bluuebunny/crossref_metadata_2025 huggingface dataset:
Unselected women with elevated levels of factor VIII:C or homocysteine are not at increased risk for obstetric complications
Authors: van de Poel Marlène , Bank Ivan , Hamulyák Karly , Libourel Eduard , Koopman Maria , Prins Martin , van der Meer Jan , Büller Harry , Middeldorp Saskia
Published: August 2004

Acquired and hereditary thrombophilias are associated with obstetric complications such as (pre-)eclampsia, HELLP syndrome and fetal loss. Our objective was to assess the risk of obstetric complications in women with elevated levels of FVIII:C or hyperhomocysteinemia, as compared with their relatives who had normal FVIII:C or homocysteine levels. From a large family study of patients with venous thromboembolism or premature atherosclerosis and elevated levels of FVIII:C or hyperhomocysteinemia (propositi), the obstetric histories of female first degree relatives, who had been pregnant at least once, were studied. Levels of FVIII:C and homocysteine (both fasting and post-methionine loading) were determined. The number of obstetric complications was calculated and compared in women with normal and elevated levels of FVIII:C, and normal and elevated levels of homocysteine. Women with elevated levels of FVIII:C had a 15.4% risk for toxicosis, preeclampsia, or HELLP syndrome and a 23.9% for fetal loss. This was not statistically different from women with normal levels of FVIII:C. Women with hyperhomocysteinemia tended to have a lower risk for toxicosis, pre-eclampsia, or HELLP syndrome (8.0%, RR 0.6, 95% CI 0.2-1.7) and fetal loss (22.0%, RR 0.8, 95% CI 0.5-1.5) as compared to relatives with normal levels, although these differences did not reach statistical significance. If the analysis was limited to comparing extremes, the results did not materially differ. Unselected women with elevated plasma levels of FVIII:C or hyperhomocysteinemia are not at increased risk for obstetric complications as compared to their relatives with normal levels.
Arterial ischaemic stroke in children
Authors: Kirkham Fenella , Sébire Guillaume , Steinlin Maja , Sträter Ronald
Published: August 2004

Conditions associated with arterial ischaemic stroke in children include a great variety of diseases and triggers such as congenital heart malformations, sickle cell disease, infections and vasculopathies, although up to 50% are cryptogenic. An abnormal vascular status can be demonstrated by vascular imaging in up to 80% of children with ischaemic stroke, and case control studies demonstrate an association between ischaemic stroke in children and hereditary prothrombotic risk factors and infections such as Varicella. Conventional risk factors such as hypertension and dyslipidaemia may also play a role, and most children have several potential triggers rather than one single cause. This review focuses on clinical presentations, imaging methods, stroke subtypes, underlying conditions including prothrombotic risk factors, outcome and recurrence. Although data from randomised controlled trials, on which clinical practice might be based, are sparse, therapeutic approaches and future research directions are discussed.
A novel mutation in the transmembrane region of glycoprotein IX associated with Bernard-Soulier syndrome
Authors: Zhao Xiaojuan , Duan Weiming , Fu Jianxin , Lu Mingen , Wang Giamin , Bai Xia , Ruan Changgeng , Wang Zhaoyue
Published: August 2004

We describe here a novel mutation in glycoprotein (GP) IX transmembrane region in a patient with Bernard-Soulier syndrome (BSS). Flow cytometric analysis of the patient’s platelets showed that GP Iba and GP IX were expressed at decreased levels. Sequence analysis of the gene coding for GP IX revealed a homozygous (G to A) transition at nucleotide 2113, resulting in a Ala 140 (GCC) to Thr (ACC) replacement in the mature peptide, whereas no defects were found in the coding region of the GP Iba and GP Ib? gene. Allele-specific restriction enzyme analysis using HPYCH4 III revealed that the patient was homozygous and her mother and brother were heterozygous for the defect, and excluded the possibility that the mutation was a polymorphism of GP IX.To clarify the effect of this mutation on the surface expression of the GP Ib/IX complex, we introduced this mutation into the cDNA of GP IX by site-directed mutagenesis and performed in vitro transfection studies with plasmids harboring GP Iba, GP Ib? and wild-type GP IX or mutant GP IX. Mutant GP IX decreased the surface expression of GP Iba and GP IX, whereas both immunostaining and immunoblotting of the transfected Chinese hamster ovary (CHO) cells showed abundant GP Iba and GP IX in the cytoplasm of the CHO cells transfected with plasmids harboring GP Iba, GP Ib? and wild-type GP IX or mutant GP IX These findings indicate that the Ala140→Thr mutation in the transmembrane region of GP IX does not induce intracellular GP Ib/IX complex degradation, but prevents its insertion in the cytoplasmic membrane of platelets and CHO cells.
Fibrinogen regulates the expression of inflammatory chemokines through NF-κB activation of endothelial cells
Authors: Guo Min , Sahni Sanjeev , Sahni Abha , Francis Charles
Published: August 2004

The objective of this study was to characterize the role of fibrinogen in stimulating expression of inflammatory chemokines in endothelial cells through NF-κB activation. Human umbilical vein endothelial cells (HUVEC) were exposed to fibrinogen up to 3,000 µg/ml, and NF-κB activation was assessed using electrophoretic mobility shift assay (EMSA). Fibrinogen exposure resulted in a concentration dependent increase in NF-κB activation that reached a maximum at 1,000 µg/ml after 4 hours and was sustained up to 24 hours. The effect was inhibited by antibodies to αvβ3 and α5β1 and by the GRGDS peptide, indicating integrin involvement. Preincubation with Mn2+ lowered the fibrinogen concentration-dependence, consistent with integrin activation. Supershift assays demonstrated involvement of the p50, p65 and c-Rel components of NF-κB. Fibrinogen exposure also resulted in up-regulation of expression of monocyte chemoattractant protein-1 (MCP-1) and of interleukin-8 as shown by RNase protection assays and by real-time RT-PCR. Increased secretion of MCP-1 was confirmed by ELISA. Parthenolide, an IκB kinase inhibitor, prevented up-regulation of MCP-1 by fibrinogen, linking this response to NF-κB activation. From our findings, we conclude that fibrinogen regulates NF-κB activation and expression of inflammatory chemokines in endothelial cells and may be involved in mediating inflammatory processes.
Role of P-selectin and PSGL-1 in coagulation and thrombosis
Authors: R.Vandendries Erik , Furie Barbara , Furie Bruce
Published: August 2004

P-selectin and PSGL-1 are cell adhesion molecules, regulating the initial interactions between leukocytes and the blood vessel wall as well as between activated platelets and leukocytes. P-selectin is expressed on activated endothelial cells and platelets, while its major ligand PSGL-1 is expressed on leukocytes. Multiple studies have shown that these adhesion molecules are required for the normal recruitment of leukocytes during an inflammatory reaction. More recently, these adhesion molecules have been implicated in recruitment of leukocytes and leukocyte microparticles to thrombi. The P-selectinand PSGL-1-dependent delivery of circulating microparticles to thrombi appears to be important for normal tissue factor accumulation and fibrin generation in thrombi.
Dysfunctional platelet membrane receptors: from humans to mice
Authors: Ware Jerry
Published: August 2004

Insights into hemostasis and thrombosis have historically benefited from the astute diagnosis of human bleeding and thrombotic disorders followed by decades of careful biochemical characterization. This work has set the stage for the development of a number of mouse models of hemostasis and thrombosis generated by gene targeting strategies in the mouse genome. The utility of these models is the in depth analysis that can be performed on the precise molecular interactions that support hemostasis and thrombosis along with efficacy testing of various therapeutic strategies. Already the mouse has proven to be an excellent model of the processes that support hemostasis and thrombosis in the human vasculature. A brief summary of the salient phenotypes from knockout mice missing key platelet receptors is presented, including the glycoprotein (GP) Ib-IX-V and GP IIb/IIIa (αIIb/β3) receptors; the collagen receptors, GP VI and α2/β1; the protease activated receptors (PARs); and the purinergic receptors, P2Y1 and P2Y12. A few differences exist between mouse and human platelets and where appropriate those will be highlighted in this review. Concluding remarks focus on the importance of understanding the power and limitations of various in vitro, ex vivo and in vivo models currently being used and the impact of the mouse strain on the described platelet phenotype.
Comparing Warfarin With Aspirin After Biological Aortic Valve Replacement
Authors: Gherli Tiziano , Colli Andrea , Fragnito Claudio , Nicolini Francesco , Borrello Bruno , Saccani Stefano , D’Amico Roberto , Beghi Cesare
Published: August 2004

Background—

Patients with prosthetic heart valves have a higher risk of developing valve thrombosis and arterial thromboembolism. Antithrombotic therapy in the early postoperative period after biological aortic valve replacement (BAVR) is controversial. The American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of warfarin for the first 3 months after BAVR, although the American College Chest Physician guidelines suggest that the recommendations are very weak and that the risk/benefit is unclear. This prospective study investigated the efficacy of postoperative warfarin compared with aspirin in patients after aortic valve replacement.

Methods and Results—

Patients undergoing BAVR between 2001 and 2002 received 2 antithrombotic therapies: 141 patients received warfarin for the first 3 months, and 108 patients received only aspirin. The major end points evaluated were the rate of cerebral ischemic events, bleeding, and survival. There were 3 and 5 postoperative cerebral ischemic events between 24 hours and 3 months for patients treated with aspirin and warfarin, respectively. After 3 months, the incidence of cerebral ischemic events did not differ between the 2 groups. The rate of major bleeding events, the stroke-free survival, and the overall survival rates were not statistically significant between the warfarin and aspirin groups.

Conclusions—

There seem to be no advantages in performing early anticoagulation therapy compared with a low-antiplatelet regimen with regard to early cerebral ischemic events, bleeding, and survival. Currently there is no evidence to support the fact that warfarin is more effective than aspirin.
Prolonged Endoplasmic Reticulum Stress in Hypertrophic and Failing Heart After Aortic Constriction
Authors: Okada Ken-ichiro , Minamino Tetsuo , Tsukamoto Yoshitane , Liao Yulin , Tsukamoto Osamu , Takashima Seiji , Hirata Akio , Fujita Masashi , Nagamachi Yoko , Nakatani Takeshi , Yutani Chikao , Ozawa Kentaro , Ogawa Satoshi , Tomoike Hitonobu , Hori Masatsugu , Kitakaze Masafumi
Published: August 2004

Background—

The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear.

Methods and Results—

Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. On the other hand, angiotensin II upregulated ER chaperones and induced apoptosis in cultured adult rat cardiac myocytes. We also investigated possible signaling pathways for ER-initiated apoptosis. The CHOP- (a transcription factor induced by ER stress), but not JNK- or caspase-12-, dependent pathway was activated in failing hearts by TAC. Pharmacological ER stress inducers upregulated ER chaperones and induced apoptosis in cultured cardiac myocytes. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients with elevated brain natriuretic peptide levels.

Conclusions—

These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure.
Outcomes in Children With Idiopathic Pulmonary Arterial Hypertension
Authors: Yung Delphine , Widlitz Allison C. , Rosenzweig Erika Berman , Kerstein Diane , Maislin Greg , Barst Robyn J.
Published: August 2004

Background—

Treatment for idiopathic pulmonary arterial hypertension in children includes calcium channel blockade (CCB) for acute responders with vasodilator testing and chronic epoprostenol for nonresponders. We sought to determine parameters associated with survival and treatment success.

Methods and Results—

A previously identified cohort of 77 children diagnosed between 1982 and 1995 with idiopathic pulmonary arterial hypertension was followed up through 2002. For acute responders treated with CCB (n=31), survival at 1, 5, and 10 years was 97%, 97%, and 81%, respectively; treatment success was 84%, 68%, and 47%, respectively. Survival for all children treated with epoprostenol (n=35) at 1, 5, and 10 years was 94%, 81%, and 61%, respectively; treatment success was 83%, 57%, and 37%, respectively. Because of the inconsistent availability of epoprostenol before 1995, we defined a “recent medical era” subset by excluding children from the total 77 patient cohort for whom epoprostenol was recommended but was unavailable. Survival in the recent medical era (n=44) at 1, 5, and 10 years was 97%, 97%, and 78%; treatment success was 93%, 86%, and 60%, respectively. Treatment success on CCB decreased significantly when acute responders became nonresponders. Age at diagnosis predicted treatment success in the recent medical era.

Conclusions—

Survival for children with idiopathic pulmonary arterial hypertension has significantly improved with CCB and epoprostenol. Children who are acute responders are treated with CCB; they are treated with epoprostenol if they become nonresponders. The decrease in survival and in treatment success after 5 years in all children supports the role for transplant evaluation before treatment failure.
Role of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Induced Vasodilation of Coronary and Systemic Vessels
Authors: Zhang Jian , Chen Zhiqiang , Cobb Frederick R. , Stamler Jonathan S.
Published: August 2004

Background—

It has recently been shown that mitochondrial aldehyde dehydrogenase 2 (mtALDH) catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from nitroglycerin (glyceryl trinitrate [GTN]) within mitochondria, leading to production of cGMP and vasorelaxation. However, whether this mechanism operates in the systemic and coronary beds that subserve the antianginal action of GTN is not known. In this study, we address this question in an intact canine model.

Methods and Results—

Fourteen healthy mongrel dogs (weight, 20 to 25 kg) were studied. Coronary blood flow and hemodynamics were continuously monitored by a pulse Doppler flow probe implanted around the left circumflex coronary artery and with catheters in left ventricle and aorta, respectively. Each dog was given a 1-mL bolus injection of GTN, sodium nitroprusside (SNP), or adenosine through a catheter in the left atrium before and 30 minutes after infusion of cyanamide (17 mg/kg), an inhibitor of mtALDH. Cyanamide significantly inhibited both the classic dehydrogenase and GTN reductase activities of mtALDH in situ and attenuated the coronary blood flow increase and declines in blood pressure and left ventricular end-diastolic pressure produced by GTN in vivo. In contrast, mtALDH inhibition had no effect on the coronary and systemic effects of SNP and adenosine.

Conclusions—

Our data suggest that mtALDH contributes to GTN biotransformation in vivo and thus at least partly underlies the antianginal mechanism of drug action. Our findings also highlight the differences in biometabolism of clinically relevant nitrosovasodilators.
Myocardial First-Pass Perfusion Magnetic Resonance Imaging
Authors: Wolff S.D. , Schwitter J. , Coulden R. , Friedrich M.G. , Bluemke D.A. , Biederman R.W. , Martin E.T. , Lansky A.J. , Kashanian F. , Foo T.K.F. , Licato P.E. , Comeau C.R.
Published: August 2004

Background—

MRI can identify patients with obstructive coronary artery disease by imaging the left ventricular myocardium during a first-pass contrast bolus in the presence and absence of pharmacologically induced myocardial hyperemia. The purpose of this multicenter dose-ranging study was to determine the minimally efficacious dose of gadopentetate dimeglumine injection (Magnevist Injection; Berlex Laboratories) for detecting obstructive coronary artery disease.

Method and Results—

A total of 99 patients scheduled for coronary artery catheterization as part of their clinical evaluation were enrolled in this study. Patients were randomized to 1 of 3 doses of gadopentate dimeglumine: 0.05, 0.10, or 0.15 mmol/kg. First-pass perfusion imaging was performed during hyperemia (induced by a 4-minute infusion of adenosine at a rate of 140 μg · kg
−1
· min
−1
) and then again in the absence of adenosine with otherwise identical imaging parameters and the same contrast dose. Perfusion defects were evaluated subjectively by 4 blinded reviewers. Receiver-operating curve analysis showed that the areas under the receiver-operating curve were 0.90, 0.72, and 0.83 for the low-, medium-, and high-contrast doses, respectively, compared with quantitative coronary angiography (diameter stenosis ≥70%). For the low-dose group, mean sensitivity was 93±0%, mean specificity was 75±7%, and mean accuracy was 85±3%.

Conclusions—

First-pass perfusion MRI is a safe and accurate test for identifying patients with obstructive coronary artery disease. A low dose of 0.05 mmol/kg gadopentetate dimeglumine is at least as efficacious as higher doses.
Identification of the Ventricular Tachycardia Isthmus After Infarction by Pace Mapping
Authors: Brunckhorst Corinna B. , Delacretaz Etienne , Soejima Kyoko , Maisel William H. , Friedman Peter L. , Stevenson William G.
Published: August 2004

Background—

Ventricular tachycardia (VT) isthmuses can be defined by fixed or functional block. During sinus rhythm, pace mapping near the exit of an isthmus should produce a QRS similar to that of VT. Pace mapping at sites proximal to the exit may produce a similar QRS with a longer stimulus-to-QRS interval (S-QRS). The aim of the study was to determine whether a VT isthmus could be identified and followed by pace mapping.

Methods and Results—

Left ventricular pace mapping during sinus rhythm was performed at 819 sites in 11 patients with VT late after infarction, and corresponding CARTO maps were reconstructed. An isthmus site was defined by entrainment and/or VT termination by ablation. Pace-mapping data were analyzed from the identified isthmus site and from sites at progressively increasing distances from this initial isthmus site. Sites where pace mapping produced the same QRS with different S-QRS delays were identified to attempt to trace the course of the isthmus. In 11 patients, 13 confluent low-voltage infarct regions were present. In all these regions, parts of VT isthmuses were identified by pace mapping. In 11 of 13 of the identified isthmus parts, the QRS morphology of the pace map matched a VT QRS. In 10 of 11 patients, radiofrequency ablation rendered clinical VTs noninducible. Successful ablation sites were localized within an isthmus identified by pace mapping in all of these 10 patients.

Conclusions—

VT isthmuses can be identified and part of their course delineated by pace mapping during sinus rhythm. This method could help target isthmus sites for ablation during stable sinus rhythm.
Neuregulins Regulate Cardiac Parasympathetic Activity
Authors: Okoshi Katashi , Nakayama Masaharu , Yan Xinhua , Okoshi Marina P. , Schuldt Adam J.T. , Marchionni Mark A. , Lorell Beverly H.
Published: August 2004

Background—

Neuregulins are required for maintenance of acetylcholine receptor–inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances β-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1
+/−
) and examined the effects of β-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol.

Methods and Results—

We evaluated contraction and intracellular Ca
2+
transients ([Ca
2+
]
i
) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1
+/−
and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca
2+
]
o
, 25°C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca
2+
]
i
were not different between WT and NRG-1
+/−
mice. The steady-state increases in fractional shortening (FS) and peak-systolic [Ca
2+
]
i
in response to isoproterenol were similar in both groups. In WT myocytes stimulated with isoproterenol, carbachol decreased FS, peak-systolic [Ca
2+
]
i
, and cAMP levels. In NRG-1
+/−
myocytes, carbachol did not attenuate either FS or peak-systolic [Ca
2+
]
i
, associated with the failure to decrease cAMP levels. Investigation of muscarinic receptor signaling showed no difference of LV protein levels of muscarinic M
2
receptors or G protein Gα
i1,2
, Gα
i3
, and Gα
o
subunits.

Conclusions—

Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance β-adrenergic activation by inhibitory parasympathetic activity. This mechanism may contribute to the known increased risk of heart failure in injured human hearts when neuregulin signaling is suppressed.
Targeted Inactivation of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Gene Prevents Ischemic Preconditioning in Isolated Mouse Heart
Authors: Chen Hong , Liu Luis L. , Ye Linda L. , McGuckin Conor , Tamowski Susan , Scowen Paul , Tian Honglin , Murray Keith , Hatton William J. , Duan Dayue
Published: August 2004

Background—

Recent evidence suggests that chloride channels may be involved in ischemic preconditioning (IPC). In this study, we tested whether the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels, which are expressed in the heart and activated by protein kinase A and protein kinase C, are important for IPC in isolated heart preparations from wild-type (WT) and CFTR knockout (CFTR
−/−
) mice.

Methods and Results—

Hearts were isolated from age-matched WT or CFTR
−/−
(B6.129P2-Cftr
tm1Unc
and STOCKCftr
tm1Unc
-TgN 1Jaw) mice and perfused in the Langendorff or working-heart mode. All hearts were allowed to stabilize for 10 minutes before they were subjected to 30 or 45 minutes of global ischemia followed by 40 minutes of reperfusion (control group) or 3 cycles of 5 minutes of ischemia and reperfusion (IPC group) before 30 or 45 minutes of global ischemia and 40 minutes of reperfusion. Hemodynamic indices were recorded to evaluate cardiac functions. Release of creatine phosphate kinase (CPK) in the samples of coronary effluent and infarct size of the ventricles were used to estimate myocardial tissue injury. In WT adult hearts, IPC protected cardiac function during reperfusion and significantly decreased ischemia-induced CPK release and infarct size. A selective CFTR channel blocker, gemfibrozil, abrogated the protective effect of IPC. Furthermore, targeted inactivation of the CFTR gene in 2 different strains of CFTR
−/−
mice also prevented IPC’s protection of cardiac function and myocardial injury against sustained ischemia.

Conclusions—

CFTR Cl
−
channels may serve as novel and crucial mediators in mouse heart IPC.
Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload
Authors: Harris Ian S. , Zhang Shaosong , Treskov Ilya , Kovacs Attila , Weinheimer Carla , Muslin Anthony J.
Published: August 2004

Background—

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart results in the activation of the small GTPase ras and the Raf-1/MEK/ERK signaling cascade in addition to other signaling pathways.

Methods and Results—

In an attempt to determine the requirement for the serine/threonine kinase Raf-1 in the pathogenesis of cardiac hypertrophy, we generated transgenic mice with cardiac-specific expression of a dominant negative form of Raf-1 (DN-Raf). DN-Raf mice appeared normal at birth, were fertile, and had normal cardiac structure and function in the absence of provocative stimulation. In response to pressure overload, cardiac extracellular signal–regulated kinase (ERK) activation was inhibited, but c-Jun N-terminal kinase (JNK) activation and p38 mitogen-activated protein kinase (MAPK) activation were normal. DN-Raf mice were sensitized to pressure overload and the development of cardiomyocyte apoptosis, and >35% of animals died within 7 days of aortic banding. Surviving DN-Raf animals were markedly resistant to the development of cardiac hypertrophy and hypertrophic gene induction in response to transverse aortic constriction.

Conclusions—

These results establish that Raf-1 kinase activity is essential for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload.
Measures of Insulin Resistance Add Incremental Value to the Clinical Diagnosis of Metabolic Syndrome in Association With Coronary Atherosclerosis
Authors: Reilly Muredach P. , Wolfe Megan L. , Rhodes Thomas , Girman Cynthia , Mehta Nehal , Rader Daniel J.
Published: August 2004

Background—

Whether measures of insulin resistance provide incremental information regarding atherosclerotic cardiovascular disease beyond current National Cholesterol Education Program (NCEP) Adult Treatment Panel III metabolic syndrome (MetSyn) criteria or inflammatory markers is uncertain.

Methods and Results—

We examined the association of insulin resistance and MetSyn with coronary artery calcification (CAC) in 840 asymptomatic nondiabetic subjects. Both NCEP and World Health Organization–defined MetSyn were associated (ordinal regression odds ratio [OR] and 95% confidence intervals for NCEP-defined MetSyn) with CAC after controlling for age, non-MetSyn risk factors, and plasma CRP levels (OR, 1.93 [1.43 to 2.60],
P
<0.001) and after further controlling for homeostasis model assessment index (HOMA) (OR, 1.56 [1.14 to 2.15],
P
=0.006). Conversely, HOMA was significantly associated with CAC after adjusting for age, non-MetSyn risk factors, and CRP levels (OR, 1.62 [1.31 to 2.01],
P
<0.001) and after further adjusting for NCEP-defined MetSyn (OR, 1.45 [1.16 to 1.82],
P
=0.007). Addition of HOMA to the NCEP MetSyn significantly improved the association with CAC, but addition of CRP data to MetSyn or HOMA did not.

Conclusions—

Both MetSyn and HOMA index were associated with coronary atherosclerosis independent of established risk factors, including CRP. These findings support the use of biomarkers of insulin resistance in addition to NCEP MetSyn criteria in assessing cardiovascular disease risk.
Antioxidant Effects of Statins via
S
-Nitrosylation and Activation of Thioredoxin in Endothelial Cells
Authors: Haendeler Judith , Hoffmann Jörg , Zeiher Andreas M. , Dimmeler Stefanie
Published: August 2004

Background—

HMG-CoA reductase inhibitors (statins) are lipid-lowering drugs that also exert pleiotropic vasculoprotective effects via activation of the endothelial NO synthesis. NO induces
S
-nitrosylation of target proteins.
S
-Nitrosylation of the antioxidant enzyme thioredoxin was recently shown to enhance its activity, thereby reducing intracellular reactive oxygen species. Therefore, we investigated whether statins may exert an antioxidant activity in endothelial cells via
S
-nitrosylation of thioredoxin.

Methods and Results—

Statins dose- and time-dependently increased the overall level of
S
-nitrosylated proteins in endothelial cells (atorvastatin 0.1 μmol/L, 206±30% increase; simvastatin 1 μmol/L, 214±19% increase; mevastatin 1 μmol/L, 191±10% increase). The increased
S
-nitrosylation was blocked by an NO-synthase inhibitor and mevalonate. Moreover,
S
-nitrosylation of thioredoxin was also significantly augmented after atorvastatin treatment. The atorvastatin-mediated increase in
S
-nitrosylation was associated with an enhanced enzymatic activity of thioredoxin (atorvastatin, 157±9% increase). This resulted in a significant reduction of intracellular reactive oxygen species within the endothelial cells. In contrast, in endothelial cells overexpressing a thioredoxin construct in which the
S
-nitrosylation acceptor amino acid cysteine 69 was replaced by serine [TRX(C69S)], atorvastatin did not activate the redox-regulatory activity of thioredoxin. Moreover, overexpression of the non-nitrosylatable thioredoxin TRX(C69S) abolished atorvastatin-mediated reduction of reactive oxygen species.

Conclusions—

Here, we demonstrate a novel antioxidant mechanism by which statins reduce reactive oxygen species in endothelial cells. Statin-mediated
S
-nitrosylation of thioredoxin enhanced the enzymatic activity of thioredoxin, resulting in a significant reduction in intracellular reactive oxygen species.
Endothelial Dysfunction and Mild Renal Insufficiency in Essential Hypertension
Authors: Perticone Francesco , Maio Raffaele , Tripepi Giovanni , Zoccali Carmine
Published: August 2004

Background—

Mild to moderate renal insufficiency in individuals with essential hypertension is currently considered the expression of a renal microvasculopathy characterized by preglomerular arteriolar involvement and tubulo-interstitial changes. Whether endothelial dysfunction plays a role in this alteration is still undefined.

Methods and Results—

We investigated the relationship between endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm) and renal function in 500 patients with uncomplicated, never-treated, essential hypertension and serum creatinine within the normal range (ie, ≤1.5 mg/dL). Serum creatinine, creatinine clearance, and estimated glomerular filtration rate (GFR, by the Modification of Diet in Renal Disease formula) were related to the forearm blood flow response to ACh (all
P
≤0.003), and these relationships held true in multiple regression analyses that included age, gender, systolic pressure, serum cholesterol and glucose, smoking, and body mass index. Accordingly, on multiple logistic regression analysis, the risk of moderate renal dysfunction (ie, an estimated GFR <60 mL · min
−1
· 1.73 m
−2
) was 64% lower (OR 0.36, 95% CI 0.18 to 0.70) in patients in the third ACh tertile (ie, those showing the higher vasodilatory response) than in those in the first tertile (ie, showing the lower response). C-reactive protein was related directly to serum creatinine and inversely to GFR and vasodilatory response to ACh, which suggests that endothelial dysfunction is a possible mechanism linking inflammation and impaired renal function in essential hypertension.

Conclusions—

An impaired vasodilatory response to ACh appears to be associated with renal function loss in patients with essential hypertension. This association suggests that systemic endothelial dysfunction is involved in mild to moderate renal insufficiency in patients with uncomplicated essential hypertension.
C-Reactive Protein Levels and the Expansion of Screen-Detected Abdominal Aortic Aneurysms in Men
Authors: Norman Paul , Spencer Carole A. , Lawrence-Brown Michael M. , Jamrozik Konrad
Published: August 2004

Background—

C-reactive protein (CRP) levels have been shown to predict a number of cardiovascular outcomes. CRP levels have also been found to be elevated in patients with abdominal aortic aneurysms (AAAs). The aim of this study was to assess the relation between CRP levels and rates of expansion of small AAAs.

Methods and Results—

A cohort of men with small aneurysms was identified in a trial of screening with ultrasound scanning. After initial screening, men were rescanned at 6- to 12-month intervals. CRP levels were measured at the first follow-up visit. Rates of expansion and risk factors for expansion were assessed with the use of data from 545 men who attended for at least 1 scan after CRP levels were measured. These men were followed for a median of 48 (range, 5 to 69) months. The mean annual rate of expansion was 1.6 mm. The median CRP level was 2.6 mg/L in men with the smaller AAAs (30 to 39 mm, n=433) compared with 3.5 mg/L in men with larger AAAs (40 to 54 mm, n=112) (
P
=0.007). The multivariate age-adjusted logistic model confirmed initial aortic diameter to be the only factor associated with rapid expansion with an odds ratio of 7.2 (95% CI, 4.3,12.2) for an initial diameter of 40 to 54 mm relative to one of 30 to 39 mm.

Conclusions—

Most small aneurysms expand slowly. CRP levels are elevated in larger aneurysms but do not appear to be associated with rapid expansion. The most useful predictor of aneurysmal expansion in men is aortic diameter.
Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII
Authors: Sleeper M.M. , Fornasari B. , Ellinwood N.M. , Weil M.A. , Melniczek J. , O’Malley T.M. , Sammarco C.D. , Xu L. , Ponder K.P. , Haskins M.E.
Published: August 2004

Background—

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (GUSB) activity resulting in defective catabolism of glycosaminoglycans (GAGs). Cardiac disease is a major cause of death in MPS VII because of accumulation of GAGs in cardiovascular cells. Manifestations include cardiomyopathy, mitral and aortic valve thickening, and aortic root dilation and may cause death in the early months of life or may be compatible with a fairly normal lifespan. We previously reported that neonatal administration of a retroviral vector (RV) resulted in transduction of hepatocytes, which secreted GUSB into the blood and could be taken up by cells throughout the body. The goal of this study was to evaluate the effect on cardiac disease.

Methods and Results—

Six MPS VII dogs were treated intravenously with an RV-expressing canine GUSB. Echocardiographic parameters, cardiovascular lesions, and biochemical parameters of these dogs were compared with those of normal and untreated MPS VII dogs.

Conclusions—

RV-treated dogs were markedly improved compared with untreated MPS VII dogs. Most RV-treated MPS VII dogs had mild or moderate mitral regurgitation at 4 to 5 months after birth, which improved or disappeared when evaluated at 9 to 11 and at 24 months. Similarly, mitral valve thickening present early in some animals disappeared over time, whereas aortic dilation and aortic valve thickening were absent at all times. Both myocardium and aorta had significant levels of GUSB and reduction in GAGs.
Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation
Authors: Iwai Masaru , Liu Hong-Wei , Chen Rui , Ide Ayumi , Okamoto Shoko , Hata Ryuji , Sakanaka Masahiro , Shiuchi Tetsuya , Horiuchi Masatsugu
Published: August 2004

Background—

The role of angiotensin II receptor subtypes was investigated in focal brain ischemia induced by middle cerebral artery (MCA) occlusion.

Methods and Results—

In
Agtr2
+
(wild-type) mice, MCA occlusion induced focal ischemia of ≈20% to 30% of the total area in coronal section of the brain. The ischemic area was significantly larger in angiotensin II type 2 receptor–deficient (
Agtr2
−
) mice than in
Agtr2
+
mice. The neurological deficit after MCA occlusion was also greater in
Agtr2
−
mice than in
Agtr2
+
mice. The decrease in surface cerebral blood flow after MCA occlusion was significantly exaggerated in the peripheral region of the MCA territory in
Agtr2
−
mice. Superoxide production and NADPH oxidase activity were enhanced in the ischemic area of the brain in
Agtr2
−
mice. An AT
1
receptor blocker, valsartan, at a nonhypotensive dose significantly inhibited the ischemic area, neurological deficit, and reduction of cerebral blood flow as well as superoxide production and NADPH oxidase activity in
Agtr2
+
mice. These inhibitory actions of valsartan were weaker in
Agtr2
−
mice.

Conclusions—

These results suggest that AT
2
receptor stimulation has a protective effect on ischemic brain lesions, at least partly through the modulation of cerebral blood flow and superoxide production.
Troponin I Isoform Expression in Human and Experimental Atrial Fibrillation
Authors: Thijssen Victor L.J.L. , Ausma Jannie , Gorza Luisa , van der Velden Huub M.W. , Allessie Maurits A. , Van Gelder Isabelle C. , Borgers Marcel , van Eys Guillaume J.J.M.
Published: August 2004

Background—

Atrial fibrillation (AF) is accompanied by re-expression of fetal genes and activation of proteolytic enzymes. In this study both aspects were addressed with respect to troponin I (TnI) isoform expression.

Methods and Results—

Western blotting and real-time reverse transcription–polymerase chain reaction were used to study TnI isoform expression in patients with paroxysmal or chronic AF and in goats after 1, 2, 4, 8, and 16 weeks of AF. In addition to cardiac TnI (cTnI), low expression of slow-twitch skeletal TnI (ssTnI) protein was found in 60% of patients in sinus rhythm or paroxysmal AF and in 8% of patients with chronic AF. In adult goat atrium, ssTnI protein expression was undetectable. Calcium-dependent degradation of cTnI protein was found in 1 or 2 of 6 animals after 1 to 4 weeks of AF. Although always low, ssTnI mRNA levels were significantly higher in patients who expressed ssTnI protein than in those who did not. Relative ssTnI mRNA expression was significantly lower in patients with paroxysmal AF and chronic AF than in those in sinus rhythm. In goats there was a tendency toward higher relative levels of ssTnI at the onset of AF followed by a normalization when AF had become sustained.

Conclusions—

Atrial re-expression of ssTnI during paroxysmal AF in patients and during the first 2 weeks of pacing-induced AF in goats does not seem to be part of the process of AF-associated cardiomyocyte dedifferentiation but seems to result from transient cardiomyocyte stress at the onset of AF.
Profiling of Aortic Smooth Muscle Cell Gene Expression in Response to Chronic Inhibition of Nitric Oxide Synthase in Rats
Authors: Dupuis Morgan , Soubrier Florent , Brocheriou Isabelle , Raoux Ségolène , Haloui Mounsif , Louedec Liliane , Michel Jean-Baptiste , Nadaud Sophie
Published: August 2004

Background—

Chronic inhibition of nitric oxide (NO) synthesis by
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) induces hypertension associated with remodeling of the arterial wall. In this study, we aimed at identifying genes and pathways involved in this process in aortic smooth muscle cells from Fischer 344 rats, which exhibit an accelerated hypertension after administration of L-NAME.

Methods and Results—

We studied the transcriptional profile of aortic media after 15 days (moderate hypertension) and 30 days (accelerated hypertension) of L-NAME administration (50 mg · kg
−1
· d
−1
) by using rat Affymetrix Genechips, and we present a large-scale validation of the DNA chip results by real-time reverse transcription–polymerase chain reaction (RT-PCR). We observed, in aortic media, a progressive increase in the number of modulated genes during L-NAME administration, with 53 genes significantly modulated after 15 days and 147 genes after 30 days. These expression changes were confirmed at 87% by RT-PCR. We found 28 known genes regulated at both 15 and 30 days (96% confirmation by RT-PCR). The functional classification of the regulated genes highlights 3 major biological pathways modulated in aortic media during L-NAME administration: genes regulating cell proliferation, genes involved in the extracellular matrix remodeling, and genes of the NO/cGMP signaling pathway.

Conclusions—

As a consequence of the genomic approach, we observed a large increase in modulation of gene expression along the evolution of the model and the progressive implication of compensatory mechanisms, making expression profile analysis more complex.
Comparison of Dobutamine Stress Magnetic Resonance, Adenosine Stress Magnetic Resonance, and Adenosine Stress Magnetic Resonance Perfusion
Authors: Paetsch I. , Jahnke C. , Wahl A. , Gebker R. , Neuss M. , Fleck E. , Nagel E.
Published: August 2004

Background—

Dobutamine stress MR (DSMR) is highly accurate for the detection of inducible wall motion abnormalities (IWMAs). Adenosine has a more favorable safety profile and is well established for the assessment of myocardial perfusion. We evaluated the diagnostic value of IWMAs during dobutamine and adenosine stress MR and adenosine MR perfusion compared with invasive coronary angiography.

Methods and Results—

Seventy-nine consecutive patients (suspected or known coronary disease, no history of prior myocardial infarction) scheduled for cardiac catheterization underwent cardiac MR (1.5 T). After 4 minutes of adenosine infusion (140 μg · kg
−1
· min
−1
for 6 minutes), wall motion was assessed (steady-state free precession), and subsequently perfusion scans (3-slice turbo field echo-echo planar imaging; 0.05 mmol/kg Gd-BOPTA) were performed. After a 15-minute break, rest perfusion was imaged, followed by standard DSMR/atropine stress MR. Wall motion was classified as pathological if ≥1 segment showed IWMAs. The transmural extent of inducible perfusion deficits (<25%, 25% to 50%, 51% to 75%, and >75%) was used to grade segmental perfusion. Quantitative coronary angiography was performed with significant stenosis defined as >50% diameter stenosis. Fifty-three patients (67%) had coronary artery stenoses >50%; sensitivity and specificity for detection by dobutamine and adenosine stress and adenosine perfusion were 89% and 80%, 40% and 96%, and 91% and 62%, respectively. Adenosine IWMAs were seen only in segments with >75% transmural perfusion deficit.

Conclusions—

DSMR is superior to adenosine stress for the induction of IWMAs in patients with significant coronary artery disease. Visual assessment of adenosine stress perfusion is sensitive with a low specificity, whereas adenosine stress MR wall motion is highly specific because it identifies only patients with high-grade perfusion deficits. Thus, DSMR is the method of choice for current state-of-the-art treatment regimens to detect ischemia in patients with suspected or known coronary artery disease but no history of prior myocardial infarction.
Randomized, Placebo-Controlled Trial of Dalteparin for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients
Authors: Leizorovicz Alain , Cohen Alexander T. , Turpie Alexander G.G. , Olsson Carl-Gustav , Vaitkus Paul T. , Goldhaber Samuel Z.
Published: August 2004

Background—

Considerable variability exists in the use of pharmacological thromboprophylaxis among acutely ill medical patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicenter, randomized, double-blind, placebo-controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in such patients.

Methods and Results—

Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymptomatic proximal deep vein thrombosis detected by compression ultrasound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80;
P
=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%).

Conclusions—

Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.
Prior Statin Therapy Is Associated With a Decreased Rate of Severe Sepsis
Authors: Almog Yaniv , Shefer Alexander , Novack Victor , Maimon Nimrod , Barski Leonid , Eizinger Miruna , Friger Michael , Zeller Lior , Danon Abraham
Published: August 2004

Background—

Statins have anti-inflammatory properties that are independent of their lipid-lowering abilities. We hypothesized that statin therapy before the onset of an acute bacterial infection may have a protective effect against severe sepsis. The aim of this study was to determine whether patients treated with statins develop severe sepsis less frequently.

Methods and Results—

In this prospective observational cohort study, consecutive patients admitted with presumed or documented acute bacterial infection were enrolled. The primary outcomes were the rate of severe sepsis and intensive care unit (ICU) admission. Of the 361 patients enrolled, 82 (22.7%) were treated with statins before their admission. Both groups had a similar severity of illness on admission. Severe sepsis developed in 19% of patients in the no-statin group and in only 2.4% of the statin group (
P
<0.001). Statin treatment was associated with a relative risk of developing severe sepsis of 0.13 (95% CI, 0.03 to 0.52) and an absolute risk reduction of 16.6%. The overall ICU admission rate was 10.2% (37/361): 12.2% of the no-statin group required ICU admission, whereas in the statin group only 3.7% were admitted to the ICU (
P
=0.025), reflecting a relative risk of ICU admission of 0.30 (95% CI, 0.1 to 0.95).

Conclusions—

Prior therapy with statins may be associated with a reduced rate of severe sepsis and ICU admission. If supported by prospective controlled trials, statins may have a role in the primary prevention of sepsis.