bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased NADPH Oxidase Activity, gp91phox Expression, and Endothelium-Dependent Vasorelaxation During Neointima Formation in Rabbits
Authors: Paravicini Tamara M. , Gulluyan Lerna M. , Dusting Gregory J. , Drummond Grant R.
Published: July 2002

Reactive oxygen species including superoxide and hydrogen peroxide are important mediators in atherogenesis. We investigated the enzymatic source of vascular superoxide and its role in endothelium-dependent vasorelaxation during neointima formation. Silastic collars positioned around carotid arteries of rabbits for 14 days induced neointimal thickening. Using lucigenin-enhanced chemiluminescence, superoxide production was detectable in collared artery sections, but not in controls, only after inactivation of endogenous Cu
2+
/Zn
2+
-superoxide dismutase (Cu
2+
/Zn
2+
-SOD) with diethyldithiocarbamate (DETCA). Dihydroethidium staining indicated that endothelium and adventitia were the major sites of superoxide generation. Superoxide production in DETCA-treated collared arteries was enhanced further by NADPH and was inhibited by diphenyleneiodonium, suggesting NADPH oxidase was the source of the radical in collared arteries. Moreover, real-time PCR demonstrated 11-fold higher expression of the gp91phox subunit of NADPH oxidase in collared arteries than in controls. In vascular reactivity studies, endothelium-dependent vasorelaxation to acetylcholine did not differ between collared and control sections. However, treatment with DETCA reduced relaxations to acetylcholine in collared rings, but not in controls. NADPH further reduced relaxations to acetylcholine in DETCA-treated collared sections, but not in controls. In DETCA/NADPH-treated collared rings, sensitivity to nitroprusside, in contrast to acetylcholine, exceeded that of controls. Moreover, further treatment of such rings with exogenous Cu
2+
/Zn
2+
-SOD restored acetylcholine relaxations without altering nitroprusside responses. Thus, early neointimal lesions induced by periarterial collars are associated with elevated gp91phox expression and increased NAPDH-oxidase-dependent superoxide production in endothelium and adventitia. However, endothelium-dependent vasorelaxation is largely preserved due to the actions of Cu
2+
/Zn
2+
-SOD and increased smooth muscle sensitivity to nitric oxide.
Guideline Compliance Improves Stroke Outcome
Authors: Micieli Giuseppe , Cavallini Anna , Quaglini Silvana
Published: July 2002

Background and Purpose

—

Guidelines for medical practice in stroke have been proposed in different countries, but their impact on stroke outcome has not been verified to date. The aim of this study was to evaluate the impact of the American Heart Association guidelines for acute stroke and for transient ischemic attack on first-ever stroke patients.

Methods

—

Three hundred eighty-six first-ever ischemic stroke patients were admitted to the study. Those observed within 6 hours from stroke onset were eligible for the acute clinical phase of the study, while all were admitted to the early clinical phase. The follow-up lasted 6 months. Primary end points were survival and the effectiveness of treatment on disability, measured as the proportion of potential improvement in the Barthel Index score achieved during treatment. A rating of noncompliance with the guideline recommendations was calculated for each patient, and its association with the end points was investigated. The Kaplan-Meier method and log-rank test were used to estimate and compare survival curves between groups; Cox proportional hazards model and logistic regression were used to identify risk factors for mortality; and correlation tests and regression analysis were used to evaluate the influence of guideline compliance on disability. Both univariate and multivariate statistical analyses were performed.

Results

—

Survival and treatment effectiveness were directly correlated with guideline compliance. The relative risk of death for patients with a noncompliance rating ≥5 was 2.26 with respect to patients with a noncompliance rating <5 (95% CI, 1.51 to 4.67;
P
<0.0007). In this latter group, at 6 months we detected a 15% decrease in mortality (95% CI, 9.1% to 17.5%). Treatment effectiveness showed a Spearman’s rank correlation with the noncompliance rating of −0.3 (
P
<0.001). At discharge we observed a 13% increase in treatment effectiveness, while no significant differences were detectable at 3 and 6 months. These associations were confirmed by the multivariate analysis, in which we included, together with the noncompliance rating, all the variables previously identified as independent predictors of mortality and disability.

Conclusions

—

This study demonstrates an association between adherence to guidelines and stroke outcome, and it can be viewed as a study that prepares the way for a randomized controlled trial in this area. It also emphasizes the need to develop personnel and structures devoted to stroke care because an evidence-based clinical approach could significantly reduce the risk of death.
Carotid Artery Stenting Protected With an Emboli Containment System
Authors: Whitlow Patrick L. , Lylyk Pedro , Londero Hugo , Mendiz Oscar A. , Mathias Klaus , Jaeger Horst , Parodi Juan , Schönholz Claudio , Milei Jose
Published: July 2002

Background and Purpose

—

Fear of distal embolization and stroke has aroused concern regarding carotid stenting. Devices to protect the cerebral circulation may make carotid stenting safer.

Methods

—

A multidisciplinary study group tested a balloon occlusion-aspiration emboli entrapment device in conjunction with carotid stenting. The device consists of an elastomeric balloon on a steerable wire with a detachable adapter that inflates and deflates the distal temporary occlusion balloon. An aspiration catheter is used to remove trapped emboli after stenting and before occlusion balloon deflation.

Results

—

Seventy-five patients with severe internal carotid artery stenosis were treated with stents deployed with this cerebrovasculature protection system. All 75 patients (100%) had grossly visible particulate material aspirated, and all were treated successfully without major or minor stroke or death at 30 days. Preintervention stenosis was 81±10%, and residual stenosis was 5±7%. Nine patients (12%) had angiographic evidence of thrombus before intervention, but no patient had thrombus or vessel cutoff after the procedure. Four patients (5%) developed transient neurological symptoms during protection balloon occlusion, but symptoms resolved with balloon deflation. The 22 to 667 particles aspirated per patient ranged from 3.6 to 5262 μm in maximum diameter (mean, 203±256 μm). These particles included fibrous plaque debris, lipid or cholesterol vacuoles, and calcific plaque fragments.

Conclusions

—

Protected carotid stenting was performed successfully and safely in this study early in the experience with cerebrovascular protection devices. Particulate emboli are frequent with stenting, and cerebral protection will likely be necessary to minimize stroke. Randomized trials comparing protected carotid stenting with endarterectomy are warranted.
Inflammation and Stroke
Authors: van Exel E. , Gussekloo J. , de Craen A.J.M. , Bootsma-van der Wiel A. , Frölich M. , Westendorp R.G.J.
Published: July 2002

Background

—

Experimental evidence indicates that interleukin-10 (IL-10) deficiency is associated with the development of cardiovascular and cerebrovascular disease. We analyzed the relation between low IL-10 production levels, history of stroke, and incident fatal stroke.

Summary of Report

—

All 85-year-old inhabitants of Leiden, Netherlands (n=599) were visited at their place of residence (response rate, 87%). Production levels of the anti-inflammatory cytokine IL-10 were assessed in a whole blood assay whereby lipopolysaccharide was used as a stimulus. Plasma concentrations of C-reactive protein (CRP) were also used as a marker of inflammation. A history of stroke was obtained at baseline (prevalence, 10%). The number of fatal strokes was prospectively obtained for a median follow-up of 2.6 years (incidence, 1.82 per 100 person-years at risk). Subjects with a history of stroke had significantly lower median IL-10 production levels at baseline than subjects without stroke (558 versus 764 pg/mL;
P
<0.05). They also had significantly higher median CRP concentrations (6 versus 3 mg/L;
P
<0.05). The odds ratio for a history of stroke increased to 2.30 (95% CI, 1.12 to 4.72) over strata representing decreasing production levels of IL-10. The relative risk for incident fatal stroke was 2.94 (95% CI, 1.01 to 8.53) when we compared subjects with low or intermediate baseline IL-10 production levels to those with high production levels of IL-10.

Conclusions

—

Our data support the hypothesis that subjects with low IL-10 production levels have an increased risk of stroke.
Acute Ischemic Stroke Patterns in Infective and Nonbacterial Thrombotic Endocarditis
Authors: Singhal Aneesh B. , Topcuoglu Mehmet A. , Buonanno Ferdinando S.
Published: July 2002

Background and Purpose

—

Although infective endocarditis (IE) and nonbacterial thrombotic endocarditis (NBTE) are associated with cardioembolic stroke, differences in the nature of these conditions may result in differences in associated stroke patterns. We compared patterns of acute and recurrent ischemic stroke in IE and NBTE, using diffusion-weighted MRI (DWI).

Methods

—

Using ICD-9 diagnostic codes and medical record review, we identified 362 patients (387 episodes) with IE and 14 patients with NBTE. Thirty-five patients (with 27 episodes of IE, 9 NBTE) who underwent 36 initial and 29 follow-up DWI scans were selected for this study. DWI lesion size, number, and location were compared between groups and correlated with stroke syndromes and endocarditis features.

Results

—

DWI was abnormal in all but 2 patients. Four acute stroke patterns were identified: (1) single lesion, (2) territorial infarction, (3) disseminated punctate lesions, and (4) numerous small (<10 mm) and medium (10 to 30 mm) or large (>30 mm) lesions in multiple territories. All patients with NBTE exhibited pattern 4, whereas those with IE exhibited patterns 1, 2, 3, and 4 (6, 2, 8 and 9 episodes, respectively). Seventy-five percent of patients with pattern 3 exhibited the clinical syndrome of embolic encephalopathy. Vegetation size, valve, and organisms had no correlation with stroke patterns.

Conclusion

—

DWI has utility in differentiating between IE and NBTE. Patients with NBTE uniformly have multiple, widely distributed, small and large strokes, whereas patients with IE exhibit a panoply of stroke patterns.
Quality of Life Measurement After Stroke
Authors: Hobart Jeremy C. , Williams Linda S. , Moran Kimberly , Thompson Alan J.
Published: July 2002

Background and Purpose

—

The Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) is widely used to measure health status after stroke. However, a fundamental assumption for its valid use after stroke has not been comprehensively tested: is it legitimate to generate scores for 8 scales and 2 summary measures using the standard algorithms? We tested this assumption.

Methods

—

SF-36 data from 177 people after stroke were examined (71% male; mean age, 62). We tested 6 scaling criteria to determine the legitimacy of generating the 8 SF-36 scale scores using Likert’s method of summed ratings, and we tested 2 scaling criteria to determine the appropriateness of the standard SF-36 algorithms for weighting and combining scale scores to generate 2 summary measures (physical and mental).

Results

—

Scaling assumptions were fully satisfied for 6 of the 8 scales, but 3 of these 6 scales had notable floor and/or ceiling effects. Assumptions for generating 2 SF-36 summary measures were not satisfied.

Conclusions

—

In this sample, 5 of the 8 SF-36 scales had limited validity as outcome measures after stroke, and the reporting of physical and mental summary scores was not supported. Results raise questions about the use of the SF-36 in stroke, and the SF-12 that is developed from it, and highlight the importance of testing scaling assumptions when applying existing scales to new populations.
UKPDS 60
Authors: Kothari Viti , Stevens Richard J. , Adler Amanda I. , Stratton Irene M. , Manley Susan E. , Neil H. Andrew , Holman Rudy R.
Published: July 2002

Background and Purpose

—

People with type 2 diabetes are at elevated risk of stroke compared with those without diabetes. Relative risks have been examined in earlier work, but there is no readily available method for predicting the absolute risk of stroke in a diabetic individual. We developed mathematical models to estimate the risk of a first stroke using data from 4549 newly diagnosed type 2 diabetic patients enrolled in the UK Prospective Diabetes Study.

Methods

—

During 30 700 person-years of follow-up, 188 first strokes (52 fatal) occurred. Model fitting was carried out by maximum likelihood estimation using the Newton-Raphson method. Diagnostic plots were used to compare survival probabilities calculated by the model with those calculated using nonparametric methods.

Results

—

Variables included in the final model were duration of diabetes, age, sex, smoking, systolic blood pressure, total cholesterol to high-density lipoprotein cholesterol ratio and presence of atrial fibrillation. Not included in the model were body mass index, hemoglobin A1c, ethnicity, and ex-smoking status. The use of the model is illustrated with a hypothetical study power calculation.

Conclusions

—

This model forecasts the absolute risk of a first stroke in people with type 2 diabetes using variables readily available in routine clinical practice.
Expression of Human Apolipoprotein E Downregulates Amyloid Precursor Protein–Induced Ischemic Susceptibility
Authors: Koistinaho Milla , Kettunen Mikko I. , Holtzman David M. , Kauppinen Risto A. , Higgins Linda S. , Koistinaho Jari
Published: July 2002

Background and Purpose

—

Epidemiological findings and experimental data on transgenic mice show that Alzheimer’s disease–related changes render the brain more susceptible to ischemic damage. We studied whether the previously observed vulnerability in mice overexpressing the 751–amino-acid isoform of human amyloid precursor protein (APP751) is regulated by human apolipoprotein E (apoE) alleles, which determine the relative risk for Alzheimer’s disease and the susceptibility to various forms of acute brain damage.

Methods

—

Aged apoE knock out (KO) mice, mice overexpressing APP751 in the apoE KO background and mice expressing either human apoE3 or apoE4 and APP751 in the apoE KO background were exposed to permanent occlusion of the middle cerebral artery (MCA). Infarct volumes were quantified from T
2
-weighted magnetic resonance images 24 hours after the MCA occlusion. Local cortical blood flow was monitored by laser Doppler flowmetry. Ischemia-induced microgliosis was detected by immunohistochemistry.

Results

—

Overexpression of human APP751 significantly increased the infarct volumes in apoE KO mice. Furthermore, this APP751-induced ischemic vulnerability was attenuated by the coexpression of either human apoE isoform. MCA occlusion resulted in a similar relative reduction in cortical blood flow in all mouse groups. Vascular anatomy showed no variation in the MCA territory between the groups. Instead, the expression of human apoE isoforms reduced the ischemia-induced microgliosis.

Conclusions

—

Expression of either the human apoE3 or apoE4 isoform protects against the increased ischemic vulnerability observed in aged mice overexpressing human APP751, probably by modulating the inflammatory response induced by MCA occlusion.
Association Between

SAH

, an Acyl-CoA Synthetase Gene, and Hypertriglyceridemia, Obesity, and Hypertension
Authors: Iwai Naoharu , Katsuya Tomohiro , Mannami Toshifumi , Higaki Jitsuo , Ogihara Toshio , Kokame Koichi , Ogata Jun , Baba Shunroku
Published: July 2002

Background
—

The SA gene (
SAH
) has been isolated by differential screening from a genetically hypertensive rat strain as a candidate gene that may contribute to hypertension. Recently, the SA protein has been reported to be highly homologous to bovine xenobiotic–metabolizing medium-chain fatty acid:CoA ligase.

Methods and Results
—

To clarify the pathophysiological significance of
SAH
, we searched for polymorphisms of human
SAH
and performed association studies using a large cohort (4000 subjects) representing the general population in Japan. We found 2 polymorphisms in the promoter region and single-nucleotide polymorphisms in introns 5, 7, and 12 and exon 8. One of the variants, an A/G polymorphism in intron 12, just 7 bp upstream from exon 13, strongly affected plasma triglyceride, plasma cholesterol, body mass index (BMI), waist-to-hip ratio (W/H), and blood pressure status. The effect of this genotype on blood pressure seems to be conveyed through its effects on BMI and W/H. Transient expression of the SA protein in mammalian cells confirmed that it is expressed in mitochondria and has medium-chain fatty acid:CoA ligase activity. The A/G polymorphism was found to be associated with the expression level of SA mRNA in peripheral mononuclear cells in vivo.

Conclusions
—

The G allele of
SAH
was found to be associated with multiple risk factors, including hypertriglyceridemia, hypercholesterolemia, obesity, and hypertension. This observation should open a new area for future research in multiple-risk-factor syndromes.
Myocardial Magnetic Resonance Imaging Contrast Agent Concentrations After Reversible and Irreversible Ischemic Injury
Authors: Rehwald Wolfgang G. , Fieno David S. , Chen Enn-Ling , Kim Raymond J. , Judd Robert M.
Published: July 2002

Background
—

Discrepant reports have been published recently regarding the relationship of contrast-enhanced magnetic resonance image intensities to reversible and irreversible ischemic injury. Unlike image intensities, contrast agent concentrations provide data independent of the MRI technique. We used electron probe x-ray microanalysis (EPXMA) to simultaneously examine concentrations of Gd, Na, P, S, Cl, K, and Ca over a range of myocardial injuries.

Methods and Results
—

Reversible and irreversible injury were studied in 38 rabbits divided into 4 groups defined by occlusion and reperfusion time, as well as time the animals were euthanized. Gd-DTPA was administered, and the hearts were excised and rapidly frozen, cryosectioned, freeze-dried, and examined by EPXMA in up to 3 regions: remote, infarcted, and at risk but not infarcted. Infarcted regions were defined by anti-myoglobin antibody or triphenyltetrazolium chloride staining. Regions at risk were defined by fluorescent microparticles administered during occlusion. Compared with remote regions, in acutely infarcted regions, Gd was increased (235±24%,
P
<0.005) in the same 50×100-μm areas in which Na was increased (154±5%,
P
<0.001) and K was decreased (52±8%,
P
<0.001). Similarly, in chronically infarcted regions, Gd was increased (472±78%,
P
<0.001) in areas in which Na was increased (332±28%,
P
<0.001) and K was decreased (47±5%,
P
<0.001). Also compared with remote regions, however, concentrations of Gd, Na, and K were not elevated after reperfusion in regions that were at risk but not infarcted (
P
=NS).

Conclusions—

Regional elevations in myocardial MRI contrast agent concentrations are exclusively associated with irreversible ischemic injury defined histologically and by regional electrolyte concentrations.
Randomized, Placebo-Controlled Trial of Titrated Intravenous Lamifiban for Acute Coronary Syndromes
Authors:   The Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B Investigators
Published: July 2002

Background

—

Platelet glycoprotein IIb/IIIa inhibitors reduce the rate of death or myocardial infarction among patients with acute coronary syndromes without persistent ST-segment elevation, but their effects may depend on plasma concentrations. We tested whether the addition of lamifiban, titrated to achieve target plasma concentrations, to standard care would improve clinical outcomes.

Methods and Results

—

We randomized 5225 patients at 389 centers in 29 countries to receive a bolus and ≤72-hour infusion of lamifiban or placebo, adjusted for renal function, with aspirin and heparin. The primary end point was the composite of death, myocardial infarction, or severe, recurrent ischemia at 30 days. Baseline characteristics did not differ significantly by treatment. The primary end point occurred in 11.8% of lamifiban-treated patients and in 12.8% of placebo-treated patients (OR, 0.914; 95% CI, 0.769 to 1.087;
P
=0.329). Bleeding was more common in lamifiban-treated patients, but intracranial hemorrhage was not increased. Among the subgroup who had plasma lamifiban concentrations measured, 91% had a concentration >18 ng/mL at steady state, but their outcomes did not differ from those with lower concentrations.

Conclusions

—

Lamifiban showed no significant effects on clinical outcomes in patients with non–ST-elevation acute coronary syndromes, despite achievement of adequate plasma concentrations.
Mitochondrial Preference for Short Chain Fatty Acid Oxidation During Coronary Artery Constriction
Authors: Lewandowski E. Douglas , Kudej Raymond K. , White Lawrence T. , O’Donnell J. Michael , Vatner Stephen F.
Published: July 2002

Background

—

Reduced fatty acid oxidation in hypoperfused myocardium is believed to result from impaired oxidation in mitochondria. This study suggests another mechanism, that oxidative capacity exceeds regulated entry of long chain fatty acid (LCFA). The ability of myocardium to oxidize fatty acids and metabolize glucose during stenosis was examined in open chest, anesthetized pigs.

Methods and Results

—

The left anterior descending (LAD) coronary artery was infused for 40 minutes (5 mL/min LAD) with [2–
13
C] butyrate (4 mmol/L), a short chain fatty acid (SCFA), plus [2–
13
C] glucose (10 mmol/L) in either nonischemic controls (n=4) or at the end of 5 hours of LAD flow reduction (40%, n=7). With LAD constriction, left ventricular wall thickening fell 45±8% (
P
<0.01). Despite glycolytic production of lactate and alanine, hypoperfused myocardium preferentially oxidized SCFA over endogenous LCFA. SCFA accounted for 63±4% (mean±SEM) of carbon units entering oxidation in both ischemic epicardium and endocardium versus only 38±4% and 40±6% in respective samples from normal myocardium (
P
<0.002). Unexpectedly, SCFA contributions were elevated in both endocardium and epicardium despite preserved epicardial blood flow versus a 58±9% drop in endocardial flow (
P
<0.05). No significant oxidation of glucose was evident, indicating that unlabeled fuels were primarily LCFA.

Conclusions

—

Because SCFA bypass LCFA transport into mitochondria, during LAD constriction, mitochondrial capacity to oxidize fatty acid exceeds LCFA entry for oxidation. Importantly, metabolic changes were disassociated from transmural tissue perfusion. These findings suggest that signals other than oxygen availability regulate fatty acid use during hypoperfusion.
Proteolysis of Tissue Factor Pathway Inhibitor-1 by Thrombolysis in Acute Myocardial Infarction
Authors: Ott Ilka , Malcouvier Valerie , Schömig Albert , Neumann Franz-Josef
Published: July 2002

Background

—

In acute myocardial infarction (AMI), surface-bound tissue factor pathway inhibitor-1 (TFPI-1) inhibits an increased monocyte procoagulant activity. In addition, TFPI-1 is released from microvascular endothelial cells after treatment with heparin and thereby contributes to its antithrombotic properties.

Methods and Results

—

We examined 19 patients in a randomized study comparing intravenous fibrinolysis with alteplase (n=9) and revascularization by stent placement with additional abciximab treatment (n=10). We obtained blood samples for analysis of monocytic TFPI-1 surface expression by flow cytometry and plasma TFPI-1 concentrations by immunoassay before and after therapy. We found a significant decrease in surface TFPI-1 on circulating monocytes 24 hours after thrombolysis (
P
=0.006) that was not observed after stenting. Systemic plasma TFPI-1 concentrations increased immediately after stenting by 71±14% (
P
=0.008), whereas after thrombolysis, a decrease in TFPI-1 plasma concentrations of 21±11% was observed (
P
=0.075). In vitro experiments confirmed that plasmin decreased TFPI-1 surface expression dose-dependently.

Conclusions

—

Activation of the fibrinolytic system by alteplase in AMI decreases surface-associated TFPI-1 on circulating monocytes and plasma TFPI-1. Reduced TFPI-1 may contribute to thrombotic complications after fibrinolysis in AMI.
Electrophysiological Modulation of Cardiomyocytic Tissue by Transfected Fibroblasts Expressing Potassium Channels
Authors: Feld Yair , Melamed-Frank Meira , Kehat Izhak , Tal Dror , Marom Shimon , Gepstein Lior
Published: July 2002

Background
—

Traditional pharmacological therapies aiming to modify the abnormal electrophysiological substrate underlying cardiac arrhythmias may be limited by their relatively low efficacy, global cardiac activity, and significant proarrhythmic effects. We suggest a new approach, in which transfected cellular grafts expressing various ionic channels may be used to manipulate the local electrophysiological properties of cardiac tissue. To examine the feasibility of this concept, we tested the hypothesis that transfected fibroblasts expressing the voltage-sensitive potassium channel Kv1.3 can modify the electrophysiological properties of cardiomyocytic cultures.

Methods and Results
—

A high-resolution multielectrode mapping technique was used to assess the electrophysiological and structural properties of primary cultures of neonatal rat ventricular myocytes. The transfected fibroblasts, added to the cardiomyocytic cultures, caused a significant effect on the conduction properties of the hybrid cultures. These changes were manifested by significant reduction in extracellular signal amplitude and by the appearance of multiple local conduction blocks. The location of all conduction blocks correlated with the spatial distribution of the transfected fibroblasts assessed by vital staining. All electrophysiological changes were reversed after the application of Charybdotoxin, a specific Kv1.3 blocker. In contrast, conduction remained uniform in the control hybrid cultures when nontransfected fibroblasts were used.

Conclusions
—

Transfected fibroblasts are able to electrically couple with cardiac myocytes, causing a significant local and reversible modification of the tissue’s electrophysiological properties. More broadly, this study suggests that transfected cellular grafts expressing various ionic channels may be used to modify cardiac excitability, providing a possible future novel cell therapy strategy.
Differential Actions of Vasopeptidase Inhibition Versus Angiotensin-Converting Enzyme Inhibition on Diuretic Therapy in Experimental Congestive Heart Failure
Authors: Cataliotti Alessandro , Boerrigter Guido , Chen Horng H. , Jougasaki Michihisa , Costello Lisa C. , Tsuruda Toshihiro , Lee Shang-Chiun , Malatino Lorenzo S. , Burnett John C.
Published: July 2002

Background

—

Omapatrilat (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure.

Methods and Results

—

We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D.

Conclusions

—

Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.
Dynamic Changes in Three-Dimensional Architecture and Vascular Volume of Transmural Coronary Microvasculature Between Diastolic- and Systolic-Arrested Rat Hearts
Authors: Toyota Eiji , Fujimoto Katsukuni , Ogasawara Yasuo , Kajita Tatsuya , Shigeto Fumiyuki , Matsumoto Takeshi , Goto Masami , Kajiya Fumihiko
Published: July 2002

Background

—

The phase difference of coronary arterial and venous flows indicates the importance of intramyocardial capacitance vessels in storing diastolic flow and in discharging volume in systole. However, the anatomic and functional characteristics of the capacitance vessels are unclear. We aimed to clarify those characteristics with their transmural difference by 3D visualization of transmural microvessels under diastole and systole.

Methods and Results

—

We performed complete intracoronary filling of a contrast medium into Langendorff’s Wistar rat hearts under (1) St Thomas–perfused diastolic arrest (D-mode) and (2) BaCl
2
-induced systolic arrest (S-mode). Precise transmural 3D architectures of capillaries and of pre- and post-capillary microvessels (ie, microvessels larger than capillaries) were visualized clearly with a confocal laser scanning microscope and x-ray microcomputed tomography (microCT), respectively. Vascular volume fraction (VF) and systolic-induced VF reduction rate from D- to S-mode were analyzed. The net capillary VF in D-mode (20.4±0.9%) was 10 times that of larger microvessels and was reduced in S-mode by 32% without capillary collapse. Systolic-induced VF reduction rate was smaller in capillaries than in larger microvessels (48%;
P
<0.05). The larger microvessel VF in D-mode (2.2±0.2%) was reduced in S-mode, accompanied by complicated 3D deformation.

Conclusions

—

Capillaries were relatively resistant to the systolic extravascular compression compared with pre- and post-capillary microvessels, conveniently beneficial for the myocardial oxygen delivery throughout a cardiac cycle. Nevertheless, a larger change in the absolute volume of capillaries may function as effective capacitance. On one hand, the pre- and post-capillary microvessels showed a larger phasic change in resistance, which may function to maintain the capillary patency during systole.
T-Cell–Mediated Lysis of Endothelial Cells in Acute Coronary Syndromes
Authors: Nakajima Takako , Schulte Stephanie , Warrington Kenneth J. , Kopecky Stephen L. , Frye Robert L. , Goronzy Jörg J. , Weyand Cornelia M.
Published: July 2002

Background

—

CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood.

Methods and Results

—

Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4
+
CD28
null
T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161
+
and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4
+
CD28
null
T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4
+
T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I–recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4
+
CD28
null
T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion.

Conclusions

—

In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell–mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.
Angiographical Follow-Up After Radioactive “Cold Ends” Stent Implantation
Authors: Wardeh A.J. , Albiero R. , Kay I.P. , Knook A.H.M. , Wijns W. , Kozuma K. , Nishida T. , Ferrero V. , Levendag P.C. , van der Giessen W.J. , Colombo A. , Serruys P.W.
Published: July 2002

Background

—

Radioactive stents with an activity of 0.75 to 12 μCi have shown >40% edge restenosis due to neointimal hyperplasia and negative remodeling. This trial evaluated whether radioactive Cold Ends stents might resolve edge restenosis by preventing remodeling at the injured extremities.

Methods and Results

—

The 25-mm long (15-mm radioactive center and 5-mm nonradioactive ends) Cold Ends stents had an activity of 3 to 12 μCi at implantation. Forty-three stents were implanted in 43 patients with de novo native coronary artery disease. Two procedural, 1 subacute, and 1 late stent thrombosis occurred. A restenosis rate of 22% was observed with a shift of the restenosis, usually occurring at the stent edges of radioactive stents, into the Cold Ends stents. The most severe restenosis occurred at the transition zone from radioactive to nonradioactive segments, a region located in dose fall-off.

Conclusion

—

Cold Ends stents did not resolve edge restenosis.
Clinical and Molecular Heterogeneity in the Brugada Syndrome
Authors: Weiss Raul , Barmada M. Michael , Nguyen Tuduy , Seibel Jolene S. , Cavlovich Doris , Kornblit Cari A. , Angelilli Adam , Villanueva Flordeliza , McNamara Dennis M. , London Barry
Published: July 2002

Background

—

Brugada syndrome is a form of idiopathic ventricular fibrillation characterized by a right bundle-branch block pattern and ST elevation (STE) in the right precordial leads of the ECG. Sodium channel blockers increase STE. Mutations of the cardiac sodium channel SCN5A cause the disorder, and an implantable cardioverter-defibrillator is often recommended for affected individuals. Mutations in other genes have not been identified, and it is not known if the efficacy of drug testing or the malignancy of arrhythmias correlates to the gene defect.

Methods and Results

—

We performed histories, physical examinations, ECGs, and drug testing on a large multigenerational family with Brugada syndrome. DNA isolated from blood samples, polymorphic genomic markers, and polymorphisms within candidate sodium channels were used for a genome-wide screen, fine mapping, and linkage analysis. We identified 12 affected individuals (right bundle-branch block, ≥1-mm STE) with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. Four affected individuals had syncope and 2 had documented ventricular arrhythmias, but there was minimal family history of sudden death. Procainamide infusions did not identify additional affected individuals. Linkage was present to an ≈15-cM region on chromosome 3p22-25 (maximum LOD score=4.00). The sodium channel genes
SCN5A
,
SCN10A
, and
SCN12A
on chromosome 3 were excluded as candidates (LOD scores ≤−2).

Conclusions

—

A Brugada syndrome locus distinct from
SCN5A
is associated with progressive conduction disease, a low sensitivity to procainamide testing, and a relatively good prognosis in a single large pedigree.
Myocardial Contrast Echocardiography Can Be Used to Assess the Microvascular Response to Vascular Endothelial Growth Factor-121
Authors: Villanueva Flordeliza S. , Abraham Judith A. , Schreiner George F. , Csikari Melissa , Fischer David , Mills James D. , Schellenberger Ute , Koci Bryan J. , Lee Joon S.
Published: July 2002

Background

—

Therapeutic angiogenesis is a new approach to treating ischemic heart disease, and the optimal method for assessing its efficacy is unclear. We used myocardial contrast echocardiography (MCE) to evaluate the therapeutic response to the angiogenic agent, vascular endothelial growth factor-121 (VEGF
121
).

Methods and Results

—

After placement of an ameroid constrictor (day 0) around the left anterior descending artery (LAD), dogs were given intracoronary VEGF
121
protein (108 μg, n=6) or placebo (n=6) on days 7 and 21, and subcutaneous VEGF
121
(1 mg) or placebo on days 8 to 20 and 22 to 27. On day 48, MCE was performed during rest and dobutamine stress. Videointensity (
y
) and pulsing interval (
t
) were fit to an exponential model (
y
=
A
[1−
e
−βt
]) used to derive indices of red cell velocity (β) and capillary area (
A
), and parameters were compared with radiolabeled microsphere flow data. VEGF
121
treatment resulted in higher resting left anterior descending artery/left circumflex flow ratio compared with placebo (
P
<0.03) and improved collateral flow reserve. β was 0.94±0.37 in VEGF
121
dogs versus 0.38±0.31 in controls (
P
<0.02), with the greatest difference in the endocardium. The parameter A was comparable in both groups, suggesting that microvascular changes did not alter capillary cross-sectional area, and histology indicated a trend toward higher arteriolar density in VEGF
121
-treated animals.

Conclusions

—

VEGF
121
protein improves collateral flow and reserve. MCE can evaluate the transmural location and structural and functional responses of the microvasculature to angiogenic interventions.
New Tools for Coronary Risk Assessment
Authors: Pearson Thomas A.
Published: July 2002

The concept of risk assessment and reduction, introduced initially by the Framingham Heart Study and refined in other models, forms the cornerstone of preventive cardiology. Risk factor assessment determines the therapeutic strategy, because the intensity of preventive intervention is tailored to the patient’s risk of coronary heart disease. The conventional risk factors for coronary heart disease include elevated serum total cholesterol and LDL cholesterol, low HDL cholesterol, elevated blood pressure, cigarette smoking, diabetes, vascular disease, menopausal status (women only), and age. Aggressive risk factor reduction, formerly used exclusively in secondary prevention, may be pivotal to optimal patient management in high-risk primary prevention. A number of noninvasive imaging modalities have the potential to measure and to monitor atherosclerosis in asymptomatic individuals and include exercise ECG testing, electron beam computed tomography, magnetic resonance coronary angiography, positron emission tomography, ankle-brachial index, and B-mode ultrasound. Novel serum markers, including C-reactive protein and homocysteine, have the ability to gauge risk in the individual patient. Systemic therapy for risk reduction in primary prevention may be preferable to local therapy (eg, angioplasty and bypass) and may more effectively prevent acute coronary events than these more invasive approaches.
Maximizing the Natriuretic Peptide System in Experimental Heart Failure
Authors: Chen Horng H. , Lainchbury John G. , Harty Gail J. , Burnett John C.
Published: July 2002

Background

—

A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF.

Methods and Results

—

We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 μmol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 μg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 μg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone.

Conclusions

—

This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.
Evidence for Synergy Between α
2
-Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation
Authors: Bruban Véronique , Estato Vanessa , Schann Stephan , Ehrhardt Jean-Daniel , Monassier Laurent , Renard Pierre , Scalbert Elizabeth , Feldman Josiane , Bousquet Pascal
Published: July 2002

Background
—

Both α
2
-adrenergic and non–α
2
-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP).

Methods and Results
—

LNP 509, which appeared in this study to be devoid of α
2A
-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46±4% and 16±2%, respectively. In D79N mice, which lack functional α
2A
-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17±2%. The hypotension induced by LNP 509 (100 μg/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I
1
-imidazoline binding sites (I
1
BS). A synergy between LNP 509 and the α
2
-adrenergic agonist α-methylnoradrenaline (α-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ventricle injection) but not, as expected, in D79N mice. Similar to LNP 509 alone, rilmenidine (fourth ventricle injection), which binds both to α
2
-adrenergic receptors and to I
1
BS, decreased BP in D79N mice. In WT animals, rilmenidine had a significantly greater effect. Microinjections performed in rabbits showed that the synergism occurred at least in part in the nucleus reticularis lateralis of the brain stem.

Conclusions
—

These results demonstrate that a central imidazoline-sensitive, but non–α
2
-adrenergic, mechanism can modify BP by itself. This mechanism, which may involve I
1
BS, interacts synergistically with an α
2
-adrenergic mechanism to decrease BP.
Platelets Activated by Collagen Through Immunoreceptor Tyrosine-Based Activation Motif Play Pivotal Role in Initiation and Generation of Neointimal Hyperplasia After Vascular Injury
Authors: Konishi Hakuoh , Katoh Youichi , Takaya Norihide , Kashiwakura Yuji , Itoh Seigo , Ra Chisei , Daida Hiroyuki
Published: July 2002

Background

—

Platelet adhesion on components of the extracellular matrix and platelet activation by those components are crucial for the arrest of posttraumatic bleeding, but they can also harm tissue by occluding diseased vessels. Recent studies have shown that the activation of platelets by collagen is mediated through the same pathway used by immune receptors, with an immunoreceptor tyrosine-based activation motif on the Fc receptor γ chain (FcRγ) playing a pivotal role.

Methods and Results

—

We examined the role of collagen-stimulated platelets in the development of injury-induced neointimal formation by using mice deficient in FcRγ. The left femoral arteries of 8- to 12-week-old FcRγ-deficient mice (n=16) and C57BL/6 (wild-type) mice (n=16) were injured by a straight spring wire (0.35-mm diameter). Segments of the injured and uninjured femoral arteries were excised at 7 days and 28 days after the vascular injury. Arterial segments were examined by immunohistochemistry and electron microscopy. Two hours after injury, electron microscopy showed marked decreases in platelet adhesion and neutrophil attachment to the vascular wall surface in FcRγ-knockout mice compared with wild-type mice. At 7 days after injury, staining with anti-neutrophil antibody showed fewer neutrophils in FcRγ-knockout mice than in wild-type mice. Computer-aided morphometry performed to measure the neointimal area, intima/media ratio, and stenotic area at 28 days after injury showed a significantly smaller ratio and area in FcRγ-knockout mice than in wild-type mice (for neointimal area, 16 635±1406 versus 31 483±2309 μm
2
, respectively; for intima/media ratio, 1.25±0.40 versus 2.68±0.04, respectively; and for stenotic area, 26.8±2.1% versus 49.3±4.1%, respectively).

Conclusions

—

These results demonstrate that FcRγ may play important roles in the initiation and generation of neointimal hyperplasia after balloon injury through the activation of platelets by collagen.
Fetal, Infant, and Childhood Growth and Adult Blood Pressure
Authors: Law C.M. , Shiell A.W. , Newsome C.A. , Syddall H.E. , Shinebourne E.A. , Fayers P.M. , Martyn C.N. , de Swiet M.
Published: July 2002

Background
—

People who are small at birth tend to have higher blood pressure in later life. However, it is not clear whether it is fetal growth restriction or the accelerated postnatal growth that often follows it that leads to higher blood pressure.

Methods and Results
—

We studied blood pressure in 346 British men and women aged 22 years whose size had been measured at birth and for the first 10 years of life. Their childhood growth was characterized using a conditional method that, free from the effect of regression to the mean, estimated catch-up growth. People who had been small at birth but who gained weight rapidly during early childhood (1 to 5 years) had the highest adult blood pressures. Systolic pressure increased by 1.3 mm Hg (95% CI, 0.3 to 2.3) for every standard deviation score decrease in birth weight and, independently, increased by 1.6 mm Hg (95% CI, 0.6 to 2.7) for every standard deviation score increase in early childhood weight gain. Adjustment for adult body mass index attenuated the effect of early childhood weight gain but not of birth weight. Relationships were smaller for diastolic pressure. Weight gain in the first year of life did not influence adult blood pressure.

Conclusions
—

Part of the risk of adult hypertension is set in fetal life. Accelerated weight gain in early childhood adds to this risk, which is partly mediated through the prediction of adult fatness. The primary prevention of hypertension may depend on strategies that promote fetal growth and reduce childhood obesity.