bluuebunny/crossref_metadata_2025 huggingface dataset:
Counter-Regulatory Function of Protein Tyrosine Phosphatase 1B in Platelet-Derived Growth Factor– or Fibroblast Growth Factor–Induced Motility and Proliferation of Cultured Smooth Muscle Cells and in Neointima Formation
Authors: Chang Yingzi , Ceacareanu Bogdan , Zhuang Daming , Zhang Chunxiang , Pu Qinghua , Ceacareanu Alice C. , Hassid Aviv
Published: December 2005

Objectives—

We have previously reported that vascular injury or treatment of cultured vascular smooth muscle cells with platelet-derived growth factor-BB (PDGF-BB) or fibroblast growth factor-2 (FGF2) increases the levels of protein tyrosine phosphatase (PTP)1B. The current study was designed to test the hypothesis that PTP1B attenuates PDGF- or FGF-induced motility and proliferation of cultured cells, as well as neointima formation in injured rat carotid arteries.

Methods and Results—

Treatment of cultured cells with adenovirus expressing PTP1B decreased PDGF-BB– or FGF2-induced cell motility and blocked PDGF-BB– or FGF2-induced proliferation, whereas expression of dominant negative PTP1B (C215S-PTP1B) uncovered the motogenic effect of subthreshold levels of PDGF-BB or FGF2, increased neointimal and medial cell proliferation, and induced neointimal enlargement after balloon injury. The inhibitory effect of PTP1B directed against PDGF in cultured cells was associated with dephosphorylation of the PDGFβ receptor.

Conclusions—

PTP1B suppresses cell proliferation and motility in cultured smooth muscle cells treated with PDGF-BB or FGF2, and the phosphatase plays a counter-regulatory role in vascular injury-induced cell proliferation and neointima formation. Taken together with previous studies indicating increased PTP1B levels in cells treated with growth factors, the current findings are the first to report the existence of an inhibitory feedback loop involving PDGF or FGF, and PTP1B in blood vessels.
Diet and Murine Atherosclerosis
Authors: Getz Godfrey S. , Reardon Catherine A.
Published: December 2005

Lipid-enriched diets are often used to induce or accelerate the rate of atherosclerotic lesion development in murine models of atherosclerosis. It appears that the induction of persistent hypercholesterolemia to levels >&300 mg/dL is required for the development of experimental atherosclerosis in the mouse. A variety of different diets have been used that vary in the level of cholesterol, the level and type of fatty acid, and the absence or presence of cholate. Each of these components as well as the protein source has been shown to influence lipoprotein level and/or atherosclerosis, with dietary cholesterol being the major proatherogenic component. In some instances the effects of these components on the expression of hepatic genes relevant to lipid homeostasis has been observed. An appreciation of the effect of the differences in diet composition on these processes is important to compare results from different atherosclerosis studies, so the composition of the diets used should always be reported or referenced. Cholate should not be used unless its effects are being specifically investigated.
Pravastatin Inhibits Expression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) in Watanabe Heritable Hyperlipidemic Rabbits
Authors: Hofnagel Oliver , Luechtenborg Birgit , Eschert Heike , Weissen-Plenz Gabriele , Severs Nicholas J. , Robenek Horst
Published: December 2005

Background—

LOX-1, a receptor for oxidized low-density lipoprotein (OxLDL), seems to play a critical role in foam cell formation of macrophages (Mφs) and smooth muscle cells (SMC). Inhibition of LOX-1 expression reduces foam cell formation and might influence lipid core formation in atherosclerotic lesions. Because statins are able to downregulate LOX-1 expression in vitro, we examined if pravastatin can be used to reduce LOX-1 expression and lipid core formation in lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits.

Methods and Results—

Pravastatin downregulated LOX-1 expression in cultured human Mφs and in cultured human aortic SMCs. Homozygous WHHL rabbits were treated with 50 mg kg
−1
d
−1
pravastatin for 32 weeks. Immunohistochemical studies revealed that LOX-1 was expressed in intimal Mφs and SMCs of atherosclerotic lesions. The pravastatin-treated rabbits showed, compared with untreated rabbits, a significantly reduced LOX-1 protein and mRNA expression in the aortic arch. Lipid labeling of this aorta region also demonstrated a strong reduction of the ratio of lipid core area/total lesion area in pravastatin-treated rabbits.

Conclusions—

The in vivo inhibition of LOX-1 expression by pravastatin demonstrated here represents a new pleiotropic effect of pravastatin. This in vivo inhibition of LOX-1 might be one mechanism for the lipid core reducing effect of pravastatin in atherogenesis.
Lipoprotein-Associated Phospholipase A2 and Measures of Extracoronary Atherosclerosis
Authors: Kardys Isabella , Oei Hok-Hay S. , van der Meer Irene M. , Hofman Albert , Breteler Monique M.B. , Witteman Jacqueline C.M.
Published: December 2005

Objective—

Lipoprotein-associated phospholipase A2 (Lp-PLA2) may be a new and independent predictor of cardiovascular events. The effect of Lp-PLA2 may be exerted through effects of the enzyme on the development of atherosclerosis. Therefore, we investigated the association between Lp-PLA2 activity and measures of extracoronary atherosclerosis.

Methods and Results—

Lp-PLA2 activity was determined in a random sample of 1820 participants from the Rotterdam Study, a population-based cohort study in men and women ≥55 years. Common carotid intima-media thickness, carotid plaques, ankle-arm index, and aortic calcification were examined. Atherosclerosis status could be assigned in 1609 participants. The age-adjusted odds ratio of having atherosclerosis at any site for the highest versus the lowest tertile of Lp-PLA2 activity was 1.86 (95% CI, 1.01 to 3.43) in men and 1.60 (95% CI, 1.08 to 2.37) in women. After additional adjustment for cholesterol, these associations attenuated or even disappeared. The odds ratios of having atherosclerosis at specific sites (carotid arteries and aortic-iliac-femoral tract) followed a similar pattern.

Conclusions—

Although Lp-PLA2 has been found to be independently associated with cardiovascular events, the association with measures of subclinical extracoronary atherosclerosis found in this study strongly attenuated or even disappeared after adjustment for cholesterol.
Pregnancy Prevents Hypertensive Remodeling of Cerebral Arteries
Authors: Cipolla Marilyn J. , DeLance Nicole , Vitullo Lisa
Published: December 2005

We investigated how hypertension during pregnancy affected passive structural (wall:lumen, wall stress) and active (myogenic activity) responses of the cerebral circulation. Female nonpregnant (NP; n=8) Sprague Dawley rats were compared with late-pregnant (LP; day 19 to 20, n=6) rats. Some animals were treated with the NO synthase inhibitor nitro-
l
-arginine in their drinking water to raise blood pressure. LP rats (n=6) were treated for the last 7 days of pregnancy (last trimester) to mimic preeclampsia and compared with NP rats treated for the same duration (n=8). Active and passive responses were determined on isolated and pressurized third-order posterior cerebral arteries. Nitro-
l
-arginine treatment significantly raised blood pressure in both groups of animals that was associated with increased wall thickness and wall:lumen ratio in the NP hypertensive animals versus controls (
P
<0.05). In contrast, this response to pressure was absent in LP animals, which had similar wall measurements. In addition, arteries from NP hypertensive animals had increased myogenic tone and pressure of forced dilatation compared with NP control animals (
P
<0.01). Again, this response was lacking in the LP hypertensive animals that had similar tone and pressure of forced dilatation as normotensive controls. The increased tone and wall thickness decreased wall stress in the NP hypertensive animals, a response that did not occur in LP hypertensive animals. Because medial hypertrophy is considered a protective response to elevated blood pressure, these results suggest that hypertension in pregnancy may predispose the cerebral circulation to autoregulatory breakthrough and blood–brain–barrier disruption when blood pressure is elevated, as during eclampsia.
Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat
Authors: Padia Shetal H. , Howell Nancy L. , Siragy Helmy M. , Carey Robert M.
Published: December 2005

Whereas angiotensin (Ang) II is the major effector peptide of the renin–angiotensin system, its metabolite, des-aspartyl1-Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT1) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT2) blocker, on Na+excretion (UNaV) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on UNaV with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na+intake, RI CAND increased UNaV from 0.07±0.08 to 0.82±0.17 μmol/min (P<0.01); this response was abolished by PD. During Na+restriction, CAND increased UNaV from 0.06±0.02 to 0.1±0.02 μmol/min (P<0.05); this response also was blocked by PD. In rats with both kidneys intact, in the absence of CAND, unilateral RI infusion of Ang III did not significantly alter UNaV. However, with systemic CAND infusion, RI Ang III increased UNaV from 0.08±0.01 μmol/min to 0.18±0.04 μmol/min (P<0.01) at 3.5 nmol/kg per minute, and UNaV remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter UNaV at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT1receptor blockade engenders natriuresis by activation of AT2receptors. AT2receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT1receptor blockade.
Does Obesity Induce Resistance to the Long-Term Cardiovascular and Metabolic Actions of Melanocortin 3/4 Receptor Activation?
Authors: da Silva Alexandre A. , Kuo Jay J. , Tallam Lakshmi S. , Liu Jiankang , Hall John E.
Published: December 2005

Previous studies suggest that blockade of melanocortin 3 and 4 receptors (MC3/4-R) markedly attenuates the chronic hypertensive effects of leptin. Although obesity has been reported to be associated with leptin “resistance,” it is unclear whether obesity alters the cardiovascular and metabolic effects of chronic MC3/4-R activation. Therefore, we tested whether the cardiovascular and metabolic actions of MC3/4-R activation are attenuated in Sprague-Dawley rats fed a high-fat diet (HF, n=6) compared with rats fed a standard chow (NF, n=6) for 12 months. A 21G steel cannula was placed in the lateral ventricle for ICV infusion, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) 24 hours/day and IV infusions. After a 5-day control period, rats were infused with MC3/4-R agonist melanotan II (10 ng/h, ICV), for 10 days followed by a 5-day recovery period. HF rats were heavier (558±21 versus 485±13 g) with 140% more visceral fat than NF rats, hyperleptinemic (8.9±0.5 versus 2.7±0.5 ng/mL), and insulin resistant. HF rats also had higher MAP (109±3 versus 100±1 mm Hg). Chronic melanotan II infusion significantly increased MAP in HF and NF (7±2 and 6±1 mm Hg), decreased caloric intake (−32±2 and −25 ±2 kcal/day), and reduced insulin levels in both groups by ≈50%. Thus, the metabolic and cardiovascular actions of chronic MC3/4-R activation are preserved in diet-induced obesity, supporting a potential role for the hypothalamic melanocortin system in obesity hypertension.
Synergistic Acceleration of Arterial Stiffening in the Presence of Raised Blood Pressure and Raised Plasma Glucose
Authors: Tomiyama Hirofumi , Hashimoto Hideki , Hirayama Yoji , Yambe Minoru , Yamada Jiko , Koji Yutaka , Shiina Kazuki , Yamamoto Yoshio , Yamashina Akira
Published: December 2005

Arterial stiffness is recognized as a marker of arterial damage and an indicator of cardiovascular risk. This observational study was conducted to examine the synergistic effect of raised blood pressure (RBP; ≥130/85 mm Hg) and raised plasma glucose (RPG; ≥110 mg/dL) even at levels below those conventionally used to define hypertension and diabetes on the rate of increase of the pulse wave velocity (PWV) over a 3-year period in 2080 Japanese men (age 42±9 years). First, the subjects were classified into 4 groups based on the presence at the first examination of RBP, RPG, both abnormalities, or neither abnormality. The estimated annual rate of increase of the PWV was higher in subjects with both the abnormalities than in those with either abnormality alone or neither of the 2 abnormalities. Second, the subjects were also classified based on the evolutional status of these abnormalities during the study period; persistence of both of the abnormalities synergistically accelerated the rate of increase of the PWV (68.3±7.1 cm/s per year), as compared with the persistence of either abnormality alone (persistence of RBP alone: 18.2±1.6 cm/s per year; persistence of RPG alone: 21.2±7.4 cm/s per year) or persistence of neither abnormality (11.1±0.8 cm/s per year;
P
<0.01). Thus, blood pressure and fasting plasma glucose levels even below those defining hypertension and diabetes may synergistically lead to progression of arteriosclerotic arterial damage. This synergistic progression may contribute to the additive increases in the risk of cardiovascular events, at least in part.
Leptin Regulates Cardiomyocyte Contractile Function Through Endothelin-1 Receptor–NADPH Oxidase Pathway
Authors: Dong Feng , Zhang Xiaochun , Ren Jun
Published: December 2005

Leptin, the obese gene product, plays an important role in the regulation of cardiac function. However, the mechanism behind leptin-induced cardiomyocyte contractile response is poorly understood. This study was designed to examine whether endothelin-1 receptor and NADPH oxidase play any role in leptin-induced cardiac contractile response. Isolated murine cardiomyocytes were exposed to leptin (5, 50, and 100 nmol/L) for 60 minutes in the absence or presence of the ET
A
receptor antagonist BQ123 (1 μmol/L), the ET
B
receptor antagonist BQ788 (1 μmol/L), or the NADPH oxidase inhibitor apocynin (100 μmol/L) before mechanical function was studied. Superoxide levels were measured by dihydroethidium fluorescent dye and the superoxide dismutase–inhibitable reduction of cytochrome c. NADPH oxidase subunit expression (p22
phox
, p47
phox
, p67
phox
, and gp91
phox
) was evaluated with Western blot. Leptin depressed peak shortening and maximal velocity of shortening/relengthening (±dL/dt), prolonged the duration of relengthening (TR
90
) without affecting the time-to-peak cell shortening. Consistent with the mechanical characteristics, myocytes treated with leptin displayed a reduced electrically stimulated rise in intracellular Ca
2+
(change in fura-2 fluorescence intensity) associated with a prolonged intracellular Ca
2+
decay rate. All of the abnormalities were significantly attenuated by apocynin, BQ123, or BQ788. Intracellular superoxide generation was enhanced after leptin treatment, which was partially blocked by apocynin, BQ123, or BQ788. Leptin had no effect on p22
phox
and gp91
phox
but upregulated protein expression of p67
phox
and p47
phox
, both of which were inhibited by apocynin, BQ123, or BQ788. These results suggest that leptin suppresses cardiac contractile function in ventricular myocytes through the endothelin-1 receptor and NADPH oxidase-mediated pathway.
Retinal Vessel Diameters and Risk of Hypertension
Authors: Ikram M. Kamran , Witteman Jacqueline C.M. , Vingerling Johannes R. , Breteler Monique M.B. , Hofman Albert , de Jong Paulus T.V.M.
Published: December 2005

Generalized retinal arteriolar narrowing is an important sign of systemic hypertension, and a lower arteriolar:venular diameter ratio predicts the risk of hypertension. We investigated whether this association was based on arteriolar or venular diameters or both. This study was based on the prospective population-based Rotterdam Study (1990–1993) and included 1900 participants (≥55 years of age) of whom 739 persons had normal blood pressure (systolic <120 mm Hg and diastolic <80 mm Hg) and 1161 prehypertension (systolic 120 to 139 mm Hg or diastolic 80 to 89 mm Hg). For each participant, retinal arteriolar and venular diameters were measured on digitized images of 1 eye. After a mean follow-up of 6.6 years, 808 persons developed hypertension, defined as either systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. Adjusted for age, gender, follow-up time, body mass index, smoking, diabetes mellitus, total and high-density lipoprotein cholesterol, C-reactive protein, and intima-media thickness, arteriolar narrowing was associated with an increased risk of hypertension (odds ratio per SD: 1.38; 95% CI, 1.23 to 1.55); for venular narrowing this was less striking (OR: 1.17; 95% CI, 1.04 to 1.32). Each SD decrease in the arteriolar:venular diameter ratio significantly increased the risk of hypertension by 24%. To examine the effect of baseline blood pressure, we stratified persons into those with “normal blood pressure” or “prehypertension.” Within these strata, arteriolar narrowing was still related to incident hypertension. These data show that both retinal arteriolar and venular narrowing may precede the development of systemic hypertension.
Aortic Pulse Wave Velocity Is Associated With the Presence and Quantity of Coronary Artery Calcium
Authors: Kullo Iftikhar J. , Bielak Lawrence F. , Turner Stephen T. , Sheedy Patrick F. , Peyser Patricia A.
Published: December 2005

We investigated the relationship of aortic pulse wave velocity (aPWV), a measure of central arterial stiffness, with the presence and quantity of coronary artery calcium (CAC) in a community-based sample of adults without prior history of heart attack or stroke (n=401, mean age 59.8 years, 53% men). ECG-gated waveforms of the right carotid and right femoral artery were obtained by applanation tonometry, and aPWV was calculated using established methods. CAC was measured noninvasively by electron beam computed tomography, and CAC score was calculated. aPWV was significantly correlated with log(CAC +1;
r
=0.41;
P
<0.0001) and pulse pressure (
r
=0.47;
P
<0.0001). Multivariable logistic and linear regression models were used to identify independent predictors of the presence and quantity of CAC, respectively. In multivariable logistic regression analyses, aPWV was associated with the presence of CAC (
P
=0.011) after adjustment for age, male sex, total cholesterol, high-density lipoprotein cholesterol, diabetes, history of smoking, systolic blood pressure, body mass index, and use of hypertension and statin medications. In multivariable linear regression analyses, aPWV was significantly associated with log(CAC +1) after adjustment for the covariates enumerated above (
P
<0.0001). aPWV remained significantly associated with both the presence and quantity of CAC even after the additional adjustment for diastolic blood pressure. We conclude that aPWV is related to subclinical coronary atherosclerosis independent of conventional risk factors (including indices of blood pressure) and may be a biomarker of cardiovascular risk in asymptomatic individuals.
Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts
Authors: Kreusser Michael M. , Haass Markus , Buss Sebastian J. , Hardt Stefan E. , Gerber Stefan H. , Kinscherf Ralf , Katus Hugo A. , Backs Johannes
Published: December 2005

An impairment of cardiac norepinephrine reuptake through the neuronal norepinephrine transporter promotes depletion of cardiac norepinephrine stores and local cardiac sympathetic activation in heart failure. Nerve growth factor regulates differentiation and survival of adult sympathetic cells and is decreased in failing hearts. We hypothesized that injection of nerve growth factor into stellate ganglia normalizes cardiac norepinephrine homeostasis in experimental heart failure. Rats with transverse aortic constriction characterized by heart failure, depleted cardiac norepinephrine stores, and impaired cardiac norepinephrine reuptake were used as an experimental model. Nerve growth factor (20 μg) or saline was directly injected into left stellate ganglia 4 weeks after transverse aortic constriction. Thirty-two hours after injection, determinants of cardiac norepinephrine homeostasis were measured. As compared with saline, nerve growth factor refilled depleted cardiac norepinephrine stores and improved cardiac [3H]-norepinephrine uptake into isolated perfused hearts of transverse aortic constricted rats. In addition, pharmacological blockade of the norepinephrine transporter led to a higher increase in the overflow of endogenous norepinephrine from hearts of nerve growth factor-injected than saline-injected transverse aortic constricted rats. Norepinephrine transporter mRNA levels and the density of cardiac sympathetic nerves were not changed. Thirty-two hours after nerve growth factor injection, echocardiography revealed an increase in fractional shortening as compared with 2 days before injection. In conclusion, nerve growth factor attenuates local cardiac sympathetic overdrive of hypertrophic hearts by improving cardiac norepinephrine reuptake and might represent a novel therapeutic principle in the treatment of heart failure.
Enhanced Vascular Responses to Adrenomedullin in Mice Overexpressing Receptor-Activity–Modifying Protein 2
Authors: Tam C.W. , Husmann K. , Clark N.C. , Clark J.E. , Lazar Z. , Ittner L.M. , Götz J. , Douglas G. , Grant A.D. , Sugden D. , Poston L. , Poston R. , McFadzean I. , Marber M.S. , Fischer J.A. , Born W. , Brain S.D.
Published: December 2005

Adrenomedullin (AM) levels are elevated in cardiovascular disease, but little is known of the role of specific receptor components. AM acts via the calcitonin receptor-like receptor (CLR) interacting with a receptor-activity–modifying protein (RAMP). The AM
1
receptor is composed of CLR and RAMP2, and the calcitonin gene–related peptide (CGRP) receptor of CLR and RAMP1, as determined by molecular and cell-based analysis. This study examines the relevance of RAMP2 in vivo. Transgenic (TG) mice that overexpress RAMP2 in smooth muscle were generated. The role of RAMP2 in the regulation of blood pressure and in vascular function was investigated. Basal blood pressure, acute angiotensin II–raised blood pressure, and cardiovascular properties were similar in wild-type (WT) and TG mice. However, the hypotensive effect of IV AM, unlike CGRP, was enhanced in TG mice (
P
<0.05), whereas a negative inotropic action was excluded by left-ventricular pressure–volume analysis. In aorta relaxation studies, TG vessels responded in a more sensitive manner to AM (EC
50
, 8.0±1.5 nmol/L) than WT (EC
50
, 17.9±3.6 nmol/L). These responses were attenuated by the AM receptor antagonist, AM
22-52
, such that residual responses were identical in all mice. Remaining relaxations were further inhibited by CGRP receptor antagonists, although neither affected AM responses when given alone. Mesenteric and cutaneous resistance vessels were also more sensitive to AM in TG than WT mice. Thus RAMP2 plays a key role in the sensitivity and potency of AM-induced hypotensive responses via the AM
1
receptor, providing evidence that this receptor is a selective target for novel therapeutic approaches.
Differences in Vascular Bed Disease Susceptibility Reflect Differences in Gene Expression Response to Atherogenic Stimuli
Authors: Deng David Xing-Fei , Tsalenko Anya , Vailaya Aditya , Ben-Dor Amir , Kundu Ramendra , Estay Ivette , Tabibiazar Raymond , Kincaid Robert , Yakhini Zohar , Bruhn Laurakay , Quertermous Thomas
Published: December 2005

Atherosclerosis occurs predominantly in arteries and only rarely in veins. The goal of this study was to test whether differences in the molecular responses of venous and arterial endothelial cells (ECs) to atherosclerotic stimuli might contribute to vascular bed differences in susceptibility to atherosclerosis. We compared gene expression profiles of primary cultured ECs from human saphenous vein (SVEC) and coronary artery (CAEC) exposed to atherogenic stimuli. In addition to identifying differentially expressed genes, we applied statistical analysis of gene ontology and pathway annotation terms to identify signaling differences related to cell type and stimulus. Differential gene expression of untreated venous and arterial endothelial cells yielded 285 genes more highly expressed in untreated SVEC (
P
<0.005 and fold change >1.5). These genes represented various atherosclerosis-related pathways including responses to proliferation, oxidoreductase activity, antiinflammatory responses, cell growth, and hemostasis functions. Moreover, stimulation with oxidized LDL induced dramatically greater gene expression responses in CAEC compared with SVEC, relating to adhesion, proliferation, and apoptosis pathways. In contrast, interleukin 1β and tumor necrosis factor α activated similar gene expression responses in both CAEC and SVEC. The differences in functional response and gene expression were further validated by an in vitro proliferation assay and in vivo immunostaining of αβ-crystallin protein. Our results strongly suggest that different inherent gene expression programs in arterial versus venous endothelial cells contribute to differences in atherosclerotic disease susceptibility.
Comprehensive Transcriptome of Proteases and Protease Inhibitors in Vascular Cells
Authors: Shi Guo-Ping , Dolganov Gregory M.
Published: December 2005

Background and Purpose—

Smooth muscle cells, endothelial cells, and macrophages are essential components of the vasculature, of which the homeostatic gene expression participate importantly in the maintenance of vascular wall integrity. The pathogenesis of vascular diseases, such as cerebral ischemia, atherosclerosis, and abdominal aortic aneurysms, often associates with inflammation and altered gene expression, including proteolytic enzymes that play multiple and important roles in extracellular matrix degradation, cell proliferation and migration, and latent enzyme or growth factor activation.

Methods and Results—

Human saphenous vein smooth muscle cells, endothelial cells, and monocyte-derived macrophages from 3 independent donors were stimulated with interleukin 1β, interferon γ, tumor necrosis factor α, basic fibroblast growth factor, and vascular endothelial growth factor, 5 common proinflammatory mediators often found in diseased human microvessels and macrovessels. Quantitative real-time PCR was used to examine the mRNA levels of 49 proteolytic enzymes and their inhibitors, selected from 4 protease families, in these vascular cells.

Conclusions—

Although primary cultured cells from different donors may behave differently in response to these proinflammatory cytokines, data from this study revealed a broad view of vascular cell protease expression profiles under inflammatory conditions, critical to studies of inflammation-associated vascular tissue remodeling.
Association of
Phosphodiesterase 4D
With Ischemic Stroke
Authors: Woo Daniel , Kaushal Ritesh , Kissela Brett , Sekar Padmini , Wolujewicz Michael , Pal Prodipto , Alwell Kathleen , Haverbusch Mary , Ewing Irene , Miller Rosie , Kleindorfer Dawn , Flaherty Matthew , Chakraborty Ranajit , Deka Ranjan , Broderick Joseph
Published: December 2005

Background and Purpose—

The
Phosphodiesterase 4D (PDE4D)
gene was reported recently to be associated with ischemic stroke in an Icelandic population. The association was found predominately with large vessel and cardioembolic stroke. However, 2 recent reports were unable to confirm this association, although a trend toward association with cardioembolic stroke was reported. None of the reports included significant proportions of blacks. We tested for genotype and haplotype association of polymorphisms of the
PDE4D
gene with ischemic stroke in a population-based, biracial, case-control study.

Methods—

A total of 357 cases of ischemic stroke and 482 stroke-free controls from the same community were examined. Single nucleotide polymorphisms (SNPs) were chosen based on significant associations reported previously. Linkage disequilibrium (LD), SNP, and haplotype association analysis was performed using PHASE 2.0 and Haploview 3.2.

Results—

Although several univariate associations were identified, only 1 SNP (rs2910829) was found to be significantly associated with cardioembolic stroke among both whites and blacks. The rs152312 SNP was associated with cardioembolic stroke among whites after multiple comparison corrections. The same SNP was not associated with cardioembolic stroke among blacks. However, significant haplotype association was identified for both whites and blacks for all ischemic stroke, cardioembolic stroke, and stroke of unknown origin. Haplotype association was identified for small vessel stroke among whites.

Conclusions—

PDE4D
is a risk factor for ischemic stroke and, in particular, for cardioembolic stroke, among whites and blacks. Further study of this gene is warranted.
The Impact of Functional Status at Three Months on Long-Term Survival After Spontaneous Intracerebral Hemorrhage
Authors: Saloheimo Pertti , Lapp Tuuli-Maaria , Juvela Seppo , Hillbom Matti
Published: December 2005

Background and Purpose—

Few studies have assessed long-term prognosis and risk factors for death after spontaneous intracerebral hemorrhage (ICH). Patients who survive the acute phase may run different prognoses, depending on their disability, treatment, and lifestyle. The present study was performed to find out the predictors for long-term mortality after ICH.

Methods—

We assessed 7-year prognosis in a population-based cohort of patients who had survived the first 3 months after ICH (n=140). Controls (n=206) living in the same geographical area were randomly drawn from the population register and followed up for the same time.

Results—

Seven-year mortality was significantly higher in ICH patients than in controls (32.9 and 19.4%, respectively;
P
=0.0034). The annual risk for death in ICH patients was 5.6%, and the annual risk for fatal recurrent ICH was 1.3%. The ICH patients with good recovery at 3 months showed similar risk for death as controls. Recurrent ICH and pneumonia were the most common causes of death in ICH patients. Cigarette smoking, age, and diabetes seemed to increase the risk for death in patients and controls.

Conclusions—

Survivors of ICH run a higher long-term risk for death than age- and sex-matched controls. However, those who show good recovery at 3 months run a similar outcome as controls.
The Significance of Various Blood Pressure Indices for Long-Term Stroke, Coronary Heart Disease, and All-Cause Mortality in Men
Authors: Weitzman Dahlia , Goldbourt Uri
Published: December 2005

Background and Purpose—

Studies of blood pressure (BP) indices as disease predictors have offered conflicting conclusions. We compare pulse pressure (PP), systolic BP (SBP) and diastolic BP (DBP), and mean arterial pressure (MAP) as risk markers for long-term mortality with emphasis on stroke.

Methods—

Male civil servants (40 to 65 years of age; n=9611) were examined in 1963 and followed up until 1986. Multivariate analysis was used to assess the association between BP indices and subsequent mortality. Stroke mortality was analyzed separately for initially normotensive (SBP≤140 and DBP≤90 mm Hg), hypertensive (SBP>140 and DBP>90 mm Hg), and men with isolated systolic hypertension (ISH; SBP>140 and DBP≤90 mm Hg).

Results—

During follow-up, 3167 men died, including 932 of coronary heart disease and 339 of stroke. All 4 BP indices were predictive of fatal stroke among hypertensive and normotensive men (hazard ratios [HRs] fluctuated between 1.59 and 2.51). In models with 2 BP indices among normotensive men, SBP but not DBP remained a predictor of stroke mortality. MAP and PP were independent predictors of stroke mortality. Among hypertensive men, SBP and DBP were independent predictors of stroke mortality (HRs, 1.68 and 1.51, respectively). MAP but not PP remained a predictor of stroke mortality. In men with ISH, the 4 BP indices predicted fatal stroke, with HRs fluctuating between 1.24 and 2.04.

Conclusions—

All 4 BP indices were predictors of stroke mortality among hypertensive and normotensive men, with DBP possibly the weaker predictor among the latter. Models with 2 BP indices yielded complex associations.
Eliciting Information on Differential Sensation of Heat in Those With and Without Poststroke Aphasia Using a Visual Analogue Scale
Authors: Korner-Bitensky Nicol , Kehayia Eva , Tremblay Nicole , Mazer Barbara , Singer Fanny , Tarasuk Jill
Published: December 2005

Background and Purpose—

Aphasia can result in an inability to communicate the presence, location, or intensity of pain. Although visual analogue scales (VASs) exist, it is unknown whether they are useful in assessing pain in individuals with aphasia. The objective was to determine whether those with poststroke aphasia could respond differentially to thermal stimuli of varying intensities using a standardized VAS.

Methods—

Five groups of participants were assessed: those without stroke, those with stroke but without aphasia, and 3 groups with varying degrees of aphasia. A 10-cm vertical VAS was used to measure responses to varying thermal intensities delivered on the participant’s forearm.

Results—

Across all 5 groups, a similar proportion demonstrated ability to discriminate between 2 temperatures (χ
2
=1.899;
P
=0.75). When presented with 4 temperatures, all groups performed more poorly, yet with similar success rates across groups (χ
2
=0.1267;
P
=0.88). The repeated-measures ANOVA revealed no effect of group but a significant effect of temperature (
P
<0.0001).

Conclusion—

A VAS may be useful in clinical identification of differing intensities of stimuli in a substantial proportion of those with aphasia.
Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator
Authors: Molina Carlos A. , Ribo Marc , Rubiera Marta , Montaner Joan , Santamarina Esteban , Delgado-Mederos Raquel , Arenillas Juan F. , Huertas Rafael , Purroy Francisco , Delgado Pilar , Alvarez-Sabín José
Published: December 2005

Background and Purpose—

We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring.

Methods—

We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded.

Results—

Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (
P
=0.004). Two-hour complete recanalization rate was significantly (
P
=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26±18 minutes in the tPA/US group and 19±12 minutes in the tPA/US/MB group (
P
=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score.

Conclusions—

Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.
Metabolic Syndrome as an Independent Risk Factor of Silent Brain Infarction in Healthy People
Authors: Kwon Hyung-Min , Kim Beom Joon , Lee Seung-Hoon , Choi Seung Ho , Oh Byung-Hee , Yoon Byung-Woo
Published: December 2005

Background and Purpose—

Metabolic syndrome (MetS) is associated with an increased risk of the subsequent development of cardiovascular disease or stroke. Moreover, a silent brain infarction (SBI) can predict clinical overt stroke or dementia. We examined the associations between SBI and MetS in apparently healthy individuals.

Methods—

We evaluated 1588 neurologically healthy subjects (927 males and 661 females) who underwent brain MRI at Seoul National University Hospital Healthcare System Gangnam Center. MetS was defined using the criteria of the National Cholesterol Education Program Adult Treatment Panel III. We examined associations between full syndrome (≥3 of the 5 conditions) as well as its components and SBI by controlling possible confounders.

Results—

Eighty-eight (5.5%) were found to have ≥1 SBI on MRI. Age was found to be significantly related to SBI prevalence (odds ratio [OR], 1.06; 95% CI, 1.04 to 1.09). A history of coronary artery disease was associated with an elevated odds ratio of SBI (OR, 2.83; 95% CI, 1.38 to 5.82), and MetS was significantly associated with SBI (OR, 2.18; 95% CI, 1.38 to 3.44). The components model of MetS showed a strong significance between an elevated blood pressure (OR, 3.75; 95% CI, 2.05 to 6.85) and an impaired fasting glucose (OR, 1.74; 95% CI, 1.08 to 2.80) and the risk of SBI.

Conclusions—

MetS was found to be significantly associated with SBI. This finding has clinical utility in terms of identifying healthy people at increased risk of developing SBI.
Shunt-Associated Migraine Responds Favorably to Atrial Septal Repair
Authors: Anzola Gian P. , Frisoni Giovanni B. , Morandi Eva , Casilli Francesco , Onorato Eustaquio
Published: December 2005

Background and Purpose—

Transcatheter closure of patent foramen ovale (PFO) has been reported to improve migraine in patients with cerebrovascular disorders in noncontrolled studies. The aim of the study was to compare the course of migraine assessed prospectively over a 12-month period in symptomatic (for cerebrovascular disease) and asymptomatic patients undergoing PFO closure and in patients with PFO treated medically.

Methods—

Twenty-three stroke symptomatic (SS; 39±10 years of age; males/females [M/F] 5/18) and 27 stroke asymptomatic (SA; 40±12 years of age; M/F 5/22) patients with migraine underwent PFO closure. Twenty-seven patients with migraine and PFO (controls [CTRLS]; 36±11 years of age; M/F 4/23) were followed up medically. Migraine severity was assessed at baseline with a scale that takes into account the frequency, duration, and intensity of the attacks and the occurrence of aura (score range 0 to 10). Six months later, the patients were given a structured diary to annotate monthly with the same scale the characteristics of the attacks for the next 6 months. By the end of 1 year, the migraine score was averaged for the last 6 months.

Results—

Baseline severity of migraine did not differ between groups (6.3 to 6.1 and 6.7 in SS, SA, and CTRLS groups, respectively). At the 1-year assessment, the overall migraine score had significantly improved by 3.7 and 2.8 points in SS and SA, respectively (
P
<0.001 on repeated-measure ANOVA), whereas it had nonsignificantly worsened by 0.1 points in CTRLS. Multiple linear regression analysis showed that the improvement in SS and SA was independent of migraine type, age, and cerebrovascular risk factors. Twenty-one of 21 patients with migraine with aura in the CTRLS group still had aura at the end of follow-up, whereas only 3 of 14 among SA and 4 of 19 among SS continued to have migraine preceded by aura (
P
<0.0001 on Fisher exact test).

Conclusions—

Compared with medical treatment, closure of PFO brings about a significant overall improvement in migraine. This seems to occur irrespective of migraine type and of previous cerebrovascular disease. In addition to the overall improvement, in migraine with aura, the occurrence of aura is dramatically reduced.
Sleep and Exertional Periodic Breathing in Chronic Heart Failure
Authors: Corrà Ugo , Pistono Massimo , Mezzani Alessandro , Braghiroli Alberto , Giordano Andrea , Lanfranchi Paola , Bosimini Enzo , Gnemmi Marco , Giannuzzi Pantaleo
Published: December 2005

Background—

Sleep and exertional periodic breathing are proverbial in chronic heart failure (CHF), and each alone indicates poor prognosis. Whether these conditions are associated and whether excess risk may be attributed to respiratory disorders in general, rather than specifically during sleep or exercise, is unknown.

Methods and Results—

We studied 133 CHF patients with left ventricular ejection fraction (LVEF) ≤40%. During 1170±631 days of follow-up, 31 patients (23%) died. Nonsurvivors had higher New York Heart Association class, ventilatory response (V̇
e
/V̇
co
2
slope), and apnea-hypopnea index (AHI) and lower peak V̇
o
2
(all
P
<0.01); lower LVEF and prescription of β-blockers, and shorter transmitral deceleration time (all
P
<0.05). Exertional oscillatory ventilation (EOV), established by cyclic fluctuations in minute ventilation that persisted for ≥60% of exercise duration with an amplitude ≥15% of the average resting value, was significantly more frequent in nonsurvivors (42% versus 15%,
P
<0.01). Multivariable analysis selected AHI (hazard ratio [HR] 5.66, 95% CI 2.3 to 19.9,
P
<0.01), peak V̇
o
2
(HR 0.93, 95% CI 0.90 to 0.97,
P
<0.01), and β-blocker prescription (HR 0.34, 95% CI 0.13 to 0.87,
P
<0.05) as predictors of cardiac events. The best cutoff for AHI was >30/h. EOV was significantly related to AHI >30/h (χ
2
14.6,
P
<0.01): 78% of EOV patients showed AHI >30/h. Multivariable analysis, including breathing disorders alone (EOV, AHI >30/h) or in combination (EOV plus AHI >30/h), selected combined disorders as the strongest predictor of events (HR 6.65, 95% CI 2.6 to 17.1,
P
<0.01).

Conclusions—

In CHF, EOV is significantly associated with AHI >30/h. Although each breathing disorder alone is linked to total mortality, their combination has a crucial prognostic burden.
Cardiac-Specific Overexpression of Diacylglycerol Kinase ζ Prevents Gq Protein-Coupled Receptor Agonist-Induced Cardiac Hypertrophy in Transgenic Mice
Authors: Arimoto Takanori , Takeishi Yasuchika , Takahashi Hiroki , Shishido Tetsuro , Niizeki Takeshi , Koyama Yo , Shiga Ryoko , Nozaki Naoki , Nakajima Osamu , Nishimaru Kazuhide , Abe Jun-ichi , Endoh Masao , Walsh Richard A. , Goto Kaoru , Kubota Isao
Published: December 2005

Background—

Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqα protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy.

Methods and Results—

To test this hypothesis, we generated transgenic (DGKζ-TG) mice with cardiac-specific overexpression of DGKζ. There were no differences in heart size and heart weight between DGKζ-TG and wild-type littermate mice. The left ventricular function was normal in DGKζ-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKζ-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKζ-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKζ-TG mouse hearts, suggesting that DGKζ regulated PKC activity by controlling cellular diacylglycerol levels.

Conclusions—

These results demonstrated the first evidence that DGKζ negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.
Increased Small Low-Density Lipoprotein Particle Number
Authors: Kathiresan Sekar , Otvos James D. , Sullivan Lisa M. , Keyes Michelle J. , Schaefer Ernst J. , Wilson Peter W.F. , D’Agostino Ralph B. , Vasan Ramachandran S. , Robins Sander J.
Published: December 2005

Background—

Levels of LDL cholesterol (LDL-C) are frequently not elevated in individuals with the metabolic syndrome (MetSyn). However, the atherogenic potential of LDL may depend on the number and size of LDL particles in addition to the cholesterol content of LDL.

Methods and Results—

We examined the sex-specific cross-sectional relations of small LDL particle number (determined by nuclear magnetic resonance spectroscopy) to the presence of MetSyn and its components in 2993 Framingham Heart Study participants (mean age, 51 years; 53% women) without cardiovascular disease (CVD) and the relations of small LDL particle number to CVD incidence in people with MetSyn. The MetSyn (≥3 of 5 traits as defined by the National Cholesterol Education Adult Treatment Panel III) was present in 27% of men and 17% of women. In both sexes, small LDL particle number increased from 0 to 5 MetSyn traits, a pattern partly accounted for by strong correlations between small LDL particle number and serum triglycerides (
r
=0.61,
P
<0.0001) and HDL-C (
r
=−0.55,
P
<0.0001). Compared with participants without the MetSyn, those with the MetSyn had a higher CVD event rate. However, among participants with the MetSyn, CVD rates were similar for groups with an elevated versus a lower number of small LDL particles (defined by the sex-specific median).

Conclusions—

Small LDL particle number is elevated in the MetSyn, increases with the number of MetSyn components, and most prominently is correlated with triglycerides and HDL-C. Whereas increased small LDL particle number identified the MetSyn with high sensitivity, a higher small LDL particle number was not associated with greater CVD event rates in people with the MetSyn.