viability was quantified with propidium iodide (5 μmol/L), and production of free radicals was measured with 2′,7′-dichlorofluorescin diacetate. PC with 10 minutes of simulated ischemia before 10 minutes of reoxygenation or morphine (1 μmol/L) or BW373U86 (10 pmol/L) infusion for 10 minutes followed by a 10-minute drug-free period before 1 hour of ischemia and 3 hours of reoxygenation reduced cell death to the same extent (*
P
<0.05) (PC, 20±1%, n=7*; morphine, 32±4%, n=8*; BW373U86, 21±6%; controls, 52±5%, n=8). Like PC, morphine and BW373U86 increased free radical production 2-fold before ischemia (0.35±0.10, n=6*; 0.41±0.08, n=4* versus controls, 0.15±0.05, n=8, arbitrary units). Protection and increased free radical signals during morphine infusion were abolished with either the thiol reductant 2-mercaptopropionyl glycine (400 μmol/L), an antioxidant; naloxone (10 μmol/L), a nonselective morphine receptor antagonist; BNTX (0.1 μmol/L), a selective opioid δ
1
receptor antagonist; or 5-hydroxydecanoate (100 μmol/L), a selective mitochondrial K
ATP
channel antagonist.

Conclusions
—These results suggest that direct stimulation of cardiocyte opioid δ
1
receptors leads to activation of mitochondrial K
ATP
channels. The resultant increase of intracellular free radical signals may be an important component of the signaling pathways by which morphine mimics preconditioning in cardiomyocytes.
Myocardial Free Fatty Acid and Glucose Use After Carvedilol Treatment in Patients With Congestive Heart Failure
Authors: Wallhaus Thomas R. , Taylor Michael , DeGrado Timothy R. , Russell Douglas C. , Stanko Peter , Nickles Robert J. , Stone Charles K.
Published: June 2012

Background
—Use of β-adrenoreceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial oxygen consumption and an improvement in myocardial energy efficiency. One potential mechanism for this beneficial effect is a shift in myocardial substrate use from increased free fatty acid (FFA) oxidation to increased glucose oxidation.

Methods and Results
—We studied the effect of carvedilol therapy on myocardial FFA and glucose use in 9 patients with stable New York Heart Association functional class III ischemic cardiomyopathy (left ventricular ejection fraction ≤35%) using myocardial positron emission tomography studies and resting echocardiograms before and 3 months after carvedilol treatment. Myocardial uptake of the novel long chain fatty acid metabolic tracer 14(R, S)-[
18
F]fluoro-6-thia-heptadecanoic acid ([
18
F]-FTHA) was used to determine myocardial FFA use, and [
18
F]fluoro-2-deoxy-glucose ([
18
F]-FDG) was used to determine myocardial glucose use. After carvedilol treatment, the mean myocardial uptake rate for [
18
F]-FTHA decreased (from 20.4±8.6 to 9.7±2.3 mL · 100 g
–1
· min
–1
;
P
<0.005), mean fatty acid use decreased (from 19.3±7.0 to 8.2±1.8 μmoL · 100 g
–1
· min
–1
;
P
<0.005), the mean myocardial uptake rate for [
18
F]-FDG was unchanged (from 1.4±0.4 to 2.4±0.8 mL · 100 g
–1
· min
–1
;
P
=0.14), and mean glucose use was unchanged (from 11.1±3.1 to 18.7±6.0 μmoL · 100 g
–1
· min
–1
;
P
=0.12). Serum FFA and glucose concentrations were unchanged, and mean left ventricular ejection fraction improved (from 26±2% to 37±4%;
P
<0.05).

Conclusions
—Carvedilol treatment in patients with heart failure results in a 57% decrease in myocardial FFA use without a significant change in glucose use. These metabolic changes could contribute to the observed improvements in energy efficiency seen in patients with heart failure.
Familial Thoracic Aortic Aneurysms and Dissections
Authors: Guo Dongchuan , Hasham Sumera , Kuang Shao-Qing , Vaughan Carl J. , Boerwinkle Eric , Chen Hua , Abuelo Dianne , Dietz Harry C. , Basson Craig T. , Shete Sanjay S. , Milewicz Dianna M.
Published: June 2012

Background
—Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome.

Methods and Results
—Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker
D5S2029
. In 6 families, the phenotype was not linked to the 5q locus.

Conclusions
—A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.
Temporal Gradients in Shear, but Not Spatial Gradients, Stimulate Endothelial Cell Proliferation
Authors: White Charles R. , Haidekker Mark , Bao Xuping , Frangos John A.
Published: June 2012

Background
—The effect of temporal and spatial gradients in shear on primary human endothelial cell (HUVEC) proliferation was investigated. The sudden-expansion flow chamber (SEFC) model was used to differentiate the effect of temporal gradients in shear from that of spatial gradients. With a sudden onset of flow, cells are exposed to both temporal and spatial gradients of shear. The temporal gradients can be eliminated by slowly ramping up the flow.

Methods and Results
—HUVEC proliferation in the SEFC remained unstimulated when the onset of flow was slowly ramped. Sudden onset of flow stimulated a 105% increase of HUVEC proliferation (relative to ramped onset) within the region of flow reattachment. To further separate temporal and spatial gradients, a conventional parallel-plate flow chamber was used. A single 0.5-second impulse of 10 dyne/cm
2
increased HUVEC proliferation 54±3% relative to control. When flow was slowly ramped over 30 seconds, HUVEC proliferation was not significantly different from controls. Steady laminar shear over 20 minutes inhibited HUVEC proliferation relative to controls regardless of step (36±8%) or ramp (21±5%) onsets of flow.

Conclusions
—The results indicate that temporal gradients in shear stress stimulate endothelial cell proliferation, whereas spatial gradients affect endothelial proliferation no differently than steady uniform shear stress.
Modulation of C-Reactive Protein–Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs
Authors: Pasceri Vincenzo , Chang Jed , Willerson James T. , Yeh Edward T. H.
Published: June 2012

Background
—C-reactive protein (CRP) induces adhesion molecule expression by endothelial cells. However, the effects of CRP on chemokine expression by endothelial cells are not known.

Methods and Results
—We tested the effects of CRP on the production of the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES in cultured human umbilical vein endothelial cells. The secretion of chemokines was assessed by ELISA. Incubation with 100 μg/mL recombinant human CRP induced a 7-fold increase in MCP-1 but no change in RANTES secretion. We showed that the effect of CRP on MCP-1 was present even at 5 μg/mL CRP, with stepwise increases as the CRP concentration was increased to 10, 50, and 100 μg/mL. The effect of CRP on MCP-1 induction was not influenced by aspirin (at concentrations up to 1 mmol/L), but it was significantly inhibited by 5 μmol/L simvastatin. The peroxisome proliferator-activated receptor-α activators fenofibrate (100 μmol/L) and Wy-14649 (100 μmol/L) almost completely abolished the induction of MCP-1, but the peroxisome proliferator-activated receptor-γ activator ciglitazone had only a moderate effect.

Conclusions
—These results further strengthen the role of CRP in the pathogenesis of vascular inflammation and, likely, atherosclerosis and provide a crucial insight into a novel mechanism of action of anti-atherosclerosis drugs such as simvastatin and fenofibrate.