bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Anatomic Isthmus Block With the Modified Right Atrial Maze Procedure for Late Atrial Tachycardia in Fontan Patients
Authors: Deal Barbara J. , Mavroudis Constantine , Backer Carl L. , Buck Scott H. , Johnsrude Christopher
Published: October 2002

Background

—

Late atrial reentry tachycardia (AT) after Fontan repair is common, with limited efficacy of medical therapy in preventing AT recurrence. In this study, two approaches to surgical arrhythmia ablation in patients with refractory AT undergoing Fontan revision are compared: cryoablation of the inferomedial right atrium (RA), and a more extensive modified RA maze procedure designed to eliminate all potential RA reentrant circuits.

Methods and Results

—

Fontan revision was performed in 23 patients with AT, using inferomedial RA cryoablation (Group 1, n=8) and modified RA maze procedure (Group 2, n=15). There was no difference in age at initial Fontan, age at Fontan revision, age at onset of AT, or number of failed antiarrhythmic medications. Patients underwent preoperative, intraoperative, and postoperative electrophysiological studies. Thirty-eight different tachycardia circuits were induced in preoperative studies with 3 major areas of RA involvement: the lower lateral RA, the atrial septum, and the inferomedial RA. At postoperative electrophysiological study, AT was inducible in 62% of Group 1 patients but only 7% of Group 2 patients (
P
<0.02). With mean follow-up of 43 months, 5 of 8 patients in Group 1 experienced AT recurrence compared with none in Group 2 (
P
<0.001). There was no significant difference in length of hospital stay or complication rate comparing the two groups.

Conclusion

—

Modified RA maze procedure is superior to anatomic isthmus block in treating reentrant AT in postoperative Fontan patients. The modified RA maze has eliminated AT recurrence at mid-term follow-up with low morbidity and mortality.
Elevated Levels of Oxidative DNA Damage and DNA Repair Enzymes in Human Atherosclerotic Plaques
Authors: Martinet Wim , Knaapen Michiel W.M. , De Meyer Guido R.Y. , Herman Arnold G. , Kockx Mark M.
Published: October 2002

Background—

The formation of reactive oxygen species is a critical event in atherosclerosis because it promotes cell proliferation, hypertrophy, growth arrest, and/or apoptosis and oxidation of LDL. In the present study, we investigated whether reactive oxygen species-induced oxidative damage to DNA occurs in human atherosclerotic plaques and whether this is accompanied by the upregulation of DNA repair mechanisms.

Methods and Results—

We observed increased immunoreactivity against the oxidative DNA damage marker 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG) in plaques of the carotid artery compared with the adjacent inner media and nonatherosclerotic mammary arteries. Strong 8-oxo-dG immunoreactivity was found in all cell types of the plaque including macrophages, smooth muscle cells, and endothelial cells. As shown by competitive ELISA, carotid plaques contained 160±29 8-oxo-dG residues/10
5
dG versus 3±1 8-oxo-dG residues/10
5
dG in mammary arteries. Single-cell gel electrophoresis showed elevated levels of DNA strand breaks in the plaque. The overall number of apoptotic nuclei was low (1% to 2%) and did not correlate with the amount of 8-oxo-dG immunoreactive cells (>90%). This suggests that initial damage to DNA occurs at a sublethal level. Several DNA repair systems that are involved in base excision repair (redox factor/AP endonuclease [Ref 1] and poly(ADP-ribose) polymerase 1 [PARP-1]) or nonspecific repair pathways (p53, DNA-dependent protein kinase) were upregulated, as shown by Western blotting and immunohistochemistry. Overexpression of DNA repair enzymes was associated with elevated levels of proliferating cell nuclear antigen.

Conclusions—

Our findings provide evidence that oxidative DNA damage and repair increase significantly in human atherosclerotic plaques.
Assessing Myocardial Viability and Infarct Transmurality With Left Ventricular Electromechanical Mapping in Patients With Stable Coronary Artery Disease
Authors: Perin Emerson C. , Silva Guilherme V. , Sarmento-Leite Rogerio , Sousa Andre L.S. , Howell Marcus , Muthupillai Raja , Lambert Brenda , Vaughn William K. , Flamm Scott D.
Published: October 2002

Background—

This study was designed to define myocardial viability and establish practical cut-off values for differentiating normal myocardial tissue from subendocardial and transmural scar tissue by using electromechanical mapping (EMM). We validated our results by delayed-enhancement cardiac MRI (DE-MRI).

Methods and Results—

We prospectively studied 15 ambulatory patients with stable coronary disease who were candidates for cardiac catheterization. Within 48 hours of EMM, DE-MRI was performed. Using EMM software, we created a bull’s eye precisely matched to that generated by DE-MRI. Segment by segment, we compared the MRI results to the corresponding unipolar voltage value for that same segment in the EMM bull’s eye. Of 300 total segments, 275 were compared. The segments were divided into normal (n=211), subendocardial scar (n=49), and transmural scar (n=15). We found that subendocardial (6.8±2.9 mV) and transmural (4.6±1.9 mV) scar segments had significantly less unipolar voltage than normal (11.6±4.5 mV) segments (
P
<0.05 for each comparison). When normal myocardium was compared with myocardium with subendocardial scar, the threshold for differentiating between the two areas was 7.9 mV (sensitivity, 80%; specificity, 80%). Comparison of normal tissue to transmural scar yielded a threshold of 6.9 mV (sensitivity, 93%; specificity, 88%).

Conclusions—

Our results demonstrate that normal myocardium can be accurately distinguished from myocardium with subendocardial or transmural infarcts on the basis of unipolar voltage values obtained through EMM. This is the first study to validate these results by using cardiac DE-MRI in humans.
Prevention of Diabetes-Induced Microangiopathy by Human Tissue Kallikrein Gene Transfer
Authors: Emanueli Costanza , Salis Maria B. , Pinna Alessandra , Stacca Tiziana , Milia Anna F. , Spano Alessandra , Chao Julie , Chao Lee , Sciola Luigi , Madeddu Paolo
Published: October 2002

Background—

Microvascular insufficiency represents a major cause of end-organ failure among diabetics.

Methods and Results—

In streptozotocin-induced diabetic mice, we evaluated the potential of human tissue kallikrein (hTK) gene as a sole therapy against peripheral microangiopathy. Local delivery of hTK gene halted the progression of microvascular rarefaction in hindlimb skeletal muscle by inhibiting apoptosis, thus ensuring an improved hemodynamic recovery in case of supervening vascular occlusion. The curative action of hTK did not necessitate insulin supplementation. Application of gene therapy at a stage of established microangiopathy stimulated vascular regeneration.

Conclusions—

Our studies indicate that hTK may represent a useful tool for the treatment of microvascular complications in diabetics.
CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species
Authors: Urbich Carmen , Dernbach Elisabeth , Aicher Alexandra , Zeiher Andreas M. , Dimmeler Stefanie
Published: October 2002

Background—

The CD40/CD40 ligand system is involved in atherogenesis. Activated T lymphocytes and platelets, which express high amounts of CD40 ligand (CD40L) on their surface, contribute significantly to plaque instability with ensuing thrombus formation, leading to acute coronary syndromes. Because reendothelialization may play a pivotal role for plaque stabilization, we investigated a potential role of CD40L on endothelial cell (EC) migration.

Methods and Results—

Stimulation of ECs with recombinant CD40L prevented vascular endothelial growth factor (VEGF)-induced EC migration, as determined by a “scratched wound assay.” In addition, activated T lymphocytes and platelets significantly inhibited VEGF-induced EC migration and tube formation in vitro. Because the activation of endothelial nitric oxide (NO) synthase and the release of NO are required for EC migration and angiogenesis, we analyzed the effect of NO. Coincubation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) did not reverse the inhibitory effect of CD40L on VEGF-induced EC migration and tube formation. In addition, EC migration induced by SNAP was completely inhibited by CD40L. CD40L, however, induced the production of reactive oxygen species and reduced endothelial NO bioavailability. This reactive oxygen species-dependent effect of CD40L stimulation was reversed with vitamin C or
N
-acetylcysteine.

Conclusions—

The activation of the CD40 receptor inhibits EC migration by increasing reactive oxygen species. The blockade of EC migration by CD40L may critically affect endothelial regeneration after plaque erosion and thereby may contribute to the increased risk for development of acute coronary events in patients with high circulating levels of CD40L.
Plasma Matrix Metalloproteinase-9 as a Marker of Blood Stasis in Varicose Veins
Authors: Jacob Marie-Paule , Cazaubon Michèle , Scemama Anthony , Prié Dominique , Blanchet Françoise , Guillin Marie-Claude , Michel Jean-Baptiste
Published: October 2002

Background

—

Possible intermediate circulating markers linking blood stasis to vein remodeling were explored in patients with varicose veins in the lower limbs.

Methods and Results

—

Blood was sampled at rest (supine position) and after a stasis of 30 minutes both in the varicose vein (limbs hanging down) and in the brachial vein (arm hanging down) as a paired control. Several endothelial and leukocyte markers were measured in plasma with the use of ELISA kits. Angiotensin-converting enzyme activity was determined by use of a specific substrate. Matrix metalloproteinases (MMPs) 9 and 2 were evaluated with the use of gelatin zymography. No markers were significantly modified after 30 minutes of blood stasis in the brachial vein. After 30 minutes of blood stasis in the varicose vein, oxygen partial pressure decreased (
P
<0.01). Although thrombomodulin, von Willebrand factor, vascular endothelial growth factor, and MMP-2 were not modified in these conditions, the proteins released by proteolysis from the endothelial membrane intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and angiotensin-converting enzyme were increased (
P
<0.01). After blood stasis in varicose veins, the leukocyte markers lactoferrin, myeloperoxidase, and interleukin-8 were not modified, whereas L-selectin shed from leukocytes increased (
P
<0.05), and a major increase in pro-MMP-9, which is released from tertiary granules during polymorphonuclear activation, was observed (
P
=0.0001).

Conclusions

—

The marked increase in plasma pro-MMP-9 activity provides evidence of polymorphonuclear activation and granule release in the varicose vein in response to postural blood stasis. Similarly, detection in the plasma of membrane proteins shed from the endothelium or leukocytes provides evidence of pericellular proteolysis.
Prognostic Implications of Abnormalities in Renal Function in Patients With Acute Coronary Syndromes
Authors: Al Suwaidi Jassim , Reddan Donal N. , Williams Kathryn , Pieper Karen S. , Harrington Robert A. , Califf Robert M. , Granger Christopher B. , Ohman E. Magnus , Holmes David R.
Published: October 2002

Background—

Outcomes in patients with mild to moderate renal function (RF) abnormalities presenting with acute coronary syndromes (ACS) are not well defined.

Methods and Results—

A convenience sample of 4 ACS trial databases including all enrolled patients was assessed to determine 30- and 180-day outcomes. The 4 trials were Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb, GUSTO-III, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A). Patients were stratified into ST-segment elevation (STE) and non–ST-segment elevation (NSE) groups and by the presence or absence of abnormal RF (creatinine clearance <70 mL/min). In the STE group, 7670 of 18 621 patients (41%) had abnormal RF. In the NSE group, 8152 of 19 304 (42%) had abnormal RF. Patients with abnormal RF were older, more often female, and more likely to have adverse baseline characteristics. They had higher mortality and higher mortality/nonfatal myocardial infarction (MI) at both 30 and 180 days, regardless of ST-segment status. Creatinine clearance was independently associated with risk of mortality (hazard ratio 0.79 in the STE group and 0.81 in the NSE group) and with risk of mortality/MI (hazard ratio 0.93) in the NSE group at 180 days.

Conclusions—

Patients presenting with ACS frequently have abnormal RF. Abnormal RF is a marker of adverse baseline clinical characteristics and is independently associated with increased risk of death and death/MI.
Low Serum Insulin-Like Growth Factor I Is Associated With Increased Risk of Ischemic Heart Disease
Authors: Juul Anders , Scheike Thomas , Davidsen Michael , Gyllenborg Jesper , Jørgensen Torben
Published: October 2002

Background—

Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD).

Methods and Results—

We conducted a nested case-control study within a large prospective study on cardiovascular epidemiology (DAN-MONICA). We measured IGF-I and IGFBP-3 in serum from 231 individuals who had a diagnosis of IHD 7.63 years after blood sampling and among 374 control subjects matched for age, sex, and calendar time. At baseline when all individuals were free of disease, subjects in the low IGF-I quartile had significantly higher risk of IHD during the 15-year follow-up period, with a relative risk (RR) of 1.94 (95% CI, 1.03 to 3.66) of IHD compared with the high IGF-I quartile group, when IGFBP-3, body mass index, smoking, menopause, diabetes, and use of antihypertensives were controlled for. Conversely, individuals in the high IGFBP-3 quartile group had an adjusted RR of 2.16 (95% CI, 1.18 to 3.95) of having IHD. Identification of a high-risk population with low IGF-I and high IGFBP-3 levels resulted in markedly higher risk of IHD (RR 4.07; 95% CI, 1.48 to 11.22) compared with the index group.

Conclusions—

Individuals without IHD but with low circulating IGF-I levels and high IGFBP-3 levels have significantly increased risk of developing IHD during a 15-year follow-up period. Our findings suggest that IGF-I may be involved in the pathogenesis of IHD.
Exercise-Induced Increase in Baroreflex Sensitivity Predicts Improved Prognosis After Myocardial Infarction
Authors: La Rovere Maria Teresa , Bersano Chiara , Gnemmi Marco , Specchia Giuseppe , Schwartz Peter J.
Published: October 2002

Background—

Despite the rational expectation for a survival benefit produced by exercise training among post–myocardial infarction (MI) patients, direct evidence remains elusive. Clinically, changes in autonomic balance toward lower vagal activity have consistently been associated with increased mortality risk; conversely, among both control and post-MI dogs, exercise training improved vagal reflexes and prevented sudden death. Accordingly, we tested the hypothesis that exercise training, if accompanied by a shift toward increased vagal activity of an autonomic marker such as baroreflex sensitivity (BRS), could reduce mortality in post-MI patients.

Methods and Results—

Ninety-five consecutive male patients surviving a first uncomplicated MI were randomly assigned to a 4-week endurance training period or to no training. Age (51±8 versus 52±8 years), site of MI (anterior 41% versus 43%), left ventricular ejection fraction (52±13 versus 51±14%), and BRS (7.9±5.4 versus 7.9±3.4 ms/mm Hg) did not differ between the two groups. After 4 weeks, BRS improved by 26% (
P
=0.04) in trained patients, whereas it did not change in nontrained patients. During a 10-year follow-up, cardiac mortality among the 16 trained patients who had an exercise-induced increase in BRS ≥3 ms/mm Hg (responders) was strikingly lower compared with that of the trained patients without such a BRS increase (nonresponders) and that of the nontrained patients (0 of 16 versus 18 of 79 [23%],
P
=0.04). Cardiac mortality was also lower among responders irrespective of training (4% versus 24%,
P
=0.04).

Conclusions—

Post-MI exercise training can favorably modify long-term survival, provided that it is associated with a clear shift of the autonomic balance toward an increase in vagal activity.
TIMP-1
Authors: Lindsay M. Mitchell , Maxwell Paul , Dunn Francis G.
Published: October 2002

This study was designed to document noninvasively the pathological mechanisms responsible for myocardial fibrosis and to assess the clinical utility of plasma markers of collagen synthesis and degradation as screening tools for the assessment of fibrosis in hypertension. We studied 100 never-treated hypertensive patients and 50 normal subjects. Echocardiographic assessment was made of left ventricular (LV) mass and diastolic filling using measurement of E:A ratio, E wave deceleration time (E dec), and isovolumic relaxation time (IVRT). The presence of diastolic dysfunction was taken as a surrogate marker for the presence of myocardial fibrosis. Plasma carboxy-terminal propeptide of collagen type I (PICP), carboxy-terminal telopeptide of collagen type I (CITP), and tissue inhibitor of matrix metalloproteinases type I (TIMP-1) were measured as markers of collagen synthesis, degradation, and inhibition of degradation, respectively. Plasma TIMP-1 was significantly elevated in the hypertensive cohort (358 ng/mL versus 253 ng/mL,
P
<0.001) as were CITP (5.2 μg/L versus 2.9 μg/L,
P
<0.001), and PICP (200 μg/L versus 166 μg/L,
P
<0.05). TIMP-1 was significantly elevated in patients with diastolic dysfunction (421 ng/mL versus 283 ng/mL
P
<0.01) and correlated with markers of diastolic filling, namely E:A ratio (
r
=0.26,
P
<0.05) and E Dec (
r
=0.41,
P
<0.01). A plasma TIMP-1 level of >500 ng/mL had a specificity of 97% and a positive predictive value of 96% in predicting diastolic dysfunction. In patients with untreated hypertension, there is evidence of increased collagen synthesis, degradation, and inhibition of degradation resulting in fibrosis. Our results demonstrate that plasma TIMP-1 correlates with markers of LV diastolic filling, is predictive of LV dysfunction, and is a potential noninvasive marker of fibrosis.
Relation of the G Protein β
3
-Subunit Polymorphism With Left Ventricle Structure and Function
Authors: Sedláček Kamil , Fischer Marcus , Erdmann Jeanette , Hengstenberg Christian , Holmer Stephan , Kürzinger Susanne , Muscholl Michael , Luchner Andreas , Riegger Günter A. , Hense Hans-Werner , Schunkert Heribert
Published: October 2002

The G protein β
3
-subunit C825T polymorphism results in a truncated splice variant protein that is associated with enhanced transmembrane signaling, increased proliferative activity, and arterial hypertension. The aim of the present study was to further investigate the association of this polymorphism with left ventricular (LV) structure and function. A total of 2052 individuals from a large-scale population-based sample were investigated for the G protein β
3
-subunit C825T polymorphism and echocardiographic parameters of LV structure and function. Complete genotyping and echocardiographic data were available in 1720 individuals (829 men and 891 women). The mean LV mass indices in men with CC (n=384) and TT (n=84) genotypes were 98.3±1.2 g/m
2
and 100.0±2.8 g/m
2
, respectively (
P
=0.64). In women, the corresponding values were 83.1±1.0 g/m
2
for the CC genotype (n=397) and 83.8±2.1 g/m
2
for the TT genotype (n=91,
P
=0.32). Likewise, LV dimensions or parameters of the diastolic function and serologic markers of LV mass were not associated with the C825T variant. Finally, multivariate analyses accounting for potentially confounding factors failed to show any influence of this polymorphism on echocardiographic parameters. In conclusion, we were not able to confirm the previously published associations of the G protein β
3
-subunit C825T polymorphism with LV structure and diastolic function.
ET
B
Receptor in Renal Medulla Is Enhanced by Local Sodium During Low Salt Intake
Authors: Vanni Simone , Polidori Gianluca , Cecioni Ilaria , Serni Sergio , Carini Marco , Modesti Pietro Amedeo
Published: October 2002

Renal endothelin-1 participates in sodium and water handling, and its urinary excretion is increased in sodium-retentive states. We compared the cortical and medullary renal expression of prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin type A and type B receptors in patients who underwent nephrectomy after normal (108 mmol/d NaCl; n=6) or low (20 mmol/d NaCl; n=6) sodium diet and investigated whether sodium exerts a direct role on endothelin receptor binding in vitro. With normal sodium diet prepro-endothelin-1 mRNA was 3-fold higher in renal medulla than in cortex (
P
<0.01), whereas endothelin-converting enzyme-1 mRNA was equally distributed. Endothelin-1 receptor density was 2-fold higher in renal medulla than in cortex (
P
<0.05). Type B was the main receptor subtype in both regions. In the renal cortex, low sodium diet caused a 194% increase in prepro-endothelin-1 mRNA (
P
<0.05), whereas endothelin-converting enzyme-1 type B and type A receptors remained unchanged. In contrast, in the renal medulla the increase in prepro-endothelin-1 mRNA (+30%,
P
<0.05) was associated with a selective increase in type B receptor for both mRNA expression (+37%,
P
<0.05) and binding density (+55%,
P
<0.05). Increasing in vitro sodium concentrations between 154 and 308 mmol/L significantly enhanced type B receptor density (
P
<0.05) and affinity (
P
<0.05). In conclusion, during low sodium diet, renal prepro-endothelin-1 synthesis increases mainly in the renal cortex (where no changes in receptors occur), whereas type B receptor is selectively enhanced in the renal medulla. The range of sodium concentrations that are physiologically present in vivo in the renal medulla selectively modulate type B receptor density and affinity.
Cardiac Gap Junction Channels Show Quantitative Differences in Selectivity
Authors: Valiunas Virginijus , Beyer Eric C. , Brink Peter R.
Published: October 2002

Several proteins including connexin40 (Cx40) and connexin43 (Cx43) form gap junctions between cells of the heart; they may be found separately or may be coexpressed. These connexins form channels with differing conductance and permeability properties. Cx40 and Cx43 are each required for normal electrical conduction between cells in different regions of the heart. We hypothesized that the major difference between these connexins might be in their selective intercellular passage of small molecules such as second messengers, which can be assessed using biologically inert fluorescent probes. Therefore, we designed experimental paradigms to quantitate the permeability properties of these cardiac connexins using simultaneous measurement of junctional conductance (
g
j
) by the double whole-cell patch-clamp technique and intercellular transfer of Lucifer Yellow (LY) by fluorescence microscopy. These studies were performed in HeLa cells stably transfected with Cx40 or Cx43 or cotransfected with both connexins. We found that homotypic Cx43 channels were about 5 times more permeable to LY than homotypic Cx40 channels (flux of ≈1560 versus ≈300 molecules/channel per second). Channels between heterotypic (Cx40-Cx43) cell pairs and between pairs of coexpressing cells exhibited intermediate LY permeability. The permeability ratio for LY relative to monovalent cation (K
+
) ranged from 0.0025 for Cx40 to 0.028 for Cx43. These permeability ratios suggest that the connexins are highly selective for solutes in the size and charge range of many second messengers. Moreover, the data indicate that coexpression of connexins does not generate unique permeability characteristics, but rather results in an intermediate permeability for solutes involved in metabolic/biochemical coupling.
Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice
Authors: Mehrabian Margarete , Allayee Hooman , Wong Jack , Shih Weibin , Wang Xu-Ping , Shaposhnik Zory , Funk Colin D. , Lusis Aldons J.
Published: October 2002

We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor–null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor–null (LDLR
−/−
) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold;
P
<0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE
− /−
and LDLR
−/−
deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO
+/−
mice was transplanted into LDLR
−/−
, there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA
Authors: Park Ho-Jin , Kong Dequan , Iruela-Arispe Luisa , Begley Ulrike , Tang Dongjiang , Galper Jonas B.
Published: October 2002

Angiogenesis is implicated in the pathogenesis of cancer, rheumatoid arthritis, and atherosclerosis and in the treatment of coronary artery and peripheral vascular disease. Here, cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are shown to interfere with angiogenesis. In vivo, the HMG-CoA reductase inhibitor simvastatin dose-dependently inhibited capillary growth in both vascular endothelial growth factor–stimulated chick chorioallantoic membranes and basic fibroblast growth factor–stimulated mouse corneas. In vitro, the development of tubelike structures by human microvascular endothelial cells cultured on 3D collagen gels was inhibited at simvastatin concentrations similar to those found in the serum of patients on therapeutic doses of this agent. HMG-CoA reductase inhibitors interfered with angiogenesis via inhibition of the geranylgeranylation and membrane localization of RhoA. Simvastatin inhibited membrane localization of RhoA with a concentration dependence similar to that for the inhibition of tube formation, whereas geranylgeranyl pyrophosphate, the substrate for the geranylgeranylation of Rho, reversed the effect of simvastatin on tube formation and on the membrane localization of RhoA. Furthermore, tube formation was inhibited by GGTI, a specific inhibitor of the geranylgeranylation of Rho; by C3 exotoxin, which inactivates Rho; and by the adenoviral expression of a dominant-negative RhoA mutant. The expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on tube formation. Finally, HMG-CoA reductase inhibitors inhibited signaling by vascular endothelial growth factor, Akt, and focal adhesion kinase, three RhoA-dependent pathways known to be involved in angiogenesis. This study demonstrates a new relationship between lipid metabolism and angiogenesis and an antiangiogenic effect of HMG-CoA reductase inhibitors with possible important therapeutic implications.
Inducible Expression of BNIP3 Provokes Mitochondrial Defects and Hypoxia-Mediated Cell Death of Ventricular Myocytes
Authors: Regula Kelly M. , Ens Karen , Kirshenbaum Lorrie A.
Published: October 2002

In this study, we provide evidence for the operation of BNIP3 as a key regulator of mitochondrial function and cell death of ventricular myocytes during hypoxia. In contrast to normoxic cells, a 5.6-fold increase (
P
<0.05) in myocyte death was observed in cells subjected to hypoxia. Moreover, a significant increase in BNIP3 expression was detected in postnatal ventricular myocytes and adult rat hearts subjected to hypoxia. An increase in BNIP3 expression was detected in adult rat hearts in vivo with chronic heart failure. Subcellular fractionation experiments indicated that endogenous BNIP3 was integrated into the mitochondrial membranes during hypoxia. Adenovirus-mediated delivery of full-length BNIP3 to myocytes was toxic and provoked an 8.3-fold increase (
P
<0.05) in myocyte death with features typical of apoptosis. Mitochondrial defects consistent with opening of the permeability transition pore (PT pore) were observed in cells expressing BNIP3 but not in cells expressing BNIP3 missing the carboxyl-terminal transmembrane domain (BNIP3ΔTM), necessary for mitochondrial insertion. The pan-caspase inhibitor z-VAD-fmk (25 to 100 μmol/L) suppressed BNIP3-induced cell death of ventricular myocytes in a dose-dependent manner. Bongkrekic acid (50 μmol/L), an inhibitor of the PT pore, prevented BNIP3-induced mitochondrial defects and cell death. Expression of BNIP3ΔTM suppressed the hypoxia-induced integration of the endogenous BNIP3 protein and cell death of ventricular myocytes. To our knowledge, the data provide the first evidence for the involvement of BNIP3 as an inducible factor that provokes mitochondrial defects and cell death of ventricular myocytes during hypoxia.
Inactivation of Enhanced Expression of G
i
Proteins by Pertussis Toxin Attenuates the Development of High Blood Pressure in Spontaneously Hypertensive Rats
Authors: Li Yuan , Anand-Srivastava Madhu B.
Published: October 2002

We have previously shown that the enhanced expression of G
i
proteins in spontaneously hypertensive rats (SHR) that precedes the development of high blood pressure may be one of the contributing factors in the pathogenesis of hypertension. In the present study, we demonstrate that the inactivation of G
i
proteins by intraperitoneal injection of pertussis toxin (PT, 1.5 μg/100 g body wt) into 2-week-old prehypertensive SHR prevented the development of hypertension up to 4 weeks and that, thereafter, it started to increase and reached the same level found in untreated SHR after 6 weeks. A second injection of PT after 4 weeks delayed the increase in blood pressure for another week. The PT-induced decrease in blood pressure in 6-week-old SHR was associated with a decreased level of G
iα
-2 and G
iα
-3 proteins in the heart, as determined by in vitro ADP ribosylation and immunoblotting. The decreased level of G
i
proteins was reflected in decreased G
i
functions. Furthermore, an augmentation of blood pressure to the same level in PT-treated SHR as found in untreated SHR was associated with enhanced expression and function of G
i
. These results indicate that the inactivation of G
i
proteins by PT treatment in prehypertensive SHR attenuates the development of hypertension and suggest that the enhanced levels of G
i
proteins that result in the decreased levels of cAMP and associated impaired cellular functions may be contributing factors in the pathogenesis of hypertension in SHR.
Examining the Lacunar Hypothesis With Diffusion and Perfusion Magnetic Resonance Imaging
Authors: Gerraty Richard P. , Parsons Mark W. , Barber P. Alan , Darby David G. , Desmond Patricia M. , Tress Brian M. , Davis Stephen M.
Published: October 2002

Background

—

The clinical diagnosis of subcortical cerebral infarction is inaccurate for lesion location and pathogenesis. Clinically suspected small perforating artery occlusions may be embolic infarcts, with important implications for investigation and treatment. New MRI techniques may allow more accurate determination of the stroke mechanism soon after admission.

Methods

—

In a prospective series of 106 patients evaluated with acute diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) within 24 hours of stroke, we enrolled 19 with a lacunar syndrome. On the basis of the topography, DWI and PWI findings, and outcome T
2
MRI, we determined whether the mechanism of infarction was single perforating vessel occlusion or large artery embolism.

Results

—

Thirteen patients had pure motor stroke, 2 had ataxic hemiparesis, and 4 had sensorimotor stroke. Six patients had lacunes on MRI, none with PWI lesions. Four patients had subcortical and distal cortical infarcts on DWI. Nine had solitary restricted striatocapsular infarcts. Seven of these 9 had PWI studies, 5 with PWI lesions. The presence of a PWI lesion reliably differentiated striatocapsular from lacunar infarction for solitary small subcortical infarcts (
P
=0.03).

Conclusion

—

DWI and PWI altered the final diagnosis of infarct pathogenesis from small perforating artery occlusion to large artery embolism in 13 of 19 patients presenting with lacunar syndromes. Lacunes cannot be reliably diagnosed on clinical grounds.
Source of Microembolic Signals in Patients With High-Grade Carotid Stenosis
Authors: Stork Jacinda L. , Kimura Kazumi , Levi Christopher R. , Chambers Brian R. , Abbott Anne L. , Donnan Geoffrey A.
Published: October 2002

Background and Purpose

—

In patients with both symptomatic and asymptomatic carotid artery stenoses, the relationship between carotid plaque characteristics and transcranial Doppler (TCD)–detected microembolic signals (MES) is unclear. The purpose of this study was to examine the relationship between macroscopically described plaque characteristics and MES in patients undergoing carotid endarterectomy.

Methods

—

Sequential patients scheduled for carotid endarterectomy underwent preoperative 30-minute TCD monitoring of the ipsilateral middle cerebral artery to detect MES. TCD signal analysis, by researchers who were blinded to patient information, was performed offline. Clinical variables of patients and macroscopic carotid plaque features seen at surgery were documented prospectively.

Results

—

Of the 109 patients (74 male, 35 female; mean age, 68.8±8.7 years) enrolled, 71 had ipsilateral carotid territory symptoms. MES were detected in 27 of all patients (25%). Twenty-two of 71 symptomatic patients (31%) compared with 5 of 38 asymptomatic patients (13%) had MES (
P
=0.046). Also, symptomatic patients had more emboli (total MES counts) than asymptomatic patients (
P
=0.010). The presence or absence of MES was not associated with plaque characteristics.

Conclusions

—

Our data do not confirm previous reports of an association between MES and macroscopic plaque characteristics. We hypothesize that smaller platelet aggregates and fibrin clots, which are not detected macroscopically, are the most likely sources of TCD-detected MES.
Online Automatic Discrimination Between Solid and Gaseous Cerebral Microemboli With the First Multifrequency Transcranial Doppler
Authors: Russell David , Brucher Rainer
Published: October 2002

Background and Purpose

—

The aim of this study was to assess the first multifrequency transcranial Doppler system that was specially developed to automatically detect and discriminate between solid and gaseous cerebral microemboli.

Methods

—

The multifrequency transcranial Doppler instrumentation insonates simultaneously with 2.5 and 2.0 MHz. Differentiation between solid and gaseous microemboli is based on the principle that solid microemboli reflect more ultrasound at the higher than at the lower frequency, whereas the opposite is the case for gaseous microemboli. In the in vitro studies, 159 plastic spheres (50 or 80 μm in diameter) and 105 gas bubbles (8 to 25 μm) were studied in a pulsatile closed-loop system containing irodinium or pig blood. In vivo studies were carried out for 1 hour in 15 patients with mechanical heart valves and in 45 patients with carotid stenosis. This gave a total of 60 hours of online automatic monitoring in patients.

Results

—

In the in vitro studies, 152 of the 159 (95.6%) plastic spheres were classified as solid, and 7 (4.4%) were classified as uncertain solid. Of the 105 gas bubbles, 99 (94.3%) were classified as gaseous and 6 (5.7%) as uncertain gaseous. Thus, correct classification was made for 251 (95.1%) of the 264 embolic events studied. A comparison between the automatic multifrequency discrimination and the known embolic classification gave a κ value of 0.897 (
P
<0.0001). The multifrequency Doppler classified 433 (84.2%) of the 514 emboli detected in the mechanical heart valve patients as gaseous, 74 (14.4%) as solid, and 7 (1.4%) as uncertain (3 uncertain solid, 4 uncertain gas). Thirty-two emboli were detected in 17 (38%) of the 45 carotid stenosis patients; 30 (93.7%) were classified as solid and 2 (6.3%) as uncertain solid.

Conclusions

—

This study has shown that multifrequency transcranial Doppler can be used to automatically differentiate between solid and gaseous microemboli online. Most detected microemboli in this initial study of mechanical heart valves were classified as gaseous, whereas most were classified as solid in the patients with carotid stenosis.
Release of Fatty Acid Amides in a Patient With Hemispheric Stroke
Authors: Schäbitz Wolf-R. , Giuffrida Andrea , Berger Christian , Aschoff Alfred , Schwaninger Markus , Schwab Stefan , Piomelli Daniele
Published: October 2002

Background

—

Excitotoxic insults such as stroke may induce release of fatty acid ethanolamides (FAEs), contributing to the downstream events in the ischemic cascade. We therefore studied release of FAEs such as anandamide, palmitylethanolamide (PEA), and oleylethanolamide (OEA) in the brain of a patient suffering from malignant hemispheric infarction treated with hypothermia.

Case Description

—

A patient with life-threatening hemispheric stroke was treated with moderate hypothermia (33°C) that was maintained for 3 days, followed by a 3-day rewarming period. Microdialysis was applied to measure glutamate, lactate, and glycerol by using a microdialysis analyzer. FAEs were measured by microdialysis coupled with high-performance liquid chromatography/mass spectrometry. Release of neuroprotective fatty amides occurred within the first day after ischemia and reached high concentrations for all 3 substances in tissue surrounding the primary ischemic lesion: anandamide up to 42 pmol/mL, PEA up to 120 pmol/mL, and OEA up to 242 pmol/mL. There was a significant correlation with elevation of lactate as early marker for the hypoxic insult.

Conclusions

—

This is the first report demonstrating release of FAEs in vivo during human stroke and may suggest contribution of the FAE signaling system to the pathophysiological events after ischemia.
Linoleic Acid, Other Fatty Acids, and the Risk of Stroke
Authors: Iso Hiroyasu , Sato Shinichi , Umemura Utako , Kudo Minako , Koike Kazuko , Kitamura Akihiko , Imano Hironori , Okamura Tomonori , Naito Yoshihiko , Shimamoto Takashi
Published: October 2002

Background and Purpose

—

The role of serum fatty acids as a risk factor for stroke and stroke subtypes is largely unknown.

Methods

—

A prospective nested case-control study of Japanese 40 to 85 years of age was conducted through the use of frozen serum samples from 7450 participants in cardiovascular risk surveys collected from 1984 to 1989 for 1 community and 1989 to 1992 for the other 2 communities. By the end of 1998, we identified 197 incident strokes whose subtypes were confirmed by imaging studies. Three controls per case were selected by matching for sex, age, community, year of serum storage, and fasting status.

Results

—

Compared with controls, total (n=197), hemorrhagic (n=75), and ischemic (n=122) strokes had similar proportions of n3 polyunsaturated fatty acids, lower proportions of linoleic and arachidonic acids, and higher proportions of saturated and monosaturated acids, determined by gas chromatography. The multivariate odds ratios associated with a 1-SD increase in linoleic acid (5%) after adjustment for hypertension, diabetes, serum total cholesterol, and other cardiovascular risk factors were 0.72 [95% confidence interval (CI), 0.59 to 0.89] for total stroke, 0.66 (95% CI, 0.49 to 0.88) for ischemic stroke, 0.63 (95% CI, 0.46 to 0.88) for lacunar infarction, and 0.81 (95% CI, 0.59 to 1.12) for hemorrhagic stroke. The respective odds ratios for saturated fatty acids (4%) were 1.13 (95% CI, 1.05 to 1.65), 1.35 (95% CI, 1.01 to 1.79), 1.44 (95% CI, 1.03 to 2.01), and 1.21 (95% CI, 0.82 to 1.80). Further adjustment for other fatty acids attenuated these relations, but the relation between linoleic acid and risk of ischemic stroke remained statistically significant.

Conclusions

—

A higher intake of linoleic acid may protect against ischemic stroke, possibly through potential mechanisms of decreased blood pressure, reduced platelet aggregation, and enhanced deformability of erythrocyte cells.
Study Design and Outcome Measures in Studies on Aneurysmal Subarachnoid Hemorrhage
Authors: van der Schaaf Irene C. , Ruigrok Ynte M. , Rinkel Gabriël J.E. , Algra Ale , van Gijn Jan
Published: October 2002

Background and Purpose

—

Methods of performing and reporting randomized clinical trials (RCTs) are available, but weaknesses still occur. For observational studies, methodology is less well described, and weaknesses are even more likely. In recent guidelines for patients with subarachnoid hemorrhage (SAH), 25% of treatment recommendations are based on clinical trials. To interpret the results of research on the therapeutic effect of treatment modalities, definition of outcome measures is essential. We assessed quality of study design and outcome measures and presence and precision of definitions concerning major complications of SAH in studies evaluating treatment strategies in patients with aneurysmal SAH.

Methods

—

We retrieved and reviewed all articles on treatment strategies in patients with SAH that fulfilled a prespecified set of criteria and were published during 1990–1999 in 10 general, neurosurgical, or neurological journals. We categorized articles into RCTs, observational studies with a control group, and observational studies without a control group. We assessed study design by means of a prespecified set of methodological criteria. For outcome measures we assessed whether a prespecified outcome measurement was defined and whether any handicap scale was used. For complications after SAH we assessed whether the definition included a description of the clinical features and a technical investigation with criteria for abnormal results.

Results

—

We identified 18 RCTs, 24 observational studies with a control group, and 41 uncontrolled observational studies. Two RCTs, no observational studies with a control group, and 15 observational studies without a control group met all criteria for study design. A primary outcome measure was specified in 67 of the 83 studies and was defined in 59. Any measure of handicap or information on degree of dependence was given in 65 of 83 studies. A complete definition of delayed cerebral ischemia was given in 13 of 66 studies, of rebleeding in 2 of 26 studies, and of hydrocephalus in 2 of 14 studies.

Conclusions

—

Most studies on treatment strategies in SAH suffer from methodological weaknesses. This implies that current management of patients with SAH is based on weak evidence.
Neuropsychological Predictors of Incident Dementia in Patients With Vascular Cognitive Impairment, Without Dementia
Authors: Ingles Janet L. , Wentzel Carolyn , Fisk John D. , Rockwood Kenneth
Published: October 2002

Background

—

Vascular cognitive impairment that does not fulfill dementia criteria (ie, vascular cognitive impairment, no dementia [CIND]) is common. Although progression to dementia is frequent, little is known about factors that predict progression. We examined whether performance on neuropsychological tests administered at baseline could predict incident cases of dementia in patients with vascular CIND after 5 years.

Summary of Report

—

The Canadian Study of Health and Aging is a prospective, cohort study of 10 263 randomly selected persons aged ≥65 years. Of 149 people diagnosed with vascular CIND, 125 completed a battery of neuropsychological tests at baseline. Follow-up cognitive diagnoses were available for 102 individuals. After 5 years, 45 patients (44%) developed dementia. Low baseline scores on tests of memory and category fluency were associated with incident dementia.

Conclusions

—

Neuropsychological measures can indicate risk of dementia in patients with vascular CIND. This study did not suggest a prediction-to-progression profile distinct from that seen in Alzheimer disease.
Cerebral Hypoperfusion Generates Cortical Watershed Microinfarcts in Alzheimer Disease
Authors: Suter Oda-Christina , Sunthorn Thanomphone , Kraftsik Rudolf , Straubel Joel , Darekar Pushpa , Khalili Kamel , Miklossy Judith
Published: October 2002

Background and Purpose

—

The watershed cortical areas are the first to be deprived of sufficient blood flow in the event of cerebral hypoperfusion and will be the sites of watershed microinfarcts. Cerebral hypoperfusion is associated with Alzheimer disease (AD), but information regarding the occurrence of watershed cortical infarcts in AD is lacking.

Methods

—

Brains of 184 autopsy cases (105 definite AD cases and 79 age-matched controls) were selected and analyzed by histochemical and immunohistochemical techniques. The 3-dimensional reconstruction of the whole cerebrum, with 3-mm spaced serial sections, was performed in 6 AD cases to study the intrahemispheric and interhemispheric distribution of the cortical microinfarcts.

Results

—

A significant association (
P
=0.001) was found between the occurrence of watershed cortical infarcts and AD (32.4% versus 2.5% in controls). The microinfarcts were restricted to the watershed cortical zones. Congophilic angiopathy was revealed to be an important risk factor. Perturbed hemodynamic factors (eg, decreased blood pressure) may play a role in the genesis of cortical watershed microinfarcts.

Conclusions

—

In AD, cerebral hypoperfusion induces not only white matter changes but cortical watershed microinfarcts as well, further aggravating the degenerative process and worsening dementia. To prevent the formation of watershed cortical microinfarcts in AD, monitoring blood pressure and treating arterial hypotension are essential.
Art Education and Urban Aesthetics
Authors: de Sousa Vianna Rachel
Published: October 2002

The widespread problem of visual illiteracy prevents people from perceiving the aesthetic quality of their surroundings. This inability represents a barrier to full participation by the public in debates over the kinds of cities they want to live in, and yet the physical qualities of the environment strongly affect the social and psychological well-being of its inhabitants. This article argues that art educators have an important role in fostering the awareness, understanding and appreciation of urban aesthetics. It then recounts the author's field study, which investigated the effectiveness of three instruments for developing understanding of urban aesthetics. The article concludes with some suggestions for art educators interested in developing programs for studying the urban environment.