bluuebunny/crossref_metadata_2025 huggingface dataset:
Extension of Increased Atherosclerotic Wall Thickness Into High Shear Stress Regions Is Associated With Loss of Compensatory Remodeling
Authors: Wentzel Jolanda J. , Janssen Elbert , Vos Jeroen , Schuurbiers Johan C.H. , Krams Rob , Serruys Patrick W. , de Feyter Pim J. , Slager Cornelis J.
Published: June 2003

Background—

Atherosclerosis preferentially develops at average low shear stress (SS) locations. SS-related signaling maintains lumen dimensions by inducing outward arterial remodeling. Prolonged plaque accumulation at low SS predilection locations explains an inverse relation between wall thickness (WT) and SS. No data exist on WT-SS relations when lumen narrowing and loss of compensatory remodeling commence.

Methods and Results—

In 14 patients, an angiographically normal artery (stenosis <50%) was investigated with ANGiography and ivUS (ANGUS) to provide 3D lumen and wall geometry. Selection of segments >5 mm in length, in between side branches, yielded 25 segments in 12 patients. SS at the wall was calculated by computational fluid dynamics. WT smaller than 0.2*lumen diameter was defined as normal. Largest arc of normal WT defined reference cross sections. Lumen area relative to the reference cross sections defined area stenosis (AS). Average segmental AS smaller or greater than 10% defined preserved or narrowed lumen, respectively. Total vessel area relative to the reference defined vascular remodeling (VR). For the preserved lumens (n=11, AS=1.7±5.6%,
P
=NS), axially averaged WT and SS were inversely related (slope, −0.46±0.55 mm/Pa,
P
<0.05) and VR was positive (7±9%,
P
<0.05). Narrowed segments (n=13, 1 excluded, AS=18±6%,
P
<0.05) showed no relation between WT and SS or vascular remodeling.

Conclusions—

In patient coronary arteries, the often-reported inverse WT-SS relationship appears restricted to lumen preservation and positive vascular remodeling. Its disappearance with lumen narrowing suggests a growing importance of non-SS–related plaque progression.
Racial Differences in Outcome in the Multicenter UnSustained Tachycardia Trial (MUSTT)
Authors: Russo Andrea M. , Hafley Gail E. , Lee Kerry L. , Stamato Nicholas J. , Lehmann Michael H. , Page Richard L. , Kus Teresa , Buxton Alfred E. ,   the MUSTT Investigators
Published: June 2003

Background—

The Multicenter UnSustained Tachycardia Trial (MUSTT) demonstrated the benefit of implantable cardioverter-defibrillators (ICDs) in patients with coronary disease, asymptomatic nonsustained ventricular tachycardia, and reduced left ventricular function. Previous studies have shown racial differences in risk of sudden death in patients with ischemic heart disease.

Methods and Results—

We analyzed the influence of race on results of MUSTT. Whites were more likely to have prior revascularization and inducible, randomizable sustained ventricular arrhythmias and less likely to have left ventricular hypertrophy than were blacks. Compared with blacks, whites randomly assigned to electrophysiologically (EP)-guided therapy had a lower risk of arrhythmic death/cardiac arrest (adjusted
P
=0.003) and lower total mortality rates (adjusted
P
=0.051). In contrast, there was no racial difference in the risk of arrhythmic death/cardiac arrest among patients randomly assigned to no EP-guided therapy (adjusted
P
=0.477). Among whites, EP-guided therapy resulted in a survival benefit compared with no EP-guided therapy. However, survival of blacks randomly assigned to no EP-guided therapy was better than blacks receiving EP-guided therapy. This difference is partially explained by a higher ICD implantation rate in whites versus blacks (50% versus 28%,
P
=0.034). Whites were more likely to remain inducible after serial EP-guided drug testing (67% versus 42%,
P
=0.011), making them more likely to become eligible for ICDs.

Conclusions—

The outcome in this trial and the benefit of EP-guided therapy appeared to be influenced by race. In addition to differences in ICD implantation rates, differences in arrhythmic substrates and proarrhythmic responses to antiarrhythmic drugs may have influenced outcome.
Differentiation of Heart Failure Related to Dilated Cardiomyopathy and Coronary Artery Disease Using Gadolinium-Enhanced Cardiovascular Magnetic Resonance
Authors: McCrohon J.A. , Moon J.C.C. , Prasad S.K. , McKenna W.J. , Lorenz C.H. , Coats A.J.S. , Pennell D.J.
Published: June 2003

Background—

Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) from left ventricular (LV) dysfunction caused by coronary artery disease (CAD).

Methods and Results—

Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%).

Conclusions—

Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM.
Targeted In Vivo Labeling of Receptors for Vascular Endothelial Growth Factor
Authors: Lu Erxiong , Wagner William R. , Schellenberger Ute , Abraham Judith A. , Klibanov Alexander L. , Woulfe Steven R. , Csikari Melissa M. , Fischer David , Schreiner George F. , Brandenburger Gary H. , Villanueva Flordeliza S.
Published: June 2003

Background—

A method for identifying tissue experiencing hypoxic stress due to atherosclerotic vascular disease would be clinically useful. Vascular endothelial growth factor-121 (VEGF
121
) is an angiogenic protein secreted in response to hypoxia that binds to VEGF receptors overexpressed by ischemic microvasculature. We tested the hypothesis that VEGF receptors could serve as markers for ischemic tissue and hence provide a target for imaging such tissue with radiolabeled human VEGF
121
.

Methods and Results—

A rabbit model of unilateral hindlimb ischemia was created by femoral artery excision (n=14). Control rabbits (n=5) underwent identical surgery without femoral excision. On postoperative day 10, rabbits were intravenously administered 100 μCi of
111
In-labeled recombinant human VEGF
121
, and biodistribution studies and planar imaging were conducted at 3, 24, and 48 hours. On postmortem gamma counting, there was greater accumulation of
111
In-labeled VEGF
121
in ischemic than in control tissue (
P
<0.02). Differential uptake of isotope by ischemic muscle was not seen in rabbits injected with
125
I-labeled human serum albumin (n=6). Radioactivity imaged in hindlimb regions of interest was significantly higher in ischemic muscle than in sham-operated and contralateral nonoperated hindlimb at 3 hours (
P
<0.02). Immunohistochemical staining confirmed upregulation of VEGF receptors in ischemic skeletal muscle.

Conclusions—

Identification of the ischemic state via targeted radiolabeling of hypoxia-induced angiogenic receptors is possible. This approach could be useful for monitoring the efficacy of revascularization strategies such as therapeutic angiogenesis.
Pancreatic Bile Salt-Dependent Lipase Induces Smooth Muscle Cells Proliferation
Authors: Augé Nathalie , Rebaï Ouafa , Lepetit-Thévenin Josette , Bruneau Nadine , Thiers Jean-Claude , Mas Eric , Lombardo Dominique , Negre-Salvayre Anne , Vérine Alain
Published: June 2003

Background—

Because bile salt-dependent lipase (BSDL), an enzyme secreted by the pancreatic acinar cells and associated with LDL in circulating blood, also locates with smooth muscle cells (SMCs) in atherosclerotic lesions, we aimed to investigate its effects on SMCs.

Methods and Results—

Immunohistochemical experiments allowed us to detect an expression of BSDL in atherosclerotic lesions from hypercholesterolemic monkeys and from human arteries. BSDL was found to be associated with SMCs but not with macrophages. BSDL was significantly mitogenic for cultured SMCs. This effect was inhibited by heparin and anti-BSDL antibodies, whereas heat-denaturated and diisopropylfluorophosphate-treated BSDL were inefficient. The mitogenic effect of BSDL was associated with an activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway, which was inhibited by heparin, and involved several mechanisms, among them diacylglycerol and oleic acid production as well as a rapid basic fibroblast growth factor release.

Conclusions—

Circulating BSDL is associated with SMCs within the intimal arteria and may trigger SMC proliferation, which could contribute to the development of atherosclerotic lesions.
Staphylococcus aureus
Bacteremia After Median Sternotomy
Authors: Fowler Vance G. , Kaye Keith S. , Simel David L. , Cabell Christopher H. , McClachlan Douglas , Smith Peter K. , Levin Scott , Sexton Daniel J. , Reller L. Barth , Corey G. Ralph , Oddone Eugene Z.
Published: June 2003

Background—

Mediastinitis is a complication of coronary artery bypass graft surgery (CABG) that can be difficult to diagnose. This study evaluated the utility of blood culture results in identifying patients with mediastinitis.

Methods and Results—

All unique patients undergoing CABG at our institution over a 60-month study period (n=5500) and all blood cultures performed on these patients ≤90 days after CABG were identified. Mediastinitis was identified by prospective active infection control surveillance. Eight hundred fifty-five (15.5%) patients had ≥1 blood culture drawn within 90 days of CABG. Mediastinitis occurred in 46 of 60 (76.7%) patients with blood cultures positive for
Staphylococcus aureus
, 15 of 126 (11.9%) patients with blood cultures positive for other pathogens, 37 of 669 (5.5%) patients with blood cultures with no growth, and 44 of 4645 (0.9%) patients with no blood cultures obtained. The isolation of
S aureus
from even 1 blood culture drawn after ≤90 days of CABG was strongly associated with mediastinitis (likelihood ratio [LR], 25; 95% CI, 14.7 to 44.4). Bacteremia attributable to other organisms did not alter pretest suspicion for mediastinitis (LR, 1.0; 95% CI, 0.6 to 1.7). Patients with negative blood cultures were less likely to have mediastinitis (LR, 0.45; 95% CI, 0.35 to 0.58). The association between
S aureus
bacteremia and mediastinitis remained highly significant when all unique patients undergoing CABG were analyzed in a logistic regression model and when a case-control analysis was used to evaluate patients with ≥1 blood culture obtained after CABG.

Conclusions—

Among patients with blood cultures drawn after CABG,
S aureus
bacteremia strongly suggests the presence of mediastinitis.
Randomized Evaluation of Polytetrafluoroethylene-Covered Stent in Saphenous Vein Grafts
Authors: Stankovic Goran , Colombo Antonio , Presbitero Patrizia , van den Branden Frank , Inglese Luigi , Cernigliaro Carmelo , Niccoli Luigi , Bartorelli Antonio L. , Rubartelli Paolo , Reifart Nicholaus , Heyndrickx Guy R. , Saunamäki Kari , Morice Marie Claude , Sgura Fabio A. , Di Mario Carlo
Published: June 2003

Background—

Treatment of lesions located in saphenous vein grafts (SVGs) is associated with increased procedural risk and a high rate of restenosis.

Methods and Results—

We conducted a randomized, multicenter trial to evaluate the usefulness of a polytetrafluoroethylene (PTFE)-covered stent compared with a bare stainless steel (SS) stent for prevention of restenosis and major adverse cardiac events (MACE) in patients undergoing SVG treatment. The primary end point was angiographic restenosis at 6 months. Secondary end points were 30-day and 6-month MACE rates, defined as the cumulative of death, myocardial infarction (MI), and target lesion revascularization. Between September 1999 and January 2002, 301 patients with SVG lesions were randomized to either the PTFE-covered JoStent coronary stent graft (PTFE group, n=156) or the SS JoFlex stent (control group, n=145). Angiographic and procedural success rates were similar between the 2 groups (97.4% versus 97.9% and 87.3% versus 93.8%, respectively). The incidence of 30-day MACE was higher in the PTFE group (10.9% versus 4.1%,
P
=0.047) and was mainly attributed to MI (10.3% versus 3.4%,
P
=0.037). The primary end point, the restenosis rate at 6-month follow-up, was similar between the 2 groups (24.2% versus 24.8%,
P
=0.237). Although the 6-month non–Q-wave MI rate was higher in the PTFE group (12.8% versus 4.1%,
P
=0.013), the cumulative MACE rate was not different (23.1% versus 15.9%,
P
=0.153).

Conclusions—

The study did not demonstrate a difference in restenosis rate and 6-month clinical outcome between the PTFE-covered stent and the SS stent for treatment of SVG lesions. However, a higher incidence of nonfatal myocardial infarctions was found in patients treated with the PTFE-covered stent.
C-Reactive Protein, Carotid Intima-Media Thickness, and Incidence of Ischemic Stroke in the Elderly
Authors: Cao Jie J. , Thach Chau , Manolio Teri A. , Psaty Bruce M. , Kuller Lewis H. , Chaves Paulo H.M. , Polak Joseph F. , Sutton-Tyrrell Kim , Herrington David M. , Price Thomas R. , Cushman Mary
Published: June 2003

Background—

Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT.

Methods and Results—

We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (
P
<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT.

Conclusions—

We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.
Effect of Antidepressants and Their Relative Affinity for the Serotonin Transporter on the Risk of Myocardial Infarction
Authors: Sauer William H. , Berlin Jesse A. , Kimmel Stephen E.
Published: June 2003

Background—

Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), attenuate platelet activation by depleting serotonin storage and may decrease risk of myocardial infarction (MI). These drugs differ in their affinity for the platelet serotonin transporter and therefore may vary in their effects on MI protection.

Methods and Results—

A case-control study of first MI in patients aged 40 through 75 years was conducted among 36 hospitals in a 5-county area during a 3-year period. Case subjects were patients hospitalized with a first MI, and control subjects were randomly selected from the same geographic area. Detailed information regarding medication use and other clinical and demographic data were obtained by telephone interview. Among the 1080 cases and 4256 controls who participated, there were 223 users of antidepressants with high serotonin transporter affinity, all of which were SSRIs (paroxetine, fluoxetine, and sertraline). After adjustment with multivariable logistic regression for age, gender, race, education, physical activity, quantity of cigarettes smoked per day, body mass index, aspirin use, family history of MI, and history of diabetes, hypertension, or hypercholesterolemia, the odds ratio for MI among current users of antidepressants with high serotonin transporter affinity compared with nonusers was 0.59 (95% CI 0.39 to 0.91;
P
=0.02). Increasing serotonin transporter affinity was associated with reduced odds of MI among users of all SSRIs (
P
for trend <0.01) but not tricyclic (
P
=0.77) or atypical (
P
=0.70) antidepressants. There was no association detected between non-SSRI antidepressant use and MI.

Conclusions—

Increasing serotonin transporter affinity correlates with greater MI protection with SSRI but not other antidepressant exposure.
Habitual Dietary Intake of n-3 and n-6 Fatty Acids in Relation to Inflammatory Markers Among US Men and Women
Authors: Pischon Tobias , Hankinson Susan E. , Hotamisligil Gökhan S. , Rifai Nader , Willett Walter C. , Rimm Eric B.
Published: June 2003

Background—

Polyunsaturated fatty acid intake favorably affects chronic inflammatory-related diseases such as cardiovascular disease; however, high intake of n-6 fatty acids may attenuate the known beneficial effects of n-3 fatty acids.

Methods and Results—

We investigated habitual dietary n-3 fatty acid intake and its interaction with n-6 fatty acids in relation to the plasma inflammatory markers C-reactive protein, interleukin 6, and soluble tumor necrosis factor receptors 1 and 2 (sTNF-R1 and R2) among 405 healthy men and 454 healthy women. After adjustment for other predictors of inflammation, intake of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was inversely associated with plasma levels of sTNF-R1 and sTNF-R2 (
P
=0.03 and
P
<0.001, respectively) and somewhat less so for C-reactive protein (
P
=0.08). n-3 α-linolenic acid and n-6 cis-linoleic acid were not significantly related to the inflammatory markers. We found little if any association between n-3 fatty acid (EPA+DHA) intake and tumor necrosis factor receptors among participants with low intake of n-6 but a strong inverse association among those with high n-6 intake (
P
=0.04 and 0.002 for interaction of n-3 with n-6 on sTNF-R1 and sTNF-R2, respectively).

Conclusions—

These results suggest that n-6 fatty acids do not inhibit the antiinflammatory effects of n-3 fatty acids and that the combination of both types of fatty acids is associated with the lowest levels of inflammation. The inhibition of inflammatory cytokines may be one possible mechanism for the observed beneficial effects of these fatty acids on chronic inflammatory-related diseases.
Impaired Arteriogenic Response to Acute Hindlimb Ischemia in CD4-Knockout Mice
Authors: Stabile Eugenio , Burnett Mary Susan , Watkins Craig , Kinnaird Timothy , Bachis Alessia , la Sala Andrea , Miller Jonathan M. , Shou Matie , Epstein Stephen E. , Fuchs Shmuel
Published: June 2003

Background—

T lymphocytes, components of the immune and inflammatory systems, are involved in such normal processes as wound healing and host defense against infection and in such pathological processes as tumor growth and atherosclerotic plaque development. Angiogenesis is a mechanism common to each. Because CD4+ T lymphocytes are active in regulating humoral and cellular responses of the immune system, we determined whether CD4+ cells contribute to collateral vessel development by using the mouse ischemic hindlimb model.

Methods and Results—

One week after ischemia, CD4
−/−
mice showed reduced collateral flow induction, macrophage number, and vascular endothelial growth factor levels in the ischemic muscle compared with wild-type mice. There was also delayed recovery of hindlimb function and increased muscle atrophy/fibrosis. Spleen-derived purified CD4+ T cells infused into CD4
−/−
mice selectively localized to the ischemic limb and significantly increased collateral flow as well as macrophage number and vascular endothelial growth factor levels in the ischemic muscle. Muscle function and damage also improved.

Conclusions—

These results indicate an important role of CD4+ cells in collateral development, as demonstrated by a 25% decrease in blood flow recovery after femoral artery ligation. Our data also suggest that CD4+ T cells control the arteriogenic response to acute hindlimb ischemia, at least in part, by recruiting macrophages to the site of active collateral artery formation, which in turn triggers the development of collaterals through the synthesis of arteriogenic cytokines.
Diabetes Undermines Estrogen Control of Inducible Nitric Oxide Synthase Function in Rat Aortic Smooth Muscle Cells Through Overexpression of Estrogen Receptor-β
Authors: Maggi Adriana , Cignarella Andrea , Brusadelli Alessia , Bolego Chiara , Pinna Christian , Puglisi Lina
Published: June 2003

Background—

Previous reports from our group have shown that 17β-estradiol reduces the synthesis and activity of inducible nitric oxide synthase (iNOS) in rat aortic smooth muscle cells (SMC) in response to inflammatory mediators. In this study, we investigated the effect of 17β-estradiol on iNOS function in aortic SMC from streptozotocin-diabetic rats.

Methods and Results—

Comparative analysis of NO release and of iNOS mRNA and protein content after 24-hour stimulation with a cytokine mixture revealed milder iNOS activation in diabetic than in control SMC. Furthermore, 17β-estradiol dose-dependently blocked iNOS synthesis and activity in control but not in diabetic SMC. The defective estrogen response in diabetic SMC at 24 hours could not be attributed to reduced expression of estrogen receptors (ER). In fact, mRNA and protein levels of ERα and, to a greater extent, of ERβ, were increased in diabetic compared with nondiabetic SMC. Cytokines decreased ERα and ERβ expression in both groups. However, 17β-estradiol dose-dependently restored the expression of ERα but further downregulated that of ERβ, indicating a differential regulation of ER isoforms.

Conclusions—

Estrogenic control of iNOS was impaired in diabetic SMC. This was associated with a larger increase of ERβ than of ERα protein, whereas 17β-estradiol regulated the two isoforms in an opposite fashion. Thus, modifications in the estrogen modulation of iNOS and in the expression pattern of ER may be involved in diabetic vascular dysfunction.
Care and Outcomes of Patients Newly Hospitalized for Heart Failure in the Community Treated by Cardiologists Compared With Other Specialists
Authors: Jong Philip , Gong Yanyan , Liu Peter P. , Austin Peter C. , Lee Douglas S. , Tu Jack V.
Published: June 2003

Background—

It is not known whether subspecialty care by cardiologists improves outcomes in heart failure patients from the community over care by other physicians.

Methods and Results—

Using administrative data, we monitored 38 702 consecutive patients with first-time hospitalization for heart failure in Ontario, Canada, between April 1994 and March 1996 and examined differences in processes of care and clinical outcomes between patients attended by physicians of different disciplines. We found that patients attended by cardiologists had lower 1-year risk-adjusted mortality than those attended by general internists, family practitioners, and other physicians (28.5% versus 31.7%, 34.9%, and 35.9%, respectively; all pairwise comparisons,
P
<0.001). The 1-year risk-adjusted composite outcome of death and readmission for heart failure was also lower for the cardiologists compared with family practitioners and other physicians but not general internists (54.7% versus 58.1%, 58.3%, and 55.4%;
P
<0.001,
P
<0.001, and
P
=0.39, respectively). Multivariable hierarchical modeling demonstrated a significant physician-level effect for both outcomes in favor of the cardiologists, particularly against non-general internists. Cardiologist care was associated with higher adjusted rates of invasive interventions and postdischarge prescriptions of heart failure medications.

Conclusions—

In this population-based cohort, heart failure patients attended by cardiologists in hospital had lower risk of death as well as the composite risk of death or readmission than patients attended by noncardiologists. These data raise the need to identify specialty-driven differences in processes of care for heart failure patients, which may explain the observed disparity in clinical outcomes that presently favor cardiologist care.
Novel Index for Invasively Assessing the Coronary Microcirculation
Authors: Fearon William F. , Balsam Leora B. , Farouque H. M. Omar , Robbins Robert C. , Fitzgerald Peter J. , Yock Paul G. , Yeung Alan C.
Published: June 2003

Background—

A relatively simple, invasive method for quantitatively assessing the status of the coronary microcirculation independent of the epicardial artery is lacking.

Methods and Results—

By using a coronary pressure wire and modified software, it is possible to calculate the mean transit time of room-temperature saline injected down a coronary artery. The inverse of the hyperemic mean transit time has been shown to correlate with absolute flow. We hypothesize that distal coronary pressure divided by the inverse of the hyperemic mean transit time provides an index of microcirculatory resistance (IMR) that will correlate with true microcirculatory resistance (TMR), defined as the distal left anterior descending (LAD) pressure divided by hyperemic flow, measured with an external ultrasonic flow probe. A total of 61 measurements were made in 9 Yorkshire swine at baseline and after disruption of the coronary microcirculation, both with and without an epicardial LAD stenosis. The mean IMR (16.9±6.5 U to 25.9±14.4 U,
P
=0.002) and TMR (0.51±0.14 to 0.79±0.32 mm Hg · mL
−1
· min
−1
,
P
=0.0001), as well as the % change in IMR (147±66%) and TMR (159±105%,
P
=NS versus IMR % change), increased significantly and to a similar degree after disruption of the microcirculation. These changes were independent of the status of the epicardial artery. There was a significant correlation between mean IMR and TMR values, as well as between the % change in IMR and % change in TMR.

Conclusion—

Measuring IMR may provide a simple, quantitative, invasive assessment of the coronary microcirculation.
Cyclooxygenase-2 in Human and Experimental Ischemic Proliferative Retinopathy
Authors: Sennlaub F. , Valamanesh F. , Vazquez-Tello A. , El-Asrar A.M. , Checchin D. , Brault S. , Gobeil F. , Beauchamp M.H. , Mwaikambo B. , Courtois Y. , Geboes K. , Varma D.R. , Lachapelle P. , Ong H. , Behar-Cohen F. , Chemtob S.
Published: June 2003

Background—

Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)–2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy.

Methods and Results—

We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro. Specific COX-2 but not COX-1 inhibitors prevented intravitreal neovascularization, whereas prostaglandin E
2
, mainly via its prostaglandin E receptor 3 (EP
3
), exacerbated neovascularization. COX-2 inhibition induced an upregulation of thrombospondin-1 and its CD36 receptor, consistent with the observed antiangiogenic effects of COX-2 inhibition; EP
3
stimulation reversed effects of COX-2 inhibitors on thrombospondin-1 and CD36.

Conclusion—

These findings point to an important role for COX-2 in ischemic proliferative retinopathy, as in diabetes.
Heritability and Genetic Linkage of Plasma Natriuretic Peptide Levels
Authors: Wang Thomas J. , Larson Martin G. , Levy Daniel , Benjamin Emelia J. , Corey Diane , Leip Eric P. , Vasan Ramachandran S.
Published: June 2003

Background—

Natriuretic peptides play a critical role in the maintenance of salt and water homeostasis and regulation of vascular tone. Thus, interindividual variation in plasma natriuretic peptide levels may contribute to variation in susceptibility to volume overload and hypertension. It is unknown to what extent genetic factors contribute to variation in plasma natriuretic peptide levels.

Methods and Results—

We studied 1914 Framingham Study participants (mean age 57 years, 53% women) who underwent routine echocardiography and testing for plasma N-terminal proatrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP). We estimated sex-specific multivariable models and used variance-components methods, implemented in SOLAR (Sequential Oligogenic Linkage Analysis Routines), to estimate heritability. Multipoint linkage analyses were performed using data from a 10-cM-density genome scan. Age, clinical, and echocardiographic variables accounted for 42% and 40% of the variation in log N-ANP and log BNP levels, respectively, in men. Corresponding values in women were 27% and 21%. Multivariable-adjusted heritabilities were 0.44 for log N-ANP and 0.35 for log BNP (
P
<0.0001). Genome-wide linkage analyses, based on 1142 participants from the 314 largest families, revealed 2 regions of suggestive linkage for log N-ANP and log BNP on chromosomes 2p25 (log-of-odds score 2.40) and 12p13 (log-of-odds score 2.13), respectively.

Conclusions—

In this community-based sample, a substantial proportion of the unexplained variation in plasma natriuretic peptide levels was attributable to additive genetic effects. Additional studies using candidate gene approaches may provide insight into the genetic loci that regulate plasma natriuretic peptide levels in humans.
Increased Pressor Sensitivity to Chronic Nitric Oxide Deficiency in Hyperthyroid Rats
Authors: Rodríguez-Gómez Isabel , Sainz Juan , Wangensteen Rosemary , Moreno Juan Manuel , Duarte Juan , Osuna Antonio , Vargas Félix
Published: June 2003

We studied the effects of a possible interaction between partial nitric oxide deficiency and thyroid hormone excess on the long-term control of blood pressure (BP) and morphological and renal variables and examined the role of the renin-angiotensin system in the increased BP of this interaction. Eight groups (n=8 each) of male Wistar rats were used: a control group; 3 groups that were treated with thyroxine (50 μg/d),
N
w
-nitro-
l
-arginine methyl ester (
l
-NAME; subpressor dose, 1.5 mg · kg
−1
· d
−1
), or thyroxine plus
l
-NAME; and another 4 similarly treated groups that received losartan (20 mg · kg
−1
· d
−1
) in their drinking fluid. All treatments were maintained for 3 weeks. The time course of tail systolic BP was recorded once a week. At the end of the experimental period, we measured mean arterial pressure in conscious rats and assessed the morphological, metabolic, plasma, and renal variables. Thyroxine produced a mild BP increase from the second week of treatment and an increase in plasma angiotensin II and plasma nitrates/nitrites by the end of the study. Simultaneous administration of thyroxine and a subpressor dose of
l
-NAME produced a marked BP increase that reached significance from the first week of treatment. Losartan produced normotension in thyroxine-treated rats and attenuated the BP elevation in thyroxine+
l
-NAME–treated rats. Hyperthyroid rats showed relative renal and ventricular hypertrophy, absence of absolute left ventricular hypertrophy, and proteinuria. These alterations were not changed by losartan. We conclude that an impaired nitric oxide system might have a counterregulatory homeostatic role against the prohypertensive effects of thyroid hormone and that the renin-angiotensin system plays an important role in thyroxine+
l
-NAME hypertension.
De Novo Expression of Killer Immunoglobulin-Like Receptors and Signaling Proteins Regulates the Cytotoxic Function of CD4 T Cells in Acute Coronary Syndromes
Authors: Nakajima Takako , Goek Ömer , Zhang Xiaoyu , Kopecky Stephen L. , Frye Robert L. , Goronzy Jörg J. , Weyand Cornelia M.
Published: June 2003

The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4
+
T cells with a unique phenotype, CD4
+
CD28
null
, are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4
+
CD28
+
T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4
+
CD28
null
T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4
+
CD28
null
T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4
+
CD28
null
T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs (
P
<0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4
+
T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4
+
CD28
null
T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4
+
CD28
null
T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.
Modulation of Antioxidant Enzyme Expression and Function by Estrogen
Authors: Strehlow Kerstin , Rotter Simone , Wassmann Sven , Adam Oliver , Grohé Christian , Laufs Kerstin , Böhm Michael , Nickenig Georg
Published: June 2003

Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17β-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17β-estradiol diminished angiotensin II–induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17β-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17β-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
The ACCESS Study
Authors: Schrader Joachim , Lüders Stephan , Kulschewski Anke , Berger Jürgen , Zidek Walter , Treib Johannes , Einhäupl Karl , Diener Hans Christoph , Dominiak Peter
Published: June 2003

Background and Purpose—

The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke. The study was also designed to provide an estimate of the number of cases required to perform a larger phase III efficacy study.

Methods—

Five hundred patients were recruited in a prospective, double-blind, placebo-controlled, randomized, multicenter phase II study.

Results—

This safety trial was stopped prematurely when 342 patients (339 valid) had been randomized because of an imbalance in end points. Demographic data, cardiovascular risk factors, and blood pressure on admission, on study onset, and within the whole study period were not significantly different between the 2 groups. However, the cumulative 12-month mortality and the number of vascular events differed significantly in favor of the candesartan cilexetil group (odds ratio, 0.475; 95% CI, 0.252 to 0.895). There were no significant differences in concomitant medication and in number or type of side effects.

Conclusions—

Although the mechanisms by which angiotensin type 1 (AT
1
) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar beneficial effects in cerebral and in myocardial ischemia. The fact that no cardiovascular or cerebrovascular event occurred as a result of hypotension is of significant clinical importance. When there is need for or no contraindication against early antihypertensive therapy, candesartan cilexetil is a safe therapeutic option according to the ACCESS results.
Prenatal Influences on Stroke Mortality in England and Wales
Authors: Barker David J.P. , Lackland Daniel T.
Published: June 2003

Background and Purpose—

Within Britain and the United States there are geographic variations in mortality from stroke that are not explained by differences in adult lifestyle. We report on the geographic distribution of stroke mortality in England and Wales and compare it with that in the United States.

Methods—

Data from 4 studies are presented. The geographic distribution of stroke deaths in England and Wales during 1968–1978 is compared with the distribution of (1) other causes of death during the same years, (2) neonatal and maternal mortality during 1911–1925, (3) average adult height, and (4) place of birth.

Results—

Areas of England and Wales with high stroke mortality were characterized in the past by poor living standards, demonstrated by high infant and maternal mortality rates and short stature in the adult population. People who were born in areas of high stroke mortality rather than migrating into them are at high risk. Stroke mortality is not geographically correlated with past postneonatal mortality independently of neonatal or maternal mortality. The geographic distribution of stroke mortality in the United States and England and Wales has features in common.

Conclusions—

Stroke may originate through maternal influences associated with poverty. This conclusion is supported by recent findings that rates of stroke in adult life are higher among people who had low birth weight.
Mortality and Recovery After Stroke in The Gambia
Authors: Walker Richard W. , Rolfe Michael , Kelly Peter J. , George Melville O. , James Oliver F.W.
Published: June 2003

Background and Purpose—

There are no previously published studies of the long-term outcome of stroke in sub-Saharan Africa. Our goal was to determine the case fatality, time to and cause of death, and recovery in a hospital cohort of stroke patients in The Gambia.

Methods—

For 1 year beginning April 1, 1990, any patient presenting to the Royal Victoria Hospital (Banjul) with a diagnosis of stroke or having a stroke as an inpatient was recruited. After a standardized assessment, patients were followed up at 1 month, 6 months, and 3 to 4 years to assess recovery or, for those who died, record the date and likely cause of death.

Results—

Mean age of the 106 patients (70 men) was 58 years (range, 20 to 93 years). By 1 and 6 months, 29 (27%) and 47 (44%), respectively, had died, with only 27 (25%) surviving to final follow-up (4 patients not traced). Death occurred in hospital in 43 patients (57%). Cause of death was the initial stroke in 46 (61%), further stroke in 5 (7%), infection in 9 (12%), miscellaneous in 8 (11%) (only 1 vascular), and unknown in 7 (9%). On Cox regression analysis, incontinence in the first 24 hours, sensory inattention, and impaired gag reflex on admission were significant predictors of mortality. Predictors of recovery were similar to those of developed countries.

Conclusions—

Despite the young mean age, there was a high case fatality rate. The main cause of death was the stroke itself, and ischemic heart disease was very rare.
Familial Clustering of Stroke According to Proband Age at Onset of Presenting Ischemic Stroke
Authors: Meschia James F. , Atkinson Elizabeth J. , O’Brien Peter C. , Brott Thomas G. , Brown Robert D. , Hardy John
Published: June 2003

Background and Purpose—

The magnitude of inherited risk of stroke may lessen with age, and this would have implications for optimizing genomic approaches to identifying genetic risk factors for stroke. We investigated the relationship between age and inherited risk of stroke.

Methods—

Family histories of stroke were obtained in systematic interviews with 310 adult men and women with recent CT- or MR-confirmed ischemic stroke. Probability of stroke in first-degree relatives was analyzed by logistic regression, adjusting for sibship size.

Results—

The probability of having a sibling with stroke increased as proband age at stroke presentation increased. Per decade increase in proband age, the odds ratio was 1.65 (95% confidence interval [CI], 1.20 to 2.28;
P
=0.002) for a concordant sibling and 1.69 (95% CI, 1.15 to 2.49;
P
=0.008) for ≥2 first-degree relatives with a history of stroke.

Conclusions—

Clustering of stroke was not greater in families with probands manifesting symptoms of stroke in earlier than later adulthood. The relationship between proband age and positive family history of stroke does not suggest an upper age-limit cutoff for genomewide linkage studies.
Mannitol Use in Acute Stroke
Authors: Bereczki Dániel , Mihálka László , Szatmári Szabolcs , Fekete Klára , Di Cesar David , Fülesdi Béla , Csiba László , Fekete István
Published: June 2003

Background and Purpose—

Mannitol is used worldwide to treat acute stroke, although its efficacy and safety have not been proven by randomized trials.

Methods—

In a tricenter, prospective study, we analyzed the 30-day and 1-year case fatality with respect to mannitol treatment status in 805 patients consecutively admitted within 72 hours of stroke onset. Confounding factors were compared between treated and nontreated patients.

Results—

Two thirds of the patients received intravenous mannitol as part of their routine treatment (mean dose, 47±22 g/d; mean duration, 6±3 days). The case fatality was 25% versus 16% (
P
=0.006) at 30 days and 38% versus 25% (
P
<0.001) at 1 year in the-mannitol treated and nontreated groups, respectively. Mannitol treatment effect was adjusted for age, stroke severity, fever in the first 3 days, and aspirin treatment (for ischemic strokes) in logistic regression models. Depending on the factors entered into the model, either no effect or harm could be attributed to mannitol. When the analysis was restricted to those admitted within 24 hours (n=568), case fatality differed significantly only at 1 year (35% in treated and 26% in nontreated patients,
P
=0.044). Although the prognostic scores of the Scandinavian Neurological Stroke Scale were similar in treated and nontreated patients, both in ischemic and hemorrhagic strokes, the patient groups differed in several factors that might also have influenced survival.

Conclusions—

Based on the results of this study, no recommendations can be made on the use of mannitol in acute stroke, and properly randomized, controlled trials should be performed to come to a final conclusion.
Metabolic Counterpart of Decreased Apparent Diffusion Coefficient During Hyperacute Ischemic Stroke
Authors: Nicoli F. , Lefur Y. , Denis B. , Ranjeva J.P. , Confort-Gouny S. , Cozzone P.J.
Published: June 2003

Background and Purpose—

Recent studies have shown that the brain ischemic area defined by the map of decreased apparent diffusion coefficient (ADC) obtained by diffusion-weighted imaging (DWI) during the first hours of ischemic stroke includes a significant part of ischemic penumbra. We hypothesize that the misjudgment of the final infarct size by ADC mapping may be related to a restricted ability of DWI to capture variations in the intensity of cellular suffering. In an attempt to characterize metabolically the hypoperfused brain parenchyma, we studied the relationship between ADC values and brain metabolic parameters measured by proton MR spectroscopic imaging (SI).

Methods—

Six patients with hyperacute ischemic stroke were explored within the first 7 hours after onset with the use of a MR protocol including T2*-weighted MRI, DWI, SI, perfusion-weighted imaging, and MR angiography.

Results—

This study demonstrates, for the first time, a wide gradient of ischemia-related metabolic anomalies within the abnormal area delineated by DWI during hyperacute ischemic stroke. In the narrow range of decreased mean ADC values (0.60 to 0.40×10
−9
m
2
· s
−1
), a 33% decrease in mean ADC is associated with a 122% increase in lactate/
N
-acetyl aspartate ratio. Mean ADC values never fall below 0.40×10
−9
m
2
· s
−1
within the severely affected ischemic tissue, while SI still detects a large metabolic heterogeneity inside areas showing similar decreased mean ADC values close to this threshold.

Conclusions—

Our results indicate that the region of very low mean ADC values observed during hyperacute ischemic stroke contains areas of various tissue damage intensity characterized by SI in relation to different stages of cellular metabolic injury. This observation may explain why ADC mapping does not reliably predict final infarct size.
Auditory Discrimination After Left-Hemisphere Stroke
Authors: Ilvonen Titta-Maria , Kujala Teija , Kiesiläinen Anita , Salonen Oili , Kozou Hesham , Pekkonen Eero , Roine Risto O. , Kaste Markku , Näätänen Risto
Published: June 2003

Background and Purpose—

We sought to determine the recovery of cortical auditory discrimination in aphasic, left-hemisphere-stroke patients by using an electrophysiological response called mismatch negativity (MMN) and speech-comprehension tests.

Methods—

MMN in 8 left-hemisphere stroke patients was recorded in response to duration and frequency changes in a repetitive, harmonically rich tone 4 and 10 days and again 3 and 6 months after their first unilateral stroke. Eight age-matched, healthy persons served as control subjects.

Results—

At 4 days after stroke onset, patients’ sound discrimination was impaired in their left hemisphere, as suggested by attenuated MMNs, especially to right-ear stimuli. At 3 months after stroke, however, MMN to the right-ear duration change had significantly increased and was of normal size. A significant change for the frequency MMN was found for left-ear stimuli between 3 and 6 months after stroke. During the follow-up period, progressive improvement in speech-comprehension tests was also observed. Furthermore, there was a significant correlation between the change in the duration MMN amplitude and the Boston Diagnostic Aphasia Examination speech-comprehension test from 10 days to 3 months after stroke.

Conclusions—

These results suggest that the MMN can be used as an index of the recovery of auditory discrimination.