bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Serum Antibodies to Heat-Shock Protein 65 With Coronary Calcification Levels
Authors: Zhu Jianhui , Katz Richard J. , Quyyumi Arshed A. , Canos Daniel A. , Rott David , Csako Gyorgy , Zalles-Ganley Alexandra , Ogunmakinwa Jibike , Wasserman Alan G. , Epstein Stephen E.
Published: December 2003

Background—

Previous studies demonstrated an association between antibodies to mycobacterial heat-shock protein 65 (mHSP65) and carotid artery thickening. We examined whether mHSP65 antibodies are associated with levels of coronary calcification that appear to reflect preclinical coronary artery disease (CAD).

Methods and Results—

Serum specimens from 201 healthy asymptomatic subjects (52% male; mean age, 56.6 years) undergoing electron-beam computed tomographic imaging were used to measure levels of mHSP65 and human HSP60 antibodies and antibodies to several infectious pathogens. We found that 84% of the study subjects had anti-mHSP65 IgG antibodies. Mean titers of mHSP65 antibodies were higher (1:394 versus 1:267,
P
=0.012) in individuals with than in those without elevated levels of coronary calcium (calcium score ≥150). Increasing titers of mHSP65 antibodies were significantly associated, in a dose-response manner, with elevated levels of coronary calcification. Individuals with the highest titers of mHSP65 antibodies (≥1:800) had an adjusted odds ratio (OR) of 14.3 for having elevated coronary calcium (
P
=0.004). Association of mHSP65 antibodies with elevated coronary calcification levels was independent of CAD risk factors after multivariate adjustment (
P
=0.037). Interestingly, mHSP65 antibody titers were correlated with
Helicobacter pylori
infection (
P
=0.004), which maintained significance after adjustment for CAD risk factors and seropositivities to other pathogens (adjusted OR, 3.1; 95% CI, 1.4 to 6.6). No association was found between antibodies to human HSP60 and levels of coronary calcification.

Conclusions—

Antibodies to mHSP65 are associated with elevated levels of coronary calcification and correlated with
H pylori
infection, suggesting that pathogen-triggered autoimmunity plays a role in early atherosclerosis.
Nitric Oxide and β-Adrenergic Stimulation Are Major Regulators of Preprandial and Postprandial Subcutaneous Adipose Tissue Blood Flow in Humans
Authors: Ardilouze Jean-Luc , Fielding Barbara A. , Currie Jenny M. , Frayn Keith N. , Karpe Fredrik
Published: December 2003

Background—

Blood flow mediates the metabolic and endocrine roles of adipose tissue. We have previously shown that the postprandial adipose tissue blood flow (ATBF) increase is dependent on insulin sensitivity. However, subcutaneous local insulin delivery had no demonstrable effect on either preprandial or postprandial ATBF. We hypothesized that insulin may act indirectly via sympathetic activation, mainly in the postprandial period, and that nitric oxide may be an overall major regulator of subcutaneous ATBF.

Methods and Results—

We investigated the endogenous preprandial and postprandial regulation of ATBF by applying local tissue blockade of β-adrenergic (propranolol), α-adrenergic (phentolamine and yohimbine), and nitric oxide (
N
G
-monomethyl-
l
-arginine, L-NMMA) regulation of blood flow. Healthy subjects (body mass index, 18 to 31 kg/m
2
) were challenged with 75 g glucose for endogenous stimulation of ATBF. We used the novel “microinfusion” technique, which allows for simultaneous local delivery of pharmacological agents (or contralateral saline) and measurement of ATBF with the
133
Xe washout method. Compared with control, the preprandial ATBF was not affected by propranolol but was increased by 21% (
P
<0.013) and 15% (
P
=0.004) with phentolamine and yohimbine, respectively. A decrease of 42% (2.97±0.33 versus 4.75±0.47 mL · min
−1
· 100 g tissue
−1
,
P
<0.01) was seen with L-NMMA. The postprandial response was blunted by 58% (0.81±0.42 versus 1.90±0.44 mL · min
−1
· 100 g tissue
−1
,
P
<0.004) with propranolol, but neither phentolamine, yohimbine, or L-NMMA altered this response.

Conclusions—

Nitric oxide seems to determine the absolute level of ATBF, whereas a major proportion of the postprandial enhancement of ATBF is under β-adrenergic regulation in vivo in humans.
Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats
Authors: Li Meihua , Zheng Can , Sato Takayuki , Kawada Toru , Sugimachi Masaru , Sunagawa Kenji
Published: December 2003

Background—

Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction.

Methods and Results—

Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1±5.9 versus 23.5±4.2 mm Hg,
P
<0.05) and higher maximum dp/dt of left ventricular pressure (4152±237 versus 2987±192 mm Hg/s,
P
<0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75±0.25 versus 3.14±0.22 g/kg,
P
<0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%,
P
=0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death.

Conclusions—

Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.
Antirestenotic Effects of a Locally Delivered Caspase Inhibitor in a Balloon Injury Model
Authors: Beohar Nirat , Flaherty James D. , Davidson Charles J. , Maynard Robert C. , Robbins Joel D. , Shah Atman P. , Choi James W. , MacDonald Lee A. , Jorgensen Jesse P. , Pinto Jack V. , Chandra Sonal , Klaus Heather M. , Wang Norman C. , Harris Kathleen R. , Decker Robert , Bonow Robert O.
Published: December 2003

Background—

The precise role of arterial barotrauma-mediated apoptosis in causing restenosis is unclear. The purpose of this study was to determine if a link exists between angioplasty-mediated medial smooth muscle cell apoptosis and subsequent neointimal hyperplasia.

Methods and Results—

Bilateral iliac artery angioplasty was performed in 25 male New Zealand White rabbits. Simultaneous with balloon injury, each artery was treated locally with either the caspase inhibitor
N
-benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone (ZVAD-fmk) or control. In the acute cohort that was survived to 4 hours (n=10, 7 high dose and 3 low dose), an apoptotic index was calculated using the terminal deoxynucleotidyl TUNEL method. In the intermediate cohort that was survived to 2 weeks (n=5), luminal reendothelialization was measured via CD-31 staining. In the chronic cohort that was survived to 4 weeks (n=10), neointimal area was measured. In the acute cohort, there was a 40% reduction in the apoptotic index with high-dose ZVAD-fmk (
P
=0.008) and a 33% reduction with low-dose ZVAD-fmk (
P
=0.08). At 2 weeks, there was no significant difference in the degree of luminal reendothelialization. However, at 4 weeks, there was a 33% (0.33±0.23 versus 0.22±0.20 mm
2
) (
P
<0.005) reduction in neointimal area in ZVAD-fmk–treated arteries.

Conclusions—

The local delivery of ZVAD-fmk during balloon injury inhibits smooth muscle cell apoptosis. This corresponds to a significant reduction in neointimal proliferation seen at 4 weeks without a significant change in the degree of reendothelialization at 2 weeks.
Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs
Authors: Tonduangu Daniel , Hittinger Luc , Ghaleh Bijan , Le Corvoisier Philippe , Sambin Lucien , Champagne Stéphane , Badoual Thierry , Vincent Fanny , Berdeaux Alain , Crozatier Bertrand , Su Jin Bo
Published: December 2003

Background—

This study examined the effects of chronic bradykinin infusion on hemodynamics and myocardial and endothelial functions during the development of heart failure.

Methods and Results—

Sixteen instrumented dogs were randomized to receive through the left atria either vehicle or bradykinin (1 μg/min) during ventricular pacing (250 bpm, 5 weeks). Hemodynamic and left ventricular (LV) parameters and the vasodilator responses to intravenous acetylcholine (0.3 to 3 μg/kg) and nitroglycerin (1 to 10 μg/kg) were examined in the control and after 3 and 5 weeks of pacing. The expression of endothelial NOS in femoral, carotid, and renal arteries was determined by Western blot analysis. After 3 weeks of pacing, changes in LV diastolic and systolic parameters were significantly lower in bradykinin-treated than vehicle-treated dogs (LV end-diastolic pressure, +10±3 versus +19±2 mm Hg; time constant of LV isovolumic relaxation, +11±2 versus +17±1 ms; LV wall thickening, −33±18% versus −75±9%; and cardiac output, −16±6% versus −32±6%; all
P
<0.05). Compared with vehicle-treated dogs, bradykinin-treated dogs had a reduced rightward shift of the diastolic LV pressure-diameter relation and a reduced diastolic LV wall stress. Similar trends were observed after 5 weeks. The vasodilator response to nitroglycerin was preserved in both groups. The response to acetylcholine was blunted in vehicle-treated but preserved in bradykinin-treated dogs. Vascular endothelial NOS expression decreased in vehicle-treated but was preserved in bradykinin-treated dogs.

Conclusions—

In conscious dogs, chronic bradykinin infusion delays the heart failure progression by preserving LV diastolic and systolic functions and by preserving vascular endothelial function.
Mechanism of ST Elevation and Ventricular Arrhythmias in an Experimental Brugada Syndrome Model
Authors: Kimura Masaomi , Kobayashi Takao , Owada Shingen , Ashikaga Keiichi , Higuma Takumi , Sasaki Shingo , Iwasa Atsushi , Motomura Shigeru , Okumura Ken
Published: December 2003

Background—

Although phase 2 reentry is said to be responsible for initiation of ventricular tachycardia (VT) in Brugada syndrome, information about the activation sequence during VT is limited.

Methods and Results—

We developed an experimental Brugada syndrome model using a canine isolated right ventricular preparation cross-circulated with arterial blood of a supporter dog and examined the VT mechanism. Two plaque electrodes (35×30 mm) containing 96 bipolar electrodes were attached to the endocardium and epicardium. Saddleback and coved types of ST elevation in transmural ECG were induced by pilsicainide, a pure sodium channel blocker, and pinacidil, a K
ATP
channel opener. Eighteen polymorphic VT episodes were recorded in 9 of the 12 preparations associated with ST elevation. Fourteen episodes spontaneously developed in 5 preparations after an extrasystole during basic drive pacing. Analysis of local recovery times revealed increased dispersion especially in epicardium, and the extrasystole originated from a site with a short recovery time, suggesting that phase 2 reentry was its mechanism. The other 4 VTs in 4 preparations were induced by premature stimulation. Analysis of the activation sequences during VT revealed reentry between epicardium and endocardium or reentry around an arc of a functional block confined to epicardium or endocardium with bystander activation of the other.

Conclusions—

Electrical heterogeneity in the recovery phase was induced in this experimental Brugada syndrome model, which can be a substrate for the development of phase 2 reentry and the subsequent reentry around an arc of the functional block, resulting in sustained VT.
Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition With Asymmetrical Dimethylarginine in Humans
Authors: Kielstein Jan T. , Impraim Burcu , Simmel Solveig , Bode-Böger Stefanie M. , Tsikas Dimitrios , Frölich Jürgen C. , Hoeper Marius M. , Haller Hermann , Fliser Danilo
Published: December 2003

Background—

Increased blood concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) have been linked to excess cardiovascular morbidity and mortality and to progression of renal disease. We evaluated systemic cardiovascular effects of ADMA infusion in healthy subjects using invasive techniques, ie, right heart catheter and inulin/para-aminohippurate clearance.

Methods and Results—

Plasma ADMA concentrations encountered in patients with cardiovascular diseases, ie, between 2 and 10 μmol/L, caused a significant (
P
<0.05) decrease in concentrations of plasma cGMP, the main second messenger of NO. In addition, cardiac output was significantly lower (5.3±0.4 versus 5.8±0.6 L/min;
P
<0.05 versus baseline), and systemic vascular resistance was significantly higher (1403±123 versus 1221±100 dyn · s · cm
−5
;
P
<0.05 versus baseline). The infusion of 0.25 mg ADMA · kg
−1
· min
−1
or 3 μg
N
G
-nitro-
l
-arginine methyl ester · kg
−1
· min
−1
, a potent synthetic NOS inhibitor with long action, resulted in a comparable decrease in effective renal plasma flow (from 670±40 to 596±29 mL · min
−1
;
P
<0.05) and an increase in renovascular resistance (from 79±5 to 90±7 mm Hg · mL
−1
· min
−1
;
P
<0.05). Moreover, administration of ADMA caused significant sodium retention and blood pressure increase (both
P
<0.05). The observed effects of ADMA in the systemic circulation were sustained corresponding to a mean plasma half-life of 23.5±6.8 minutes, calculated from plasma ADMA decay curves in healthy subjects.

Conclusions—

Systemic ADMA infusion is responsible for a short-term, modest decrease in cardiac output with comparable decrease in effective renal plasma flow while increasing systemic vascular resistance and blood pressure in a dose-related manner.
Hostile Behaviors Predict Cardiovascular Mortality Among Men Enrolled in the Multiple Risk Factor Intervention Trial
Authors: Matthews Karen A. , Gump Brooks B. , Harris Kelly F. , Haney Thomas L. , Barefoot John C.
Published: December 2003

Background—

Hostility is associated with incident coronary disease in most large population-based studies, but little is known about its association with cardiovascular disease (CVD) mortality in high-risk individuals. The aim of this study was to assess the association of hostility with CVD mortality in the subsequent 16 years in the Multiple Risk Factor Intervention Trial (MRFIT) participants and to explore the influence of hostility in the subset that had a nonfatal CVD event during the trial.

Methods and Results—

We coded the Structured Interview responses of 259 men who died of CVD during the 16 years of follow-up and 259 matching living control subjects. Signs of hostility were assessed by use of the Interpersonal Hostility Assessment Technique. Matching was based on center, intervention group, age, race, and interviewer; covariates included study entry diastolic blood pressure, cholesterol, smoking status, and nonfatal CVD event during the trial. High-hostile men were more likely to die of CVD than were low-hostile men. Adjusted odds ratio (OR) and 95% confidence intervals (CIs) were 1.61, 1.09 to 2.39. After the trial, high-hostile men who also had a nonfatal event during the trial were particularly likely to die of CVD, OR, 5.06, 1.42 to 8.22, compared with low-hostile men without a nonfatal event during the trial.

Conclusions—

Hostility may be a risk factor for CVD mortality among high-risk men. Interventions aimed at anger management and stress reduction along with risk factor modification may be useful for hostile patients.
Arterial Stiffness, Wave Reflections, and the Risk of Coronary Artery Disease
Authors: Weber Thomas , Auer Johann , O’Rourke Michael F. , Kvas Erich , Lassnig Elisabeth , Berent Robert , Eber Bernd
Published: December 2003

Background—

Increased arterial stiffness, determined invasively, has been shown to predict a higher risk of coronary atherosclerosis. However, invasive techniques are of limited value for screening and risk stratification in larger patient groups.

Methods and Results—

We prospectively enrolled 465 consecutive, symptomatic men undergoing coronary angiography for the assessment of suspected coronary artery disease. Arterial stiffness and wave reflections were quantified noninvasively using applanation tonometry of the radial artery with a validated transfer function to generate the corresponding ascending aortic pressure waveform. Augmented pressure (AP) was defined as the difference between the second and the first systolic peak, and augmentation index (AIx) was AP expressed as a percentage of the pulse pressure. In univariate analysis, a higher AIx was associated with an increased risk for coronary artery disease (OR, 4.06 for the difference between the first and the fourth quartile [1.72 to 9.57;
P
<0.01]). In multivariate analysis, after controlling for age, height, presence of hypertension, HDL cholesterol, and medications, the association with coronary artery disease risk remained significant (OR, 6.91;
P
<0.05). The results were exclusively driven by an increase in risk with premature vessel stiffening in the younger patient group (up to 60 years of age), with an unadjusted OR between AIx quartiles I and IV of 8.25 (
P
<0.01) and a multiple-adjusted OR between these quartiles of 16.81 (
P
<0.05).

Conclusions—

AIx and AP, noninvasively determined manifestations of arterial stiffening and increased wave reflections, are strong, independent risk markers for premature coronary artery disease.
Plasma B-Type Natriuretic Peptide Levels in Ambulatory Patients With Established Chronic Symptomatic Systolic Heart Failure
Authors: Tang W.H. Wilson , Girod John P. , Lee Michael J. , Starling Randall C. , Young James B. , Van Lente Frederick , Francis Gary S.
Published: December 2003

Background—

The diagnostic and prognostic values of plasma B-type natriuretic peptide (BNP) testing are established. However, the range of plasma BNP levels present in the setting of chronic, stable systolic heart failure (HF) is unclear.

Methods and Results—

We followed up 558 consecutive ambulatory patients with chronic, stable systolic HF (left ventricular ejection fraction <50%) treated at a specialized outpatient HF clinic between November 2001 and February 2003. Retrospective chart review was performed to determine clinical and functional data at the time of BNP testing (Biosite Triage). The clinical characteristics of patients with plasma BNP levels <100 pg/mL and those with ≥100 pg/mL were compared. In our cohort, 60 patients were considered asymptomatic, and their plasma BNP levels ranged from 5 to 572 pg/mL (median, 147 pg/mL). Of the remaining 498 symptomatic (NYHA functional class II–III) patients, 106 (21.3%) had plasma BNP levels in the “normal” diagnostic range (<100 pg/mL). Patients in this “normal BNP” subgroup were more likely to be younger, to be female, to have nonischemic pathogenesis, and to have better-preserved cardiac and renal function and less likely to have atrial fibrillation.

Conclusions—

In the ambulatory care setting, both symptomatic and asymptomatic patients with chronic, stable systolic HF may present with a wide range of plasma BNP levels. In a subset of symptomatic patients (up to 21% in our cohort), plasma BNP levels are below what would be considered “diagnostic” (<100 pg/mL).
P2Y
12
H2 Haplotype Is Associated With Peripheral Arterial Disease
Authors: Fontana Pierre , Gaussem Pascale , Aiach Martine , Fiessinger Jean-Noël , Emmerich Joseph , Reny Jean-Luc
Published: December 2003

Background—

We recently described a gain-of-function haplotype, called H2, of the adenosine diphosphate (ADP) receptor P2Y
12
gene associated with increased ADP-induced platelet aggregation ex vivo in healthy volunteers. Because platelets play a key role in atherosclerosis and arterial thrombosis, we tested the possible link between the H2 haplotype and the risk of peripheral arterial disease (PAD) in a case-control study.

Methods and Results—

We studied 184 consecutive male patients under 70 years of age with PAD and 330 age-matched control subjects free of symptomatic PAD and with no cardiovascular history. Mean age was 57.1±7.2 years (cases) and 56.7±7.6 years (control subjects). The H2 haplotype was more frequent in patients with PAD than in control subjects (30% and 21%, respectively; OR, 1.6; CI, 1.1 to 2.5;
P
=0.02 in univariate analysis). This association with PAD remained significant in multivariate regression analysis (OR, 2.3; CI, 1.4 to 3.9;
P
=0.002) after adjustment for diabetes, smoking, hypertension, hypercholesterolemia, and other selected platelet receptor gene polymorphisms.

Conclusions—

These data point to a role of the H2 haplotype in atherosclerosis and raise the possibility of relative thienopyridine resistance in carriers of the P2Y
12
H2 haplotype.
Circumstances of Death and Gross and Microscopic Observations in a Series of 200 Cases of Sudden Death Associated With Arrhythmogenic Right Ventricular Cardiomyopathy and/or Dysplasia
Authors: Tabib A. , Loire R. , Chalabreysse L. , Meyronnet D. , Miras A. , Malicier D. , Thivolet F. , Chevalier P. , Bouvagnet P.
Published: December 2003

Background—

Sudden death is a possible consequence of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Prevalence of ARVC/D in unexpected sudden cardiac death (USCD), however, remains imprecise, as do circumstances of death and ARVC/D-associated gross and microscopic findings, especially His bundle anomalies.

Methods and Results—

We reviewed 14 000 forensic autopsies required by judicial authorities from January 1980 to January 1999 in a 2 000 000-resident area. Age, gender, and circumstances of death were recorded. Hearts were examined macroscopically and microscopically. In this series, the ARVC/D group accounted for 200 consecutive cases (10.4%) of USCD, including 108 males and 92 females (average age 32.5 and 34.5 years, respectively). Nearly one third of deaths occurred during the fourth decade of life. Circumstances of death were various, but 75.6% occurred during everyday life events (at home, 63.1%; in the street, 6.6%; or at work, 6.1%); only 7 cases (3.5%) occurred during sports activity. Nineteen cases (9.5%) happened during the perioperative period. Adipose infiltration of the right ventricle was either isolated (20%) or associated with fibrosis (74.5%) and lymphocytes (5.5%). A total of 14.5% of cases had cardiac hypertrophy, assessed by an increase in heart weight and/or left ventricular wall thickness. In most cases, the His bundle and its branches were abnormal either because of infiltration of adipose tissue (8.1%), fibrosis (54.3%), or both (5.6%).

Conclusions—

In ARVC/D, both sexes are equally affected, and there is a peak of risk during the fourth decade. Death most frequently occurs during sedentary activity. His abnormalities and left ventricular hypertrophy may be associated with ARVC/D.
Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling
Authors: Yin Hang , Chao Lee , Chao Julie
Published: December 2003

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene–related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3β) but reduced GSK-3β and caspase-3 activities in the heart. The effects of AM on GSK-3β and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3β but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
High Blood Pressure in Acute Stroke and Subsequent Outcome
Authors: Willmot Mark , Leonardi-Bee Jo , Bath Philip M.W.
Published: December 2003

High blood pressure (BP) is common in acute stroke and might be associated with a poor outcome, although observational studies have given varying results. In a systematic review, articles were sought that reported both admission BP and outcome (death, death or dependency, death or deterioration, stroke recurrence, and hematoma expansion) in acute stroke. Data were analyzed by the Cochrane Review Manager software and are given as odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). Altogether, 32 studies were identified involving 10 892 patients. When all data were included, death was significantly associated with an elevated mean arterial BP ([MABP] OR, 1.61; 95% CI, 1.12 to 2.31) and a high diastolic BP ([DBP] OR, 1.71; 95% CI, 1.33 to 2.48). Combined death or dependency was associated with high systolic BP ([SBP] OR, 2.69; 95% CI, 1.13 to 6.40) and DBP (OR, 4.68; 95% CI, 1.87 to 11.70) in primary intracerebral hemorrhage (PICH). Similarly, high SBP (+11.73 mm Hg; 95% CI, 1.30 to 22.16), MABP (+9.00 mm Hg; 95% CI, 0.92 to 17.08), and DBP (+6.00 mm Hg; 95% CI, 0.19 to 11.81) were associated with death or dependency in ischemic stroke. Combined death or deterioration was associated with a high SBP (OR, 5.57; 95% CI, 1.42 to 21.86) in patients with PICH. In summary, high BP in acute ischemic stroke or PICH is associated with subsequent death, death or dependency, and death or deterioration. Moderate lowering of BP might improve outcome. Acute BP lowering needs to be tested in 1 or more large, randomized trials.
2-Hydroxyoleic Acid
Authors: Alemany Regina , Terés Silvia , Baamonde Carmela , Benet Mikhail , Vögler Oliver , Escribá Pablo V.
Published: December 2003

Recent studies have shown that diets rich in monounsaturated fatty acids (MUFAs) from olive oil, a natural source of oleic acid, have beneficial effects on blood pressure (BP) in hypertensive patients. With this in mind, we investigated whether a synthetic derivative of the MUFA oleic acid, 2-hydroxyoleic acid (2-OHOA), was capable of regulating the BP of Sprague-Dawley rats. Intraperitoneal and oral administration of 2-OHOA to rats induced significant and sustained decreases in BP in a time-dependent manner. Without affecting heart rate, treatments for 7 days provoked reductions in systolic BP of 20 to 26 mm Hg. At the molecular level, the density of Gαs, but not Gαi
2
or Gαo, increased in membranes from the hearts and aortas of 2-OHOA–treated rats, whereas in heart membranes, the density of Gαq/11 and protein kinase Cα proteins was also augmented. These molecular alterations were reflected in the increase in cAMP levels after Gαs protein and β-adrenergic receptor stimulation. On the contrary, inhibitory hormones reduced adenylyl cyclase activity to the same extent in 2-OHOA–treated rats as in vehicle-treated ones. Our results indicate that cardiovascular tissues from 2-OHOA–treated rats exhibited increased cAMP production in response to Gαs activation, which might be attributed to enhanced expression of Gαs proteins. As a result of this change, a significant reduction in systolic BP was observed. Therefore, BP can be lowered by administration of 2-OHOA, which might represent the first member of a new family of antihypertensive drugs.
Glycation, Inflammation, and RAGE
Authors: Yan Shi Fang , Ramasamy Ravichandran , Naka Yoshifumi , Schmidt Ann Marie
Published: December 2003

The cardiovascular complications of diabetes represent the leading cause of morbidity and mortality in affected subjects. The impact of hyperglycemia may be both direct and indirect: indirect consequences of elevated blood glucose lead to generation of advanced glycation endproducts, the products of nonenzymatic glycation/oxidation of proteins/lipids that accumulate in the vessel wall, and are signal transduction ligands for Receptor for AGE (RAGE). Although enhanced in diabetes, AGE accumulation also occurs in euglycemia and aging, albeit to lower degrees, driven by oxidant stress and inflammation. In hyperglycemia, production of 3-deoxyglucosone, at least in part via the polyol pathway, provides an amplification loop to sustain AGE generation, oxidant stress, and vascular activation. Furthermore, recruitment of inflammatory cells bearing S100/calgranulins, also ligands for RAGE, augments vascular dysfunction. We hypothesize that activation of RAGE is a final common pathway that transduces signals from these diverse biochemical and molecular species, leading to cardiovascular perturbation. Ultimately, these pathways synergize to construct a scaffold on which the complications of diabetes in the vasculature and heart may be built. We propose that antagonism of RAGE will provide a unique means to dismantle this scaffold and, thereby, suppress initiation/progression of vascular disease and cardiac dysfunction that accompany diabetes and aging.
Modulation of Thin Filament Activation by Breakdown or Isoform Switching of Thin Filament Proteins
Authors: Marston Steven B. , Redwood Charles S.
Published: December 2003

In the heart, the contractile apparatus is adapted to the specific demands of the organ for continuous rhythmic contraction. The specialized contractile properties of heart muscle are attributable to the expression of cardiac-specific isoforms of contractile proteins. This review describes the isoforms of the thin filament proteins actin and tropomyosin and the three troponin subunits found in human heart muscle, how the isoform profiles of these proteins change during development and disease, and the possible functional consequences of these changes. During development of the heart, there is a distinctive switch of isoform expression at or shortly after birth; however, during adult life, thin filament protein isoform composition seems to be stable despite protein turnover rates of 3 to 10 days. The pattern of isoforms of actin, tropomyosin, troponin I, troponin C, and troponin T is not affected by aging or heart disease (ischemia and dilated cardiomyopathy). The evidence for proteolysis of thin filament proteins in situ during ischemia and stunning is evaluated, and it is concluded that C-terminal cleavage of troponin I is a feature of irreversibly injured myocardium but may not play a role in reversible stunning.
Ras, Akt, and Mechanotransduction in the Cardiac Myocyte
Authors: Sugden Peter H.
Published: December 2003

The Ras subfamily of 21-kDa (“small”) guanine nucleotide binding proteins [which includes Ha-Ras, Ki(A)-Ras, Ki(B)-Ras, and N-Ras] is universally important in regulating intracellular signaling events in mammalian cells and controls their growth, proliferation, senescence, differentiation, and survival. These Ras isoforms act as membrane-associated biological switches that transduce signals from transmembrane receptors, thus potentially activating a variety of downstream signaling proteins. These include ultimately two Ser/Thr protein kinase families, the extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt (or protein kinase B). Activation of ERK1/2 has been associated with cardiac myocyte hypertrophy (ie, increased cell size and myofibrillogenesis, with concurrent transcriptional changes to a fetal pattern of gene expression), whereas activation of Akt is associated with the increased protein accretion in hypertrophy. Both ERK1/2 and Akt may promote myocyte survival. In the intact heart in vivo and in primary cultures of cardiac myocytes, mechanical strain induces hypertrophy, a process known as mechanotransduction, which may involve Ras, ERK1/2, and Akt. In this study, general and cardiospecific aspects of the regulation of Ras and Akt will be described. The various mechanisms through which mechanical strain might initiate Ras- or Akt-dependent signaling will be discussed. The overall conclusion is that although an involvement of Ras and Akt in mechanotransduction is likely, more work (particularly focusing on mechanoreception) needs to be undertaken before it is unequivocally established.
Mechanistic Role of Cytochrome P450 Monooxygenases in Oxidized Low-Density Lipoprotein–Induced Vascular Injury
Authors: Thum Thomas , Borlak Jürgen
Published: December 2003

Oxidized low-density lipoprotein (oxLDL) is an important risk factor for vascular injury. Its role on coronary vasoconstriction remains speculative. Endothelial monooxygenases (cytochrome P450s [CYPs]) are regulators of vascular tonus through production of epoxy fatty acids. We investigated the effects of oxLDL on CYP monooxygenases in human arterial coronary endothelial cells and explanted healthy and atherosclerotic aortae. We found oxLDL to induce radical oxygen species production via the action of NADPH oxidase NOX4. Intracellular radical oxygen species production prompted reduced protein expression of the transcriptional regulator nuclear factor 1 (NF-1). We identified novel DNA binding sites for NF-1 in promoter regions of CYPs. DNA binding of NF-1 was confirmed by electromobility shift assays. OxLDL repressed DNA binding of NF-1 and diminished transcript level of CYP genes targeted by this factor. The production of endothelial-derived hyperpolarization factor, a key regulator of vascular tonus, was also reduced. Repression of CYP monooxygenases was reversed, and production of endothelial-derived hyperpolarization factor was normalized after treatment of endothelium with the lectin-like oxLDL receptor antagonist κ-carrageenan or blocking of LOX-1 with a specific antibody. This suggests a mechanistic role of CYP monooxygenases in oxLDL-induced vascular injury. Therapy of endothelial dysfunction through LOX-1 receptor antagonism will be an interesting avenue to explore. The full text of this article is available online at http://www.circresaha.org.
Cdc42 Regulates the Restoration of Endothelial Barrier Function
Authors: Kouklis Panos , Konstantoulaki Maria , Vogel Stephen , Broman Michael , Malik Asrar B.
Published: December 2003

The mechanisms involved in the restoration of endothelial cell junctions subsequent to barrier disruption remain unclear. It is known that formation of adherens junctions (AJs) affects cytoskeletal actin arrangement and that Rho GTPases regulate the state of actin polymerization. In the present study, we examined the role of the Rho GTPases, Rho, Rac, and Cdc42 in the reannealing of AJs. We studied the response to thrombin, which increases endothelial permeability through disassembly of AJs, followed by recovery of barrier function through junctional reannealing within 2 hours. Cdc42 was activated late, at ≈1 hour after thrombin exposure, concurrent with its translocation from the cytoplasm to the membrane. Activation and translocation of Cdc42 preceded the reformation of AJs. Expression of the dnCdc42 mutant (N17Cdc42) significantly delayed the reformation of the VE-cadherin-containing AJs and restoration of endothelial barrier function. We also studied the lung microcirculation to address the in vivo relevance of Cdc42 signaling in barrier restoration. N17Cdc42 expression in the mouse lung endothelium markedly attenuated the endothelial barrier recovery after the permeability increase induced by activation of the thrombin receptor protease-activated receptor-1. These findings demonstrate the critical function of Cdc42 in restoring AJ-dependent, endothelial cell homotypic adhesion and barrier function. The delayed activation of Cdc42 represents a negative-feedback mechanism that signals AJ reassembly after the increase in endothelial permeability induced by inflammatory mediators such as thrombin.
Bone Marrow-Derived Cells Do Not Incorporate Into the Adult Growing Vasculature
Authors: Ziegelhoeffer Tibor , Fernandez Borja , Kostin Sawa , Heil Matthias , Voswinckel Robert , Helisch Armin , Schaper Wolfgang
Published: December 2003

Bone marrow-Derived cells have been proposed to form new vessels or at least incorporate into growing vessels in adult organisms under certain physiological and pathological conditions. We investigated whether bone marrow-Derived cells incorporate into vessels using mouse models of hindlimb ischemia (arteriogenesis and angiogenesis) and tumor growth. C57BL/6 wild-type mice were lethally irradiated and transplanted with bone marrow cells from littermates expressing enhanced green fluorescent protein (GFP). At least 6 weeks after bone marrow transplantation, the animals underwent unilateral femoral artery occlusions with or without pretreatment with vascular endothelial growth factor or were subcutaneously implanted with methylcholanthrene-induced fibrosarcoma (BFS-1) cells. Seven and 21 days after surgery, proximal hindlimb muscles with growing collateral arteries and ischemic gastrocnemius muscles as well as grown tumors and various organs were excised for histological analysis. We failed to colocalize GFP signals with endothelial or smooth muscle cell markers. Occasionally, the use of high-power laser scanning confocal microscopy uncovered false-positive results because of overlap of different fluorescent signals from adjacent cells. Nevertheless, we observed accumulations of GFP-positive cells around growing collateral arteries (3-fold increase versus nonoccluded side,
P
<0.001) and in ischemic distal hindlimbs. These cells were identified as fibroblasts, pericytes, and primarily leukocytes that stained positive for several growth factors and chemokines. Our findings suggest that in the adult organism, bone marrow-Derived cells do not promote vascular growth by incorporating into vessel walls but may function as supporting cells.
Predicting Major Neurological Improvement With Intravenous Recombinant Tissue Plasminogen Activator Treatment of Stroke
Authors: Brown Devin L. , Johnston Karen C. , Wagner Douglas P. , Haley E. Clarke
Published: December 2003

Background and Purpose—

In the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study, major neurological improvement within 24 hours (MNI) occurred significantly more frequently with recombinant tissue plasminogen activator (rtPA) treatment than with placebo. We explored the relationship between MNI and 3-month favorable outcome and sought clinical predictors of MNI.

Methods—

Data from 312 rtPA-treated patients from the NINDS trial were used to assess the ability of MNI to predict favorable outcome at 3 months as defined by a modified Rankin Scale score of 0 to 1. Next, a multivariable predictive model was developed for MNI within the same data set. Clinical variables examined included age, time to treatment (TTT), diabetes, pretreatment glucose, baseline National Institutes of Health Stroke Scale score, pretreatment blood pressure, history of atrial fibrillation, weight >100 kg, and a dense artery sign. Finally, this model was used to forecast into the placebo group of the NINDS trial to assess the uniqueness of the predictors in the rtPA-treated group.

Results—

MNI had a positive predictive value and negative predictive value of 0.70 for predicting favorable 3-month outcome. Only age [odds ratio (OR), 0.68; 95% confidence interval (CI), 0.47 to 0.99] and TTT (OR, 0.56; 95% CI, 0.34 to 0.91) appear to be independently associated with MNI. The model performed only moderately well (area under the receiver-operating characteristic curve, 0.66). Age (OR, 0.67; 95% CI, 0.45 to 0.99) but not TTT was associated with MNI in the placebo group.

Conclusions—

MNI may be a useful surrogate for thrombolytic activity and is predictive of favorable 3-month outcome. When rates of MNI in different populations of stroke patients treated with thrombolysis are compared, adjustments for age and TTT may be necessary.
Alcohol Intake and Cerebral Abnormalities on Magnetic Resonance Imaging in a Community-Based Population of Middle-Aged Adults
Authors: Ding Jingzhong , Eigenbrodt Marsha L. , Mosley Thomas H. , Hutchinson Richard G. , Folsom Aaron R. , Harris Tamara B. , Nieto F. Javier
Published: December 2003

Background and Purpose—

Although the risks associated with heavy drinking for increased stroke and neurodegenerative changes are well established, the effects on the brain of low to moderate alcohol intake are unclear. Subclinical cerebral abnormalities identified on MRI have been associated with neurocognitive decline and incident stroke. We examined the associations of alcohol intake with MRI-defined cerebral abnormalities in a middle-aged, population-based cohort.

Methods—

During 1993–1994, a total of 1909 middle-aged adults (40% men and 49% blacks) from 2 communities in the Atherosclerosis Risk in Communities (ARIC) Study (Forsyth County, North Carolina, and Jackson, Miss) underwent a cerebral MRI examination. Trained neuroradiologists coded the images for the presence of infarction and the extent (10-point scale) of white matter lesions, ventricular size, and sulcal size.

Results—

In logistic regression analyses, there was no association between alcohol intake and the presence of MRI infarction. In linear regression analyses, alcohol intake was not associated with white matter grade. However, intake of each additional alcoholic drink per week was associated with a 0.01 grade greater ventricular size (
P
=0.03) and a 0.009 grade greater sulcal size (
P
=0.02) after adjustment for age, sex, race, body mass index, smoking, income, sports index, and diabetes. The positive associations of alcohol intake with ventricular and sulcal size were consistent across sex and race subgroups.

Conclusions—

A protective effect of low to moderate alcohol intake on cerebral infarction was not found; moreover, increased alcohol intake was associated with brain atrophy.
Parity and Risk of Subarachnoid Hemorrhage in Women
Authors: Gaist David , Pedersen Lars , Cnattingius Sven , Sørensen Henrik Toft
Published: December 2003

Background and Purpose—

Subarachnoid hemorrhage (SAH) is the only type of stroke with female predominance, suggesting that reproductive factors may play a role in the etiology. We conducted a population-based study to examine the influence of parity on the risk of SAH in women.

Methods—

We linked data from 3 national Swedish registries to identify first-ever hospitalizations for SAH in a cohort of women followed up since first childbirth during 1973–1997. Within this cohort, we conducted a nested case-control study and estimated the odds ratio (OR) and 95% CI of SAH by parity adjusted for age, calendar period, and length of follow-up. Information on smoking habits before the subject’s first childbirth was available in a subset of the data (women with first childbirths during 1982–1997).

Results—

Of the 887 cases identified, 70% had suffered from SAH ≥5 years after giving birth to their last child. The OR declined with increasing parity (1 child: reference; 2: OR=0.83 [95% CI, 0.70 to 0.99]; 3: OR=0.72 [95% CI, 0.58 to 0.91]; 4: OR=0.72 [95% CI, 0.48 to 1.08]; ≥5: OR=0.67 [95% CI, 0.32 to 1.41]). Adjusting for daily cigarette consumption before first childbirth in the subsample in which this information was available reduced but did not eliminate the association of the disorder with parity.

Conclusions—

Parity may confer a moderate long-term protective effect on the risk of SAH. The biological mechanism underlying this association is currently unknown.
Acute Ischemic Stroke in Hospitalized Medicare Patients
Authors: Roychoudhury Canopy , Jacobs Bradley S. , Baker Patricia L. , Schultz Daniel , Mehta Rajendra H. , Levine Steven R.
Published: December 2003

Background and Purpose—

This study describes several quality indicators of care in hospitalized stroke patients in Michigan from 1998 to 1999.

Summary of Report—

Median times from admission to head CT/MRI (89.5 minutes) and thrombolysis (113 minutes) exceeded recommended guidelines. Deep venous thrombosis prophylaxis was used in only 13.8% of eligible patients.

Conclusions—

Timing for brain imaging and acute ischemic stroke symptom onset need to be better documented, along with more provider education for routine deep venous thrombosis prophylaxis.
Inhibition of Intercellular Adhesion Molecule-1 Protein Expression by Antisense Oligonucleotides Is Neuroprotective After Transient Middle Cerebral Artery Occlusion in Rat
Authors: Vemuganti Raghu , Dempsey Robert J. , Bowen Kellie K.
Published: December 2003

Background and Purpose—

The present study was performed to determine whether antisense inhibition of intercellular adhesion molecule-1 (ICAM-1) protein expression decreases focal ischemic brain damage.

Methods—

Male spontaneously hypertensive rats underwent 1-hour middle cerebral artery occlusion (MCAO) and 24-hour reperfusion. Rats were infused with ICAM-1 antisense or control oligodeoxynucleotides (ODNs) (48 nmol/d ICV) or vehicle, starting 24 hours before MCAO and continuing until the time of death. ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) mRNA levels were measured by real-time polymerase chain reaction. ICAM-1 protein knockdown was confirmed by Western blotting. Infarct volume was quantified by the use of cresyl violet–stained brain sections. Neurological deficits were evaluated. Mean arterial blood pressure was recorded by laser Doppler. Tissue penetration of antisense was confirmed by the use of fluorescent ODNs.

Results—

Transient MCAO upregulated ICAM-1, but not VCAM-1, mRNA expression in the ipsilateral cortex between 3 and 72 hours of reperfusion. ICAM-1 antisense infusion prevented ischemia-induced ICAM-1 protein expression and reduced total infarct volume (by 53%;
P
<0.05; 226±35 mm
3
in control ODN group and 104±27 mm
3
in antisense ODN group; n=8 each) and mean neurological deficit score (by 44%;
P
<0.05; 2.4 in control ODN group and 1.3 in antisense ODN group; n=8 each). Neither control nor antisense ODN had any effect on mean arterial blood pressure and the physiological parameters monitored during MCAO. Compared with noninfused control, intracerebroventricular infusion of artificial cerebrospinal fluid or antisense or sense ODN had no significant effect on the regional cerebral blood flow changes that accompanied ischemia and reperfusion.

Conclusions—

Increased ICAM-1 expression is implicated in the pathogenesis of focal ischemia since ICAM-1 protein knockdown decreased ischemic brain damage. The mechanism by which ICAM-1 inhibition offers neuroprotection is independent of blood pressure modulation.