bluuebunny/crossref_metadata_2025 huggingface dataset:
Poly(ADP-ribose) polymerase-1 hyperactivation and impairment of mitochondrial respiratory chain complex I function in reperfused mouse hearts
Authors: Zhou Hui-Zhong , Swanson Raymond A. , Simonis Ursula , Ma Xiaokui , Cecchini Gary , Gray Mary O.
Published: April 2006

Poly(ADP-ribose) polymerase-1 (PARP-1), the most abundant member of the PARP family, is a nuclear enzyme that catalyzes ADP-ribose transfer from NAD+to specific acceptor proteins in response to DNA damage. Excessive PARP-1 activation is an important cause of infarction and contractile dysfunction in heart tissue during interruptions of blood flow. The mechanisms by which PARP-1 inhibition and disruption dramatically improve metabolic recovery and reduce oxidative stress during cardiac reperfusion have not been fully explored. We developed a mouse heart experimental protocol to test the hypothesis that mitochondrial respiratory complex I is a downstream mediator of beneficial effects of PARP-1 inhibition or disruption. Pharmacological inhibition of PARP-1 activity produced no deterioration of hemodynamic function in C57BL/6 mouse hearts. Hearts from PARP-1 knockout mice also exhibited normal baseline contractility. Prolonged ischemia-reperfusion produced a selective defect in complex I function distal to the NADH dehydrogenase component. PARP-1 inhibition and PARP-1 gene disruption conferred equivalent protection against mitochondrial complex I injury and were strongly associated with improvement in myocardial energetics, contractility, and tissue viability. Interestingly, ischemic preconditioning abolished cardioprotection stimulated by PARP-1 gene disruption. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine or xanthine oxidase inhibitor allopurinol restored the function of preconditioned PARP-1 knockout hearts. This investigation establishes a strong association between PARP-1 hyperactivity and mitochondrial complex I dysfunction in cardiac myocytes. Our findings advance understanding of metabolic regulation in myocardium and identify potential therapeutic targets for prevention and treatment of ischemic heart disease.
Enhanced sympathetic reactivity associates with insulin resistance in the young Zucker rat
Authors: Ruggeri Piero , Brunori Andrea , Cogo Carla E. , Storace Daniela , Di Nardo Francesco , Burattini Roberto
Published: March 2006

Somatosympathetic reflexes were studied in young hyperinsulinemic, insulin-resistant (Zucker fatty) rats (ZFR) and a related control (Zucker lean) strain (ZLR). Glucose metabolism was characterized by minimal model analysis of intravenous glucose tolerance test data. Seven-week-old ZFR ( n = 18) and ZLR ( n = 17) were studied under pentobarbital anesthesia. Mean body weight and plasma glucose and insulin concentration were significantly greater ( P < 0.05) in ZFR than in ZLR, whereas basal values of mean arterial pressure (MAP) and heart rate (HR) were not significantly different. Increments of MAP (ΔMAP) and HR (ΔHR) elicited by electrical stimulation of the sciatic nerve (5-s trains of 100 pulses, 0.5-ms pulse duration, 100- to 400-μA pulse intensity) were significantly higher (ANOVA, P < 0.05) in ZFR at each level of stimulus intensity. Regression analysis showed a linear increase in ΔMAP and ΔHR with increasing sciatic nerve stimulus intensity. Pressor responses to phenylephrine after ganglionic blockade demonstrated that vascular reactivity to adrenergic stimulation is not increased in ZFR compared with ZLR. Thus this factor does not contribute to enhancement of somatosympathetic reflexes observed in this strain. Insulin sensitivity in ZFR was one-fourth ( P < 0.05) that in ZLR. These results suggest that stronger sympathetic nervous reactivity in ZFR is associated with a severe insulin-resistant state before the onset of hypertension and support the hypothesis that insulin-mediated stimulation of the sympathetic nervous system is involved in the development of cardiovascular diseases related to alterations of glucose metabolism.
Uteroplacental insufficiency increases p53 phosphorylation without triggering the p53-MDM2 functional circuit response in the IUGR rat kidney
Authors: Baserga Mariana , Hale Merica A. , Ke Xingrao , Wang Zeng Ming , Yu Xing , Callaway Christopher W. , McKnight Robert A. , Lane Robert H.
Published: March 2006

Uteroplacental insufficiency (UPI) leads to intrauterine growth restriction (IUGR), which predisposes infants toward renal insufficiency early in life and increases the risk of kidney-related adult morbidities, such as hypertension. This compromised in utero environment has been demonstrated to impair nephrogenesis, as evidenced by a reduced nephron endowment in humans and in rats rendered IUGR by UPI. Concordantly, we have observed that IUGR rats have increased kidney p53 protein levels associated with increased apoptosis. Several factors can regulate p53 gene expression and activity, including posttranslational modifications and protein-protein interactions in the cell. Among these, two important mechanisms are 1) phosphorylation of the amino terminal serine 15 [phospho-p53 (Ser15)], which increases p53 stability and apoptotic activity, and 2) the murine double-minute (MDM2) functional circuit that limits further p53-induced apoptosis by promoting proteosomal degradation of p53. We hypothesize that UPI induces an increase in phospho-p53 (Ser15) in association with an absent MDM2 response, predisposing the kidney to increased apoptosis. To test our hypothesis, we induced IUGR through bilateral uterine artery ligation of the pregnant rat. UPI significantly increased phospho-p53 (Ser15), as well as ataxia teleangiectasia-mutated kinase/A-T-related kinase and dsDNA-activated protein kinase kinase levels, which induce phosphorylation of p53. In contrast, UPI induced no increase in kidney MDM2 mRNA and protein levels in IUGR pups. We conclude that among multiple mechanisms that affect nephrogenesis, UPI induces an increase in p53 phosphorylation without a corresponding increase in MDM2 expression, and we speculate that this response may contribute to the increased apoptosis previously described in the IUGR kidney.
Lipoprotein Lipase S447X
Authors: Rip Jaap , Nierman Melchior C. , Ross Colin J. , Jukema Jan Wouter , Hayden Michael R. , Kastelein John J.P. , Stroes Erik S.G. , Kuivenhoven Jan Albert
Published: March 2006

Lipoprotein lipase (LPL) hydrolyzes triglycerides in the circulation and promotes the hepatic uptake of remnant lipoproteins. Since the gene was cloned in 1989, more than 100 LPL gene mutations have been identified, the majority of which cause loss of enzymatic function. In contrast to this, the naturally occurring LPLS447Xvariant is associated with increased lipolytic function and an anti-atherogenic lipid profile and can therefore be regarded as a gain-of-function mutation. This notion combined with the facts that 20% of the general population carries this prematurely truncated LPL and that it may protect against cardiovascular disease has led to extensive clinical and basic research into this frequent LPL mutant. It is only until recently that we begin to understand the molecular mechanisms that underlie the beneficial effects associated with LPLS447X. This review summarizes the current literature on this interesting LPL variant.
Dimethylarginine Dimethylaminohydrolase 2 Increases Vascular Endothelial Growth Factor Expression Through Sp1 Transcription Factor in Endothelial Cells
Authors: Hasegawa Kazuhiro , Wakino Shu , Tanaka Toru , Kimoto Masumi , Tatematsu Satoru , Kanda Takeshi , Yoshioka Kyoko , Homma Koichiro , Sugano Naoki , Kurabayashi Masahiko , Saruta Takao , Hayashi Koichi
Published: March 2006

Objectives—

Dimethylarginie dimethylaminohydrolase (DDAH) is a degrading enzyme for asymmetrical dimethylarginine, an endogenous NO synthase inhibitor. The molecular mechanism for DDAH-induced vascular endothelial growth factor (VEGF) expression was examined.

Methods and Results—

Although the transfection of expression vectors for 2 isoforms of DDAH, DDAH1, or DDAH2 increased DDAH activity in bovine aortic endothelial cells and human umbilical vein endothelial cells, expression and secretion of VEGF were increased only in DDAH2-transfected cells. Knocking down the DDAH2 gene reduced VEGF production, and DDAH2 overexpression enhanced both proliferation and migration of endothelial cells. The VEGF promoter activity was increased by DDAH2 transfection, which was not blocked by an NO synthase (NOS) inhibitor but required the Sp1 sites. DDAH2 overexpression increased nuclear protein levels bound to Sp1 oligonucleotides in endothelial cells. Sp1 small interfering RNA blocked DDAH2-induced upregulation of VEGF. DDAH2 transfection increased nuclear and threonine-phosphorylation levels of Sp1 in a protein kinase A (PKA)–dependent manner. Protein–protein interaction between DDAH2 and PKA was enhanced in DDAH2-transfected cells.

Conclusions—

DDAH2 upregulated the expression of VEGF through Sp1-dependent and NO/NOS system-independent promoter activation. DDAH2-increased Sp1 DNA binding activity was PKA dependent. These mechanisms may provide a novel therapeutic strategy for VEGF-related vasculopathies such as atherosclerosis.
A Simple Method of Plaque Rupture Induction in Apolipoprotein E–Deficient Mice
Authors: Sasaki Takeshi , Kuzuya Masafumi , Nakamura Kae , Cheng Xian Wu , Shibata Tami , Sato Kohji , Iguchi Akihisa
Published: March 2006

Objective—

The development of a murine model of atherosclerotic plaque rupture.

Methods and Results—

The left common carotid arteries of male apolipoprotein E (apoE)–deficient mice (9 weeks old) were ligated just proximal to their bifurcations. After 4 weeks on a standard diet, the mice received polyethylene cuff placement just proximal to the ligated site, and the animals were then processed for morphological studies at specific time points. Ligation of the carotid artery in apoE-deficient mice for 4 weeks induced marked intimal hyperplasia, which is a lipid- and collagen-rich lesion that contains a number of macrophages, T lymphocytes, and smooth muscle cells. Subsequently, the cuff placement evoked intraplaque hemorrhage and plaque rupture with fibrin(ogen)-positive luminal thrombus in this region accompanying a decrease in collagen content as well as an increase in apoptotic cells in the intima within a few days after cuff placement.

Conclusions—

We demonstrated the murine model of human plaque rupture, which is simple, fast, and highly efficient. This model would help us not only to understand the mechanism of human plaque rupture but also to assess various already-known and as-yet-unknown agents in the future.
Modulation of Smooth Muscle Cell Migration by Members of the Low-Density Lipoprotein Receptor Family
Authors: Bujo Hideaki , Saito Yasushi
Published: March 2006

Low-density lipoprotein receptor family members (LRs) play a key role in the catabolism of many membrane-associated proteins, such as complexes between proteinases and their receptors, in addition to being involved in lipoprotein metabolism as suspected by the hitherto well-established functions of low-density lipoprotein receptor, in a variety of tissues. Recent studies using receptor-deficient or -overexpressing animals and cells have suggested that certain LRs are important regulators of the migration (and proliferation) of vascular smooth muscle cells (SMCs). LR expression is markedly induced in intimal or medial SMCs during the formation of atherosclerotic lesions. Because LRs can modulate the activity of the urokinase-type plasminogen activator (uPA) receptor and possibly of the platelet-derived growth factor (PDGF) receptor, LRs may influence the migration of SMCs through functional modulation of these membrane receptors. Therefore, SMC migration may be regulated by time-restricted expression of LRs. In agreement with the concept of functional interaction between LRs and membrane signaling receptors, a negative regulator of uPA receptor protein catabolism, LR11, has been identified. Statins modulate the PDGF-induced migration of intimal SMCs via the LR11/uPA receptor cascade. Selective modification of the LRs/uPA receptor/PDGF receptor systems in SMCs may be important for suppression of atherosclerotic plaque formation as well as for preventing intimal thickening after angioplasty.
Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans
Authors: Millar John S. , Brousseau Margaret E. , Diffenderfer Margaret R. , Hugh P. , Barrett R. , Welty Francine K. , Faruqi Aisha , Wolfe Megan L. , Nartsupha Chorthip , Digenio Andres G. , Mancuso James P. , Dolnikowski Gregory G. , Schaefer Ernst J. , Rader Daniel J.
Published: March 2006

Objective—

Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins.

Methods and Results—

Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production.

Conclusions—

These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.
Granulocyte Colony Stimulating Factor Directly Inhibits Myocardial Ischemia-Reperfusion Injury Through Akt–Endothelial NO Synthase Pathway
Authors: Ueda Kazutaka , Takano Hiroyuki , Hasegawa Hiroshi , Niitsuma Yuriko , Qin Yingjie , Ohtsuka Masashi , Komuro Issei
Published: March 2006

Objective—

Granulocyte colony stimulating factor (G-CSF) has been reported recently to prevent cardiac remodeling and dysfunction after acute myocardial infarction through signal transducer and activator of transcription 3 (STAT3). In this study, we examined acute effects of G-CSF on the heart against ischemia-reperfusion injury.

Methods and Results—

Rat hearts were subjected to global 35-minute ischemia and 120-minute reperfusion in Langendorff system with or without G-CSF (300 ng/mL). G-CSF administration was started at the onset of reperfusion. Triphenyltetrazolium chloride staining revealed that G-CSF markedly reduced the infarct size. G-CSF strongly activated Janus kinase 2 (Jak2), STAT3, extracellular signal-regulated kinase (ERK), Akt, and endothelial NO synthase (NOS) in the hearts subjected to ischemia followed by 15-minute reperfusion. The G-CSF–induced reduction in infarct size was abolished by inhibitors of phosphatidylinositol 3-kinase, Jak2, and NOS but not of mitogen-activated protein kinase kinase (MEK).

Conclusions—

These results suggest that G-CSF acts directly on the myocardium during ischemia-reperfusion injury and has acute nongenomic cardioprotective effects through the Akt–endothelial NOS pathway.
The Di-Leucine Motif Contributes to Class A Scavenger Receptor-Mediated Internalization of Acetylated Lipoproteins
Authors: Chen Yaoyu , Wang Xiaohua , Ben Jingjing , Yue Shen , Bai Hui , Guan Xiaoxiang , Bai Xiaoming , Jiang Li , Ji Yong , Fan Leming , Chen Qi
Published: March 2006

Objective—The di-leucine motif exists in the intracellular domains of certain cell surface receptors, participating in the receptor-mediated endocytosis. The present study was aimed at determining the role of the di-leucine motif in class A scavenger receptor (SR-A)-mediated ligand endocytosis.

Methods and Results—cDNA coding for a mutant (SR-A mutant N3132LM) with deletion of the di-leucine structure was transfected into Chinese hamster ovary (CHO) cells. Compared with wild-type SR-A–expressing cells, the cells expressing the SR-A mutant N3132LM showed a significant decrease in uptake but almost no change in binding of the SR-A ligand acetylated low-density lipoprotein (AcLDL). Western blot analysis revealed coimmunoprecipitation of SR-A mutant and clathrin from the lysates of the mutant but not wild-type CHO cells, suggesting that AcLDL-bound SR-A mutant N3132LM is associated with the clathrin-coated pit of cellular membrane. Removal of the first 27 amino acid residues from the SR-A N-terminus further reduced AcLDL uptake by the cells with the di-leucine motif mutation.

Conclusions—The di-leucine motif of SR-A intracellular domain contributes to the SR-A–mediated cellular internalization of AcLDL. Di-leucine pair exists in the cytoplasmic domain of class A scavenger receptor. The cells expressing di-leucine mutants showed decreased uptake and unchanged binding of AcLDL. The di-leucine pair was not associated to coated pits. It suggests that di-leucine motif acts as a signal sequence to mediate SR-A into cell.
Impact of TASK-1 in Human Pulmonary Artery Smooth Muscle Cells
Authors: Olschewski Andrea , Li Yingji , Tang Bi , Hanze Jörg , Eul Bastian , Bohle Rainer M. , Wilhelm Jochen , Morty Rory E. , Brau Michael E. , Weir E. Kenneth , Kwapiszewska Grazyna , Klepetko Walter , Seeger Werner , Olschewski Horst
Published: March 2006

The excitability of pulmonary artery smooth muscle cells (PASMC) is regulated by potassium (K
+
) conductances. Although studies suggest that background K
+
currents carried by 2-pore domain K
+
channels are important regulators of resting membrane potential in PASMC, their role in human PASMC is unknown. Our study tested the hypothesis that TASK-1 leak K
+
channels contribute to the K
+
current and resting membrane potential in human PASMC. We used the whole-cell patch-clamp technique and TASK-1 small interfering RNA (siRNA). Noninactivating K
+
current performed by TASK-1 K
+
channels were identified by current characteristics and inhibition by anandamide and acidosis (pH 6.3), each resulting in significant membrane depolarization. Moreover, we showed that TASK-1 is blocked by moderate hypoxia and activated by treprostinil at clinically relevant concentrations. This is mediated via protein kinase A (PKA)-dependent phosphorylation of TASK-1. To further confirm the role of TASK-1 channels in regulation of resting membrane potential, we knocked down TASK-1 expression using TASK-1 siRNA. The knockdown of TASK-1 was reflected by a significant depolarization of resting membrane potential. Treatment of human PASMC with TASK-1 siRNA resulted in loss of sensitivity to anandamide, acidosis, alkalosis, hypoxia, and treprostinil. These results suggest that (1) TASK-1 is expressed in human PASMC; (2) TASK-1 is hypoxia-sensitive and controls the resting membrane potential, thus implicating an important role for TASK-1 K
+
channels in the regulation of pulmonary vascular tone; and (3) treprostinil activates TASK-1 at clinically relevant concentrations via PKA, which might represent an important mechanism underlying the vasorelaxing properties of prostanoids and their beneficial effect in vivo.
Ablation of Cardiac Myosin-Binding Protein-C Accelerates Stretch Activation in Murine Skinned Myocardium
Authors: Stelzer Julian E. , Dunning Sandy B. , Moss Richard L.
Published: March 2006

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament accessory protein that binds tightly to myosin, but despite evidence that mutations in the cMyBP-C gene comprise a frequent cause of hypertrophic cardiomyopathy, relatively little is known about the role(s) of cMyBP-C in myocardium. Based on earlier studies demonstrating the potential importance of stretch activation in cardiac contraction, we examined the effects of cMyBP-C on the stretch activation responses of skinned ventricular preparations from wild-type (WT) and homozygous cMyBP-C knockout mice (cMyBP-C
−/−
) previously developed in our laboratory. Sudden stretch of skinned myocardium during maximal or submaximal Ca
2+
activations resulted in an instantaneous increase in force that quickly decayed to a minimum and was followed by a delayed redevelopment of force (ie, stretch activation) to levels greater than prestretch force. Ablation of cMyBP-C dramatically altered the stretch activation response, ie, the rates of force decay and delayed force transient were accelerated compared with WT myocardium. These results suggest that cMyBP-C normally constrains the spatial position of myosin cross-bridges, which, in turn, limits both the rate and extent of interaction of cross-bridges with actin. We propose that ablation of cMyBP-C removes this constraint, increases the likelihood of cross-bridge binding to actin, and speeds the rate of delayed force development following stretch. Regardless of the specific mechanism, acceleration of cross-bridge cycling in cMyBP-C
−/−
myocardium could account for the abbreviation of systolic ejection in this mouse as a direct consequence of premature stretch activation of ventricular myocardium.
Altered S-Phase Kinase-Associated Protein-2 Levels Are a Major Mediator of Cyclic Nucleotide–Induced Inhibition of Vascular Smooth Muscle Cell Proliferation
Authors: Wu Yih-Jer , Bond Mark , Sala-Newby Graciela B. , Newby Andrew C.
Published: March 2006

Cyclic nucleotides inhibit vascular smooth muscle cell (VSMC) proliferation but the underlying molecular mechanisms are incompletely understood. We studied the role of S-phase kinase-associated protein-2 (Skp2), an F-box protein of SCF
Skp2
ubiquitin ligase responsible for polyubiquitylation of and subsequent proteolysis of p27
Kip1
, a key step leading to cell cycle progression. Skp2 mRNA and protein were upregulated in mitogen-stimulated VSMCs and after balloon injury in rat carotid arteries, where the time course and location of Skp2 expression closely paralleled that of proliferating cell nuclear antigen. Skp2 small interference RNA (siRNA) reduced Skp2 expression, increased p27
Kip1
levels, and inhibited VSMC proliferation in vitro. cAMP-elevating agents prominently inhibited VSMC proliferation and Skp2 expression through inhibiting Skp2 transcription as well as decreasing Skp2 protein stability. Consistent with this, activation of protein kinase A, a downstream target of cAMP, was shown to negatively regulate focal adhesion kinase (FAK) phosphorylation and Skp2 expression. Adenovirus-mediated Skp2 expression reversed cAMP-induced p27
Kip1
upregulation and rescued cAMP-related S-phase entry inhibition up to 50%. 8-Bromo-cGMP also moderately reduced Skp2 and cell proliferation when VSMCs were incubated with low serum concentration. Interestingly, we showed that 8-bromo-cGMP inhibited Skp2 expression also through activation of protein kinase A, not protein kinase G, which conversely enhanced FAK
Y397
phosphorylation and Skp2 expression. After balloon injury of rat carotid arteries, local forskolin treatment significantly reduced FAK
Y397
phosphorylation, Skp2 expression, VSMC proliferation, and subsequent neointimal thickening. These data demonstrate for the first time that Skp2 is an important factor in VSMC proliferation and its inhibition by cyclic nucleotides.
How Critical Is Fibrous Cap Thickness to Carotid Plaque Stability?
Authors: Li Zhi-Yong , Howarth Simon P.S. , Tang Tjun , Gillard Jonathan H.
Published: March 2006

Background and Purpose—

Acute cerebral ischemic events are associated with rupture of vulnerable carotid atheroma and subsequent thrombosis. Factors such as luminal stenosis and fibrous cap thickness have been thought to be important risk factors for plaque rupture. We used a flow–structure interaction model to simulate the interaction between blood flow and atheromatous plaque to evaluate the effect of the degree of luminal stenosis and fibrous cap thickness on plaque vulnerability.

Methods—

A coupled nonlinear time-dependent model with a flow–plaque interaction simulation was used to perform flow and stress/strain analysis in a stenotic carotid artery model. The stress distribution within the plaque and the flow conditions within the vessel were calculated for every case when varying the fibrous cap thickness from 0.1 to 2 mm and the degree of luminal stenosis from 10% to 95%. A rupture stress of 300 kPa was chosen to indicate a high risk of plaque rupture. A 1-sample
t
test was used to compare plaque stresses with the rupture stress.

Results—

High stress concentrations were found in the plaques in arteries with >70% degree of stenosis. Plaque stresses in arteries with 30% to 70% stenosis increased exponentially as fibrous cap thickness decreased. A decrease of fibrous cap thickness from 0.4 to 0.2 mm resulted in an increase of plaque stress from 141 to 409 kPa in a 40% degree stenotic artery.

Conclusions—

There is an increase in plaque stress in arteries with a thin fibrous cap. The presence of a moderate carotid stenosis (30% to 70%) with a thin fibrous cap indicates a high risk for plaque rupture. Patients in the future may be risk stratified by measuring both fibrous cap thickness and luminal stenosis.
Reduced Risk Factors for Vascular Disorders in Parkinson Disease Patients
Authors: Scigliano Giulio , Musicco Massimo , Soliveri Paola , Piccolo Immacolata , Ronchetti Gabriele , Girotti Floriano
Published: March 2006

Background and Purpose—

Sympathetic hyperactivity is a contributing cause of vascular disorders because it increases blood pressure, blood sugar, and blood lipids. Pervasive compromise of the central and peripheral autonomic nervous systems is common in idiopathic Parkinson disease (IPD) resulting in reduced sympathetic and parasympathetic function. We hypothesized that IPD was associated with reduced prevalence of cardiovascular disease risk factors as a result of reduced sympathetic activity.

Methods—

We performed a retrospective case-control study on 178 newly diagnosed consecutive IPD patients, and 533 age- (±3 years) and sex-matched controls with other neurological diseases seen over the same period at the same hospital. For each case and control the following were noted on admission: smoking, diabetes, hypertension, body mass index, serum glucose, plasma cholesterol, triglycerides and total lipid levels, and blood pressure.

Results—

Diabetes, history of smoking, high blood pressure, high blood glucose, high blood cholesterol, and triglycerides were significantly less frequent in IPD than controls.

Conclusions—

IDP is a natural model of impaired hypothalamic-pituitary-adrenal axis activity and generalized sympathetic denervation. We interpret the association of untreated IPD with reduced vascular diseases risk factors as attributable to reduced autonomic activity, suggesting that autonomic hyperactivity may be involved in the pathogenesis of vascular disorders.
Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS)
Authors: Furlan Anthony J. , Eyding Dirk , Albers Gregory W. , Al-Rawi Yasir , Lees Kennedy R. , Rowley Howard A. , Sachara Christian , Soehngen Mariola , Warach Steven , Hacke Werner
Published: March 2006

Background and Purpose—

Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke.

Methods—

DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 μg/kg and 125 μg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined.

Results—

Thirty-seven patients were randomized and received treatment (intent-to-treat; placebo: n=8; 90 μg/kg: n=14; 125 μg/kg: n=15). No symptomatic intracranial hemorrhage occurred. Reperfusion was achieved in 37.5% (95% CI [8.5; 75.5]) of placebo patients, 18.2% (2.3; 51.8) of patients treated with 90 μg/kg desmoteplase, and 53.3% (26.6; 78.7) of patients treated with 125 μg/kg desmoteplase. Good clinical outcome at 90 days occurred in 25.0% (3.2; 65.1) treated with placebo, 28.6% (8.4; 58.1) treated with 90 μg/kg desmoteplase and 60.0% (32.3; 83.7) treated with 125 μg/kg desmoteplase. In the target population (n=25), the difference compared with placebo increased and was statistically significant for good clinical outcome with 125 μg/kg desmoteplase (
P
=0.022).

Conclusions—

Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 μg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS).
The Arctic Ground Squirrel Brain Is Resistant to Injury From Cardiac Arrest During Euthermia
Authors: Dave Kunjan R. , Prado Ricardo , Raval Ami P. , Drew Kelly L. , Perez-Pinzon Miguel A.
Published: March 2006

Background and Purpose—

Hetereothermic mammals tolerate hypoxia during euthermy and torpor, and evidence suggests this tolerance may extend beyond hypoxia to cerebral ischemia. During hibernation, CA1 hippocampal neurons endure extreme fluctuations in cerebral blood flow during transitions into and out of torpor as well as reductions in cerebral blood flow during torpor. In vitro studies likewise show evidence of ischemia tolerance in hippocampal slices harvested from euthermic ground squirrels; however, no studies have investigated tolerance in a clinically relevant model of in vivo global cerebral ischemia. The purpose of the present study was to test the hypothesis that the euthermic Arctic ground squirrel (AGS;
Spermophillus parryii
) is resistant to injury from asphyxial cardiac arrest (CA).

Methods—

Estrous-matched female rats were used as a positive control. Female euthermic AGS and rats were subjected to 8-minute CA. At the end of 7 days of reperfusion, AGS and rats were fixed for histopathological assessment.

Results—

In rats subjected to CA, the number of ischemic neurons was significantly higher (
P
<0.001) compared with control rats in hippocampus and striatum. Cortex was mildly injured. Surprisingly, neuronal counts in AGS were not significantly different in CA and control groups in these brain regions.

Conclusion—

These data demonstrate that AGS are remarkably tolerant to global cerebral ischemia during euthermia. A better understanding of the mechanisms by which AGS tolerate severe reductions in blood flow during euthermia may provide novel neuroprotective strategies that may translate into significant improvements in human patient outcomes after CA.
Cerebral Blood Flow Threshold of Ischemic Penumbra and Infarct Core in Acute Ischemic Stroke
Authors: Bandera Elisabetta , Botteri Marco , Minelli Cosetta , Sutton Alex , Abrams Keith R. , Latronico Nicola
Published: March 2006

Background and Purpose—

Cerebral blood flow (CBF) reduction below critical thresholds discriminates between irreversible infarct core, penumbra, and benign oligemia (penumbra that recovers spontaneously). Thresholds are based on animal studies, and their diagnostic accuracy in humans has never been established. The purpose of this study was to assess the evidence available on CBF thresholds for infarct core and penumbra in adult stroke patients.

Methods—

Electronic database searching using Medline, Embase and the Cochrane Library, crosschecking of references, and contact with experts and authors of primary studies was used. Studies on adult stroke patients were included if they compared CBF measurements with a diagnostic gold standard (follow-up brain CT/MRI), and reported CBF thresholds. Two reviewers independently extracted the data and assessed study quality.

Results—

A meta-analysis could not be carried out because of insufficient data. The optimal reported CBF thresholds varied widely, from 14.1 to 35.0 and from 4.8 to 8.4 mL/100 g per minute for penumbra and infarct core, respectively.

Conclusions—

The use of CBF thresholds in commercial software for imaging methods cannot be recommended without further evaluation.
Lifetime Cost of Ischemic Stroke in Germany: Results and National Projections From a Population-Based Stroke Registry
Authors: Kolominsky-Rabas Peter L. , Heuschmann Peter U. , Marschall Daniela , Emmert Martin , Baltzer Nikoline , Neundörfer Bernhard , Schöffski Oliver , Krobot Karl J.
Published: March 2006

Background and Purpose—

The number of stroke patients and the healthcare costs of strokes are expected to rise. The objective of this study was to determine the direct costs of first ischemic stroke and to estimate the expected increase in costs in Germany.

Methods—

An incidence-based, bottom-up, direct-cost-of-ischemic-stroke study from the third-party payer’s perspective was performed, incorporating 10-year survival data and 5-year resource use data from the Erlangen Stroke Registry. Discounted lifetime year 2004 costs per case were obtained and applied to the expected age and sex evolution of the German resident population in the period 2006 to 2025.

Results—

The overall cost per first-year survivor of first-ever ischemic stroke was estimated to be 18 517 euros (EUR). Rehabilitation accounted for 37% of this cost, whereas in subsequent years outpatient care was the major cost driver. Discounted lifetime cost per case was 43 129 EUR overall and was higher in men (45 549 EUR) than in women (41 304 EUR). National projections for the period 2006 to 2025 showed 1.5 million and 1.9 million new cases of ischemic stroke in men and women, respectively, at a present value of 51.5 and 57.1 billion EUR, respectively.

Conclusions—

The number of stroke patients and the healthcare costs of strokes in Germany will rise continuously until the year 2025. Therefore, stroke prevention and reduction of stroke-related disability should be made priorities in health planning policies.
Spinal Cord Stimulation in the Treatment of Peripheral Vascular Disease: Results of a Single-Center Study of 258 Patients
Authors: Horsch Svante , Schulte Stefan , Hess Stefan
Published: March 2006

This report is of a retrospective study of data from 258 patients who received spinal cord stimulation (SCS) for the treatment of peripheral vascular disease as a result of arteriosclerosis. The patients’ clinical outcomes were monitored over a period of 18 months. In patients with a low baseline transcutaneous oxygen pressure (TcPO2) value of <10 mm Hg, limb survival at 18 months of follow-up (estimated by use of Kaplan-Meier survival analysis) was 77.8%, and this was even higher, at 89.5%, in patients with a medium baseline TcPO2 value of 10-30 mm Hg. This successful treatment was accompanied by a sustained increase in TcPO2 values to approximately 30 mm Hg in both of these groups. In looking at diabetic and nondiabetic patients, there is no difference in limb survival as a result of the treatment. It is concluded that SCS is an effective therapy in improving limb survival in patients with peripheral vascular disease. In addition, TcPO2 values at baseline may be a useful predictor of treatment outcome.
Time-Resolved Contrast-Enhanced Magnetic Resonance Angiography of the Lower Extremity
Authors: Krause Ulrich Josef , Pabst Thomas , Kenn Werner , Wittenberg Guenther , Hahn Dietbert
Published: March 2006

The aim of this prospective study was to evaluate the feasibility and clinical use of time-resolved magnetic resonance angiography (MRA) of the lower extremity compared to intraarterial digital subtraction angiography (IA-DSA). Twenty-two patients suffering from peripheral arterial occlusive disease underwent MRA and IA-DSA. MRA examinations were performed on a 1.5 T system equipped with a 4-element-array coil. The area from the distal abdominal aorta to the distal lower limb was covered by 2-3 examination steps. A T1-weighted gradient echo sequence with a temporal resolution of 7-10 s was used. Single-dose contrast material (0.1 mm/kg) was injected with a flow rate of 2 mL/s, followed by a 40 mL saline flush. Pre and post contrast images were subtracted, and the subtracted data set was postprocessed with maximum intensity projection (MIP). In all patients diagnostic images could be obtained. Problems with venous overlay or incomplete arterial filling were not present. Sensitivity for the detection of relevant stenoses (>50%) was 96.7%, specificity was 97%. Concerning the detection of occlusions, sensitivity was 97.8%, specificity was 99.2%. Time-resolved contrast-enhanced MRA of the lower extremity is a robust procedure with high accuracy in the detection of relevant stenoses and occlusions.
Validation of a New Method of Detecting Peripheral Artery Disease by Determination of Ankle-Brachial Index Using an Automatic Blood Pressure Device
Authors: Benchimol Alain , Bernard Virginie , Pillois Xavier , Hong Nghi Tran , Benchimol Daniel , Bonnet Jacques
Published: March 2006

Peripheral artery disease (PAD) is a predictor of total and cardiovascular mortality; its most valuable simple index is the ankle-brachial index (ABI). The present study was designed to assess whether a commercially available automatic device could be used to determine ABI in comparison with the classical Doppler method. The ABI was defined as the ratio of systolic blood pressure at each ankle to the maximal brachial systolic pressure, a pathological index being defined for a ratio <0.90. The ABI were calculated in 219 consecutive patients (aged 55 ±19 years) with systolic blood pressure measured either by using a mercury sphygmo-manometer and a continuous-wave Doppler probe or an automatic manometer Omron M4. This device has been validated for measurements in upper limbs, and so the authors undertook validation in the lower limbs versus intraarterial measurements. There was an excellent correlation between intraarterial measurements and automatic readings in the range of 70-220 mm Hg, r =0.99, p<0.001. The systolic pressures measured in upper limbs correlated well in the right ( r =0.87, p<0.001) and the left ( r =0.89, p<0.001) upper limbs; and in the left ( r =0.72, p<0.001) and the right ( r =0.68, p<0.001) lower limbs. Correlations between ABI in both methods were good in the left ( r =0.66, p<0.001) and the right ( r =0.61, p<0.001) lower limbs. The sensitivity (76%), specificity (95%), positive predictive value (86%), negative predictive value (90%), and global accuracy (89%) of a pathological automatic index to predict an abnormal Doppler index were good. The use of a simple, automatic blood pressure device to determine ABI appears feasible, easy, and precise. It would provide a practical tool for physicians not trained in Doppler to detect PAD.
Dyslipoproteinemia and Peripheral Arterial Occlusive Disease
Authors: Kröger Knut
Published: March 2006

Peripheral arterial occlusive disease (PAOD) is common in older age. PAOD is associated with an increased risk of vascular events (eg, myocardial infarction or stroke). Therefore, the prevention and treatment of PAOD is important, especially at a time when the elderly population is increasing. There is an association between lipid abnormalities and the risk of developing PAOD. However, it is not yet definitively established that early intervention with lipid-lowering drugs prevents the development of PAOD. There is evidence that vascular events in patients with PAOD can be significantly reduced by statins and that the symptoms associated with PAOD are improved by this treatment. There is an urgent need for appropriately designed lipid-lowering trials in patients with PAOD.
Large-Artery Hemodynamics After Acute Alcohol Administration in Young, Healthy Volunteers
Authors: Fazio Massimiliano , Bardelli Moreno , Fabris Bruno , Macaluso Loredana , Fiammengo Fabio , Vran Franco , Bossi Monica , Candido Riccardo , Gerloni Riccardo , Carretta Renzo
Published: March 2006

The objective of the present study was to investigate the acute effects of alcohol on blood flow volume and velocity, on wall motion of superficial large arteries, and on systemic hemodynamics in humans. In 10 healthy volunteers small doses of alcohol were administered either orally (0.3 g/kg in 250 mL water) or intravenously (7.5 mg/kg/minute in 250 mL saline in 40 minutes). The effects of alcohol were compared with those of saline 250 mL infused for 40 minutes (6.25 mL/min). Blood velocity and systodiastolic changes of wall diameter were measured in the common carotid, femoral, and brachial arteries simultaneously with cardiac output and finger blood pressure. Skin temperature was measured at the cheek, hand, and toe. Ethanol administration caused a transitory blood pressure increase accompanied by a rise in peripheral resistances at 20 minutes. Arterial blood flow was not changed by either mode of alcohol administration at any of the measurement sites. However, this result was achieved through different compensatory mechanisms in each artery. In fact, mean carotid diameter increased after both oral and intravenous ethanol administration but remained unchanged at the brachial and femoral level. Mean blood velocity was reduced after alcohol administration at the carotid but was unchanged at the brachial and femoral level after oral or intravenous alcohol administration. Skin temperature increased 20 minutes after alcohol administration at all sites. This study shows that although acute alcohol administration does not change blood flow in superficial large arteries, it causes different autoregulatory local responses of vessel walls.
Prospective Evaluation of von Willebrand Factor Release After Multiple and Single Stenting
Authors: Heper Gulumser , Murat S. Namık , Durmaz Tahir , Kalkan Faruk
Published: March 2006

The hypothesis that von Willebrand factor (vWf) release after multiple coronary stenting may be higher than release after single coronary stenting was tested. Preliminary data suggest that multiple stenting is a predictor of thrombosis, and vWf levels in the coronary sinus reflect coronary endothelial injury. Therefore vWf as an indicator of thrombogenesis and endothelial injury was studied. vWf levels were obtained in the coronary sinus at the prestenting and poststenting period in 50 patients with ischemic heart disease who underwent elective coronary stenting (25 patients in single stent group and 25 patients in multiple stent group). Eight subjects who underwent diagnostic coronary angiography were used as controls. vWf levels increased significantly after multiple stenting and vWf levels were significantly different from vWf levels after single stenting. In single stent group, vWf levels in type C lesions were significantly different from levels detected in type A and B lesions. Multiple coronary stenting induces a rapid increase in vWf expression in the coronary circulation. These changes may contribute to the pathogenesis of acute or subacute stent thrombosis and restenosis after multiple stenting.
Effects of AT1 Receptor Antagonist Losartan on sICAM-1 and TNF-a Levels in Uncomplicated Hypertensive Patients
Authors: Sardo Maria A. , Castaldo Maria , Cinquegrani Maurizio , Bonaiuto Michele , Fontana Luisa , Campo Salvatore , Campo Giuseppe M. , Altavilla Domenica , Saitta Antonino
Published: March 2006

This study was designed to determine whether the levels of soluble intercellular adhesion molecule-1 (sICAM-1) and tumor necrosis factor-a (TNF-a) were elevated in subjects with uncomplicated hypertension who presented with no other risk factors or evidence of atherosclerosis. The effects of administration of an angiotensin type-1 antagonist (losartan) on the serum concentrations of these molecules were also examined. Twenty hypertensive (HT) subjects (12 men and 8 women, mean age 49.1 ±7.2 years) without other risk factors or cardiovascular disease received placebo for 4 weeks. The patients were then treated with losartan (50 mg/day) for 24 weeks. After 4, 12, and 24 weeks of losartan treatment, sICAM-1 and TNF-a levels were measured. The same parameters were measured in 20 normotensive control subjects (C), matched for sex and age. HT had sICAM-1 and TNF-a basal values higher than C (respectively 351.7 ±97.4 vs 201.6 ±32.3 ng/mL, p<0.001 and 31.8 ±2.4 vs 15.3 ±2.2 pg/mL, p<0.001). There was a positive correlation between sICAM-1 and TNF-a levels, but no correlation in HT between the average diastolic and systolic blood pressure (clinic and ambulatory monitoring) and the sICAM-1 or TNF-a levels was observed. Losartan treatment caused a significant decrease of sICAM-1 levels at the end of the first month of treatment (300.2 ±64.4 ng/mL, p<0.05), but the values reverted to the basal levels at the following time points. No variation of TNF-a levels during losartan treatment was observed. These results show that patients with uncomplicated mild essential hypertension presented with high plasma ICAM-1 and TNF-a concentrations. Although all the patients were responsive to the antihypertensive treatment with losartan, their plasma concentrations of TNF-a were not modified, and sICAM-1 concentrations decreased only for a short period of time. This suggests that in uncomplicated hypertension other factors besides the blood pressure modulate the endothelial inflammation.
Successful Intervention for High-Output Cardiac Failure Caused by Massive Renal Arteriovenous Fistula
Authors: Khawaja Azimuddin T. , McLean Gordon K. , Srinivasan Venkatraman
Published: March 2006

Renal arteriovenous fistula is a rare clinical entity that may produce high-output cardiac failure. This report describes the case of an 81-year-old woman in whom recurrent episodes of congestive heart failure developed over a relatively short time. A massive renal arteriovenous fistula was visualized by CT scan and arteriography. Successful embolization was performed under hemodynamic monitoring with complete resolution of the patient’s symptoms.
Subclavian Steal Syndrome in Acute Myocardial Infarction Masquerading as Acute Embolism to Left Upper Extremity
Authors: Komenaka Ian K. , Nguyen Eric T. , Oyogoa Sylvanus O. , deGraft-Johnson John B. , Gardezi Syed Q.
Published: March 2006

Subclavian steal syndrome is an uncommon entity diagnosed with angiography after neurologic symptoms occur during activity with the upper extremity. Cardiac symptoms or silent ischemia have been described in patients who have undergone cardiac bypass using the ipsilateral internal mammary artery. Our patient presented with acute chest pain radiating to the left upper extremity and a diminished pulse. Angiography to rule out an acute embolus instead revealed subclavian artery occlusion. As atherosclerosis is the most common cause, the ipsilateral subclavian artery should be carefully evaluated, particularly in cardiac patients undergoing coronary angiography. Recognition of coexisting subclavian artery occlusion could prevent cardiac complications that may occur with use of the ipsilateral internal mammary artery during coronary artery bypass surgery.