bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Breast-Feeding in Infancy Lower Blood Pressure in Childhood?
Authors: Martin Richard M. , Ness Andrew R. , Gunnell David , Emmett Pauline , Smith George Davey
Published: March 2004

Background—

Breast-feeding in infancy has been associated with decreased coronary heart disease mortality, but the underlying mechanisms are unclear. We investigated the association of breast-feeding with blood pressure in a contemporary cohort.

Methods and Results—

In a prospective cohort study (ALSPAC, United Kingdom), a total of 7276 singleton, term infants born in 1991 and 1992 were examined at 7.5 years. Complete data were available for 4763 children. The systolic and diastolic blood pressures of breast-fed children were 1.2 mm Hg lower (95% CI, 0.5 to 1.9) and 0.9 mm Hg lower (0.3 to 1.4), respectively, compared with children who were never breast-fed (models controlled for age, sex, room temperature, and field observer). Blood pressure differences were attenuated but remained statistically significant in fully adjusted models controlling for social, economic, maternal, and anthropometric variables (reduction in systolic blood pressure: 0.8 mm Hg [0.1 to 1.5]; reduction in diastolic blood pressure: 0.6 mm Hg [0.1 to 1.0]). Blood pressure differences were similar whether breast-feeding was partial or exclusive. We examined the effect of breast-feeding duration. In fully adjusted models, there was a 0.2-mm Hg reduction (0.0 to 0.3) in systolic pressure for each 3 months of breast-feeding.

Conclusions—

Breast-feeding is associated with a lowering of later blood pressure in children born at term. If the association is causal, the wider promotion of breast-feeding is a potential component of the public health strategy to reduce population levels of blood pressure.
Cardiovascular Magnetic Resonance Assessment of Human Myocarditis
Authors: Mahrholdt Heiko , Goedecke Christine , Wagner Anja , Meinhardt Gabriel , Athanasiadis Anasthasios , Vogelsberg Holger , Fritz Peter , Klingel Karin , Kandolf Reinhard , Sechtem Udo
Published: March 2004

Background—

Myocarditis can occasionally lead to sudden death and may progress to dilated cardiomyopathy in up to 10% of patients. Because the initial onset is difficult to recognize clinically and the diagnostic tools available are unsatisfactory, new strategies to diagnose myocarditis are needed.

Methods and Results—

Cardiovascular MR imaging (CMR) was performed in 32 patients who were diagnosed with myocarditis by clinical criteria. To determine whether CMR visualizes areas of active myocarditis, endomyocardial biopsy was taken from the region of contrast enhancement and submitted to histopathologic analysis. Follow-up was performed 3 month later. Contrast enhancement was present in 28 patients (88%) and was usually seen with one or several foci in the myocardium. Foci were most frequently located in the lateral free wall. In the 21 patients in whom biopsy was obtained from the region of contrast enhancement, histopathologic analysis revealed active myocarditis in 19 patients (parvovirus B19, n=12; human herpes virus type 6 [HHV 6], n=5). Conversely, in the remaining 11 patients, in whom biopsy could not be taken from the region of contrast enhancement, active myocarditis was found in one case only (HHV6). At follow-up, the area of contrast enhancement decreased from 9±11% to 3±4% of left ventricular mass as the left ventricular ejection fraction improved from 47±19% to 60±10%.

Conclusions—

Contrast enhancement is a frequent finding in the clinical setting of suspected myocarditis and is associated with active inflammation defined by histopathology. Myocarditis occurs predominantly in the lateral free wall. Contrast CMR is a valuable tool for the evaluation and monitoring of inflammatory heart disease.
Arrhythmogenic Right Ventricular Cardiomyopathy Causing Sudden Cardiac Death in Boxer Dogs
Authors: Basso Cristina , Fox Philip R. , Meurs Kathryn M. , Towbin Jeffrey A. , Spier Alan W. , Calabrese Fiorella , Maron Barry J. , Thiene Gaetano
Published: March 2004

Background—

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary familial heart muscle disease associated with substantial cardiovascular morbidity and risk of sudden death. Efforts to discern relevant pathophysiological mechanisms have been impaired by lack of a suitable animal model.

Methods and Results—

ARVC was diagnosed in 23 boxer dogs (12 male; 9.1±2.3 years old). Clinical events alone or in combination included sudden death (n=9; 39%), ventricular arrhythmias of suspected right ventricular (RV) origin (n=19; 83%), syncope (n=12, 52%), and heart failure (n=3; 13%). Right ventricular enlargement or aneurysms occurred in 10 (43%). Striking histopathological abnormalities were present in each boxer dog but not in controls, including severe RV myocyte loss with replacement by fatty (n=15, 65%) or fibrofatty (n=8, 35%) tissue. Focal fibrofatty lesions were also present in both atria (n=8) and the left ventricle (LV) (n=11). Fatty replacement occupied substantially greater RV wall area in ARVC dogs than controls (40.4±18.8% versus 13.8±3.4%, respectively) (
P
<0.001); residual myocardium was correspondingly reduced (56.6±19.2% versus 84.8±3.8% in controls) (
P
<0.001). MRI demonstrated bright anterolateral and/or infundibular RV myocardial signals, confirmed as fat by histopathology. Myocarditis appeared in the RV (n=14, 61%) and LV (n=16, 70%) and in each dog with sudden death, but not in controls. Familial transmission was evident in 10 of the 23.

Conclusions—

We describe a novel, spontaneous, and genetically transmitted animal model of ARVC associated with sudden death in the boxer dog, closely resembling the human disease. This model may aid in understanding the pathogenic mechanisms of ARVC.
Explaining the Decline in Coronary Heart Disease Mortality in England and Wales Between 1981 and 2000
Authors: Unal Belgin , Critchley Julia Alison , Capewell Simon
Published: March 2004

Background—

Coronary heart disease mortality rates have been decreasing in the United Kingdom since the 1970s. Our study aimed to examine how much of the decrease in England and Wales between 1981 and 2000 could be attributed to medical and surgical treatments and how much to changes in cardiovascular risk factors.

Methods and Results—

The IMPACT mortality model was used to combine and analyze data on uptake and effectiveness of cardiological treatments and risk factor trends in England and Wales. The main data sources were published trials and meta-analyses, official statistics, clinical audits, and national surveys. Between 1981 and 2000, coronary heart disease mortality rates in England and Wales decreased by 62% in men and 45% in women 25 to 84 years old. This resulted in 68 230 fewer deaths in 2000. Some 42% of this decrease was attributed to treatments in individuals (including 11% to secondary prevention, 13% to heart failure treatments, 8% to initial treatments of acute myocardial infarction, and 3% to hypertension treatments) and 58% to population risk factor reductions (principally smoking, 48%; blood pressure, 9.5%; and cholesterol, 9.5%). Adverse trends were seen for physical activity, obesity and diabetes.

Conclusions—

More than half the coronary heart disease mortality decrease in Britain between 1981 and 2000 was attributable to reductions in major risk factors, principally smoking. This emphasizes the importance of a comprehensive strategy that promotes primary prevention, particularly for tobacco and diet, and that maximizes population coverage of effective treatments, especially for secondary prevention and heart failure. These findings may be cautiously generalizable to the United States and other developed countries.
Is Slower Early Growth Beneficial for Long-Term Cardiovascular Health?
Authors: Singhal Atul , Cole Tim J. , Fewtrell Mary , Deanfield John , Lucas Alan
Published: March 2004

Background—

Accelerated neonatal growth increases the later propensity to cardiovascular disease (CVD) in animals, whereas slower growth is thought to have a beneficial effect. To test this hypothesis in humans, we measured flow-mediated endothelium-dependent dilation (FMD) in a population subject to slower early growth and in healthy controls.

Methods and Results—

High-resolution vascular ultrasound was used to measure the change in brachial artery diameter in response to reactive hyperemia in adolescents age 13 to 16 years who were either part of a cohort born preterm and followed up prospectively (n=216) or controls born at term (n=61). Greater weight gain or linear growth in the first 2 weeks postnatally was associated with lower FMD at adolescence (regression coefficient, −0.026-mm change in mean arterial diameter per 100-g increase in weight; 95% CI, −0.040 to −0.012 mm;
P
=0.0003) independent of birthweight and potential confounding factors. Mean FMD in the half of the preterm population with the lowest rates of early growth was higher than in both the half with the greatest growth (
P
=0.001) and subjects born at term (
P
=0.03).

Conclusions—

FMD was 4% lower in adolescents with the highest compared with the lowest rate of weight gain in the first 2 weeks after birth, a substantial negative effect similar to that for insulin-dependent diabetes mellitus or smoking in adults. Our findings are consistent with the adverse effects of accelerated neonatal growth on long-term cardiovascular health and suggest that postnatal growth patterns could explain the previously reported association between birthweight and later CVD.
Three-Year Outcome After Coronary Stenting Versus Bypass Surgery for the Treatment of Multivessel Disease
Authors: Legrand Victor M.G. , Serruys Patrick W. , Unger Felix , van Hout Ben A. , Vrolix Mathias C.M. , Fransen Geert M.P. , Nielsen Torsten Toftegaard , Paulsen Peter Kildeberg , Gomes Ricardo Seabra , de Queiroz e Melo João M.G. , Marques dos Santos Neves José P. , Lindeboom Wietze , Backx Bianca
Published: March 2004

Background—

The primary results of Arterial Revascularization Therapy Study reported a greater need for repeated revascularization after percutaneous coronary intervention with stenting (PCI). However, PCI was less expensive than coronary artery bypass grafting (CABG) and offered the same degree of protection against death, stroke, and myocardial infarction.

Methods and Results—

Patients with multivessel disease (n=1205) were randomly assigned to either CABG or PCI and followed up for up to 3 years. Survival rates without stroke or myocardial infarction were similar in each group at 1 year and 3 years (90.5% versus 91.4% for PCI versus CABG at 1 year and 87.2% versus 88.4% for PCI versus CABG at 3 years). However, the respective repeat revascularization rates were 21.2% and 26.7% at 1 and 3 years in patients allocated to PCI, compared with 3.8% and 6.6% in patients allocated to CABG (
P
<0.0001). Diabetes (
P
<0.0009) and maximal pressure for stent deployment (
P
<0.002) are the strongest independent predictors of events at 3 years after PCI, whereas left anterior descending coronary artery grafting (
P
<0.006) is the best predictor of event-free survival at 3 years after CABG. The incremental cost of surgery compared with PCI for an event-free patient was 19 257

at 1 year but decreased to 10 492

at 3 years. It remained at 142 391

at 3 years when revascularization procedures were excluded in the efficacy end point, however.

Conclusions—

Three-year survival rates without stroke and myocardial infarction are identical in both groups, and the cost/benefit ratio of stenting is determined primarily by the increasing need for revascularization in the PCI group.
Anger and Hostility Predict the Development of Atrial Fibrillation in Men in the Framingham Offspring Study
Authors: Eaker Elaine D. , Sullivan Lisa M. , Kelly-Hayes Margaret , D’Agostino Ralph B. , Benjamin Emelia J.
Published: March 2004

Background—

Conflicting findings in the literature with regard to the ability of type A behavior, expressions of anger, or hostility to predict incident coronary heart disease (CHD) have created controversy. In addition, there are no prospective studies relating these characteristics to the development of atrial fibrillation (AF).

Methods and Results—

From 1984 to 1987, 3873 men and women, 18 to 77 years of age, participating in the Framingham Offspring Study, were examined and monitored for 10 years for the incidence of CHD, AF, and total mortality. Measures of type A behavior, anger, hostility, and risk factors for CHD and AF were collected at the baseline examination. After controlling for age, diabetes, hypertension, history of myocardial infarction, history of congestive heart failure, and valvular heart disease in Cox proportional hazards models, trait-anger (RR=1.1; 95% CI, 1.0 to 1.4;
P
=0.04), symptoms of anger (RR=1.2; 95% CI, 1.0 to 1.4;
P
=0.008), and hostility (RR=1.3; 95% CI, 1.1 to 1.5;
P
=0.003) were predictive of 10-year incidence of AF in men. After controlling for risk factors for CHD, none of the measures of anger, type A behavior, or hostility were related to incident CHD; however, trait-anger (RR=1.2; 95% CI, 1.1 to 1.4;
P
<0.01) was related to total mortality in men. None of the psychosocial variables were related to the 3 outcomes in women.

Conclusions—

This is the first study to examine and demonstrate a predictive relation between measures of anger and hostility to the development of AF in men. As opposed to type A behavior, measures of anger and hostility may be more productive avenues for research in studying the risk of arrhythmias and total mortality in men.
Elevated Levels of Activin A in Heart Failure
Authors: Yndestad Arne , Ueland Thor , Øie Erik , Florholmen Geir , Halvorsen Bente , Attramadal Håvard , Simonsen Svein , Frøland Stig S. , Gullestad Lars , Christensen Geir , Damås Jan Kristian , Aukrust Pål
Published: March 2004

Background—

Although modulation of inflammatory processes has been suggested as a new treatment modality in heart failure (HF), our knowledge about abnormalities in the cytokine network during HF is still limited. On the basis of a previous cDNA array study examining peripheral blood mononuclear cells from HF patients, we hypothesized a role for activin A, a member of the transforming growth factor (TGF)-β superfamily, in the pathogenesis of HF.

Methods and Results—

This study had 4 main and novel findings. First, serum levels of activin A were significantly elevated in patients with HF (n=86) compared with healthy control subjects (n=20), with increasing levels according to disease severity as assessed by clinical, hemodynamic, and neurohormonal parameters. Second, compared with control subjects, HF patients, as determined by real-time quantitative reverse transcriptase polymer chain reaction, also had markedly increased gene expression of the activin A subunit activin β
A
in T cells but not in monocytes. Third, in a rat model of HF, we demonstrated a concerted induction of the gene expression of activin β
A
and activin receptors IA, IB, IIA, and IIB after myocardial infarction. Immunohistochemical analysis localized activin A solely to cardiomyocytes. Finally, activin A markedly increased gene expression of mediators involved in infarction healing and myocardial remodeling (ie, atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-β
1
, and monocyte chemoattractant protein-1) in neonatal rat cardiomyocytes.

Conclusions—

Together with our demonstration of activin A–induced gene expression in neonatal cardiomyocytes of mediators related to myocardial remodeling, the expression pattern of activin A during clinical and experimental HF suggests an involvement of this cytokine in the pathogenesis of HF.
Vascular Anomalies in Alagille Syndrome
Authors: Kamath Binita M. , Spinner Nancy B. , Emerick Karan M. , Chudley Albert E. , Booth Carol , Piccoli David A. , Krantz Ian D.
Published: March 2004

Background—Alagille syndrome (AGS) is a dominantly inherited multisystem disorder involving the liver, heart, eyes, face, and skeleton, caused by mutations inJagged1. Intracranial bleeding is a recognized complication and cause of mortality in AGS. There are multiple case reports of intracranial vessel abnormalities and other vascular anomalies in AGS. The objective of this study was to characterize the nature and spectrum of vascular anomalies in AGS.

Methods and Results—Retrospective chart review of 268 individuals with AGS was performed. Twenty-five patients (9%) had noncardiac vascular anomalies or events. Sixteen patients had documented structural vascular abnormalities. Two had basilar artery aneurysms, 7 had internal carotid artery anomalies, and another had a middle cerebral artery aneurysm. Moyamoya disease was described in 1 patient. Three of the 16 patients had aortic aneurysms, and 2 had aortic coarctations. One of the patients with a basilar artery aneurysm also had coarctation of the aorta. One of the individuals with an internal carotid artery anomaly also had renal artery stenosis. Nine more patients had intracranial events without documented vessel abnormalities. Vascular accidents accounted for 34% of the mortality in this cohort.

Conclusions—The vascular anomalies described in our cohort of AGS individuals identify an underrecognized and potentially devastating complication of this disorder. It is a major cause of morbidity and mortality in this population, accounting for 34% of the mortality. We have also reviewed the body of evidence supporting a role forJagged1and the Notch signaling pathway in vascular development.
Morphine-Tolerant Mice Exhibit a Profound and Persistent Cardioprotective Phenotype
Authors: Peart Jason N. , Gross Garrett J.
Published: March 2004

Background—

Morphine and other opioids continue to be used as the major treatment for acute pain both before and after surgery. In this regard, much research has focused on the mechanisms of morphine tolerance and dependence in the central nervous system; however, few studies have examined the effect of morphine on peripheral organs, such as the heart, in morphine-tolerant animals. Here, we examine the effect of tolerance to the analgesic effect of morphine on ischemic tolerance in mice after prolonged morphine exposure and withdrawal.

Methods and Results—

Male C57/BL6 mice were implanted subcutaneously with either placebo or morphine pellets (25 or 75 mg). After prolonged exposure to and/or withdrawal from morphine or placebo, the hearts were excised and subjected to 25 minutes of ischemia and 45 minutes of reperfusion. Morphine-tolerant mice exhibited a markedly improved functional recovery compared with placebo and mice subjected to acute morphine. Lactate dehydrogenase release was also significantly reduced. The protection observed was equieffective 48 hours after withdrawal of pellet, whereas the onset of protection preceded analgesic tolerance.

Conclusions—

These data demonstrate that chronic exposure to morphine unexpectedly results in a profound and persistent cardioprotective phenotype.
Resumption of Electrical Conduction in Previously Isolated Pulmonary Veins
Authors: Nanthakumar Kumaraswamy , Plumb Vance J. , Epstein Andrew E. , Veenhuyzen George D. , Link Dale , Kay G. Neal
Published: March 2004

Background—

Atrial fibrillation (AF) may recur after pulmonary vein isolation (PVI) as the result of either recurrent PV conduction or non-PV foci. This study characterized the electrophysiological findings of patients with recurrent AF after initially successful PVI and the clinical outcome after a repeat procedure.

Methods and Results—

Among 185 patients undergoing PVI, 52 reported no significant improvement in their clinical course. We analyzed PV conduction in 51 PVs (15 patients) at repeat PVI. All PVs were isolated with either RF (30 W, 50°C, 60 seconds) or cryoablation (−80°C for 5 minutes). At repeat study, 42 of the previously isolated 51 PVs had return of conduction. All patients had recurrent conduction in ≥2 PVs, with only 1 non-PV focus identified. The mean number of RF applications required to re-isolate the PVs was fewer at the repeat compared with the initial procedure (10±6 versus 4±2,
P
<0.005). Over a period of 15±6 months, all but 1 patient was clinically improved by the second procedure.

Conclusions—

In patients with recurrent AF after PVI, return of PV conduction can be expected. Repeat PVI provides significant clinical benefit for these patients. These results suggest that if permanent PV isolation is the ablation strategy, different techniques may be required to improve long-term efficacy.
Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells
Authors: Rehman Jalees , Traktuev Dmitry , Li Jingling , Merfeld-Clauss Stephanie , Temm-Grove Constance J. , Bovenkerk Jason E. , Pell Carrie L. , Johnstone Brian H. , Considine Robert V. , March Keith L.
Published: March 2004

Background—

The delivery of autologous cells to increase angiogenesis is emerging as a treatment option for patients with cardiovascular disease but may be limited by the accessibility of sufficient cell numbers. The beneficial effects of delivered cells appear to be related to their pluripotency and ability to secrete growth factors. We examined nonadipocyte stromal cells from human subcutaneous fat as a novel source of therapeutic cells.

Methods and Results—

Adipose stromal cells (ASCs) were isolated from human subcutaneous adipose tissue and characterized by flow cytometry. ASCs secreted 1203±254 pg of vascular endothelial growth factor (VEGF) per 10
6
cells, 12 280±2944 pg of hepatocyte growth factor per 10
6
cells, and 1247±346 pg of transforming growth factor-β per 10
6
cells. When ASCs were cultured in hypoxic conditions, VEGF secretion increased 5-fold to 5980±1066 pg/10
6
cells (
P
=0.0016). The secretion of VEGF could also be augmented 200-fold by transfection of ASCs with a plasmid encoding VEGF (
P
<0.05). Conditioned media obtained from hypoxic ASCs significantly increased endothelial cell growth (
P
<0.001) and reduced endothelial cell apoptosis (
P
<0.05). Nude mice with ischemic hindlimbs demonstrated marked perfusion improvement when treated with human ASCs (
P
<0.05).

Conclusions—

Our experiments delineate the angiogenic and antiapoptotic potential of easily accessible subcutaneous adipose stromal cells by demonstrating the secretion of multiple potentially synergistic proangiogenic growth factors. These findings suggest that autologous delivery of either native or transduced subcutaneous ASCs, which are regulated by hypoxia, may be a novel therapeutic option to enhance angiogenesis or achieve cardiovascular protection.
ET
A
Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats
Authors: Callera Glaucia E. , Montezano Augusto C. , Touyz Rhian M. , Zorn Telma M.T. , Carvalho Maria Helena C. , Fortes Zuleica B. , Nigro Dorothy , Schiffrin Ernesto L. , Tostes Rita C.
Published: March 2004

Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)–salt hypertension. We investigated whether ET
A
receptor blockade modulates in vivo leukocyte–endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA–salt and control uninephrectomized rats were treated with the ET
A
antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA–salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte–endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA–salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte–endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ET
A
antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA–salt rats. These data indicate that ET-1 participates, via activation of ET
A
receptors, in altered leukocyte–endothelial cell interactions in DOCA–salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.
Nitric Oxide Donor Sodium Nitroprusside Dilates Rat Small Arteries by Activation of Inward Rectifier Potassium Channels
Authors: Schubert Rudolf , Krien Ulrike , Wulfsen Iris , Schiemann Dorrit , Lehmann Gernot , Ulfig Norbert , Veh Ruediger W. , Schwarz Jürgen R. , Gago Hristo
Published: March 2004

The role of vascular smooth muscle inward rectifier K
+
(K
IR
) channels in the mechanisms underlying vasodilation is still unclear. The hypothesis that K
IR
channels are involved in sodium nitroprusside (SNP)-induced dilation of rat-tail small arteries was tested. SNP relaxed tail small arteries with an EC
50
of 2.6×10
−8
mol/L. Endothelium removal did not attenuate this effect. Vessel pretreatment with hydroxocobalamin, a nitric oxide (NO) scavenger, but not with rhodanese and sodium thiosulfate, inactivators of cyanide (CN), abolished the SNP effect. Vessel pretreatment with 10
−5
mol/L Ba
2+
, a specific blocker of K
IR
channels at micromolar concentrations, reduced the SNP effect. Low concentrations of K
+
dilated the vessels; this effect was attenuated largely after pretreatment with 3×10
−5
mol/L Ba
2+
. In freshly isolated smooth muscle cells, a barium-sensitive current was observed at potentials negative to the potassium equilibrium potential. Application of 10
−4
mol/L SNP increased the barium-sensitive current 1.79±0.23-fold at −100 mV and hyperpolarized the membrane potential by 8.6±0.5 mV. In tissue from freshly dissected vessels, transcripts for K
IR
2.1 and 2.2, but not for K
IR
2.3 and 2.4, were found. However, only K
IR
2.1 antibodies immunostained the tunica media of the vessel. These data suggest that vascular smooth muscle K
IR
2.1 channels are involved in the SNP-induced dilation of rat-tail small arteries.
Reduced NOS3 Phosphorylation Mediates Reduced NO/cGMP Signaling in Mesenteric Arteries of Deoxycorticosterone Acetate-Salt Hypertensive Rats
Authors: Sasser Jennifer M. , Sullivan Jennifer C. , Elmarakby Ahmed A. , Kemp Bruce E. , Pollock David M. , Pollock Jennifer S.
Published: March 2004

Salt-sensitive hypertension is associated with impaired NO/cGMP signaling. We hypothesized that increased superoxide production by NADPH oxidase and altered endothelial NO synthase (NOS3) phosphorylation determine endothelial dysfunction in hypertension. Experiments tested if NO/cGMP signaling and NOS3 serine phosphorylation are decreased and NADPH oxidase activity is increased in mesenteric arteries from deoxycorticosterone acetate (DOCA)-salt rats compared with arteries from placebo rats. Concentration response curves to phenylephrine were performed in mesenteric arteries in the presence and absence of Nω-nitro-
l
-arginine (LNA) and antioxidants to determine the influence of basal NO and superoxide production on vascular tone. LNA increased phenylephrine sensitivity in arteries from placebo, but not DOCA-salt rats, regardless of antioxidant treatment. To determine basal cGMP production, mesenteric arteries were incubated with 3-isobutyl-1-methylxanthine in the presence or absence of LNA, sodium nitroprusside (SNP), antioxidants, or tetrahydrobiopterin. NOS-dependent cGMP production was reduced in arteries from DOCA-salt rats compared with arteries from placebo rats and was not restored by acute treatment with antioxidants or tetrahydrobiopterin. SNP-induced cGMP production was similar between groups as was NADPH oxidase activity, measured by lucigenin chemiluminescence, in mesenteric arteries. Expression and phosphorylation of NOS3 were examined by Western blotting. Phosphorylation of NOS3 was decreased in arteries from DOCA-salt rats compared with placebo at serine residues 1179 and 635. These findings indicate that diminished NO/cGMP signaling in mesenteric arteries from DOCA-salt rats is caused by reduced phosphorylation of NOS3 at serine 1179 and serine 635, rather than NO scavenging by superoxide.
Human Endothelium: Target for Aldosterone
Authors: Oberleithner Hans , Ludwig Thomas , Riethmüller Christoph , Hillebrand Uta , Albermann Lars , Schäfer Claudia , Shahin Victor , Schillers Hermann
Published: March 2004

Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies demonstrated the presence of these receptors in nonclassical locations, including the cardiovascular system. We tested the hypothesis whether endothelial cells respond to aldosterone with changes in cell volume, a measure for ion-mediated water movement across the cell membrane. By means of atomic force microscopy in fluid, we measured volume of adherent human umbilical venous endothelial cells exposed for 72 hours to 10 nmol/L aldosterone. Over this period of time, cells swell by ≈18%. Aldosterone-induced swelling is prevented by 100 nmol/L of the mineralocorticoid receptor antagonist spironolactone, added to the primary endothelial cell culture. Aldosterone-treated cells dramatically shrink when 1 μmol/L of the diuretic amiloride is applied. Cells deprived of aldosterone do not respond to amiloride. Our conclusions are: (1) aldosterone leads to sustained cell swelling inhibited by administration of spironolactone or the sodium channel blocker amiloride; (2) cells respond to amiloride after aldosterone exposure; (3) renal diuretics act on endothelial cells; and (4) both amiloride and spironolactone could be useful for medical applications to prevent aldosterone-mediated endothelial dysfunction.
High and Low Gain Switches for Regulation of cAMP Efflux Concentration
Authors: Wen Jin Fu , Cui Xun , Jin Jing Yu , Kim Soo Mi , Kim Sung Zoo , Kim Suhn Hee , Lee Ho Sub , Cho Kyung Woo
Published: March 2004

This study tests the hypothesis that particulate (p) guanylyl cyclase (GC) and soluble (s) GC are involved in the distinct roles for the regulation of cGMP-PDE-cAMP signaling and of mechanical and secretory functions in the heart. Experiments were performed in perfused beating rabbit atria. C-type natriuretic peptide (CNP) and SIN-1, an NO donor, or BAY 41-2272 (BAY), a direct activator for sGC, were used to activate pGC and sGC, respectively. CNP and SIN-1 increased cGMP and cAMP efflux in a concentration-dependent manner. Increase in cAMP was a function of cGMP. The changes in cAMP efflux concentration in terms of cGMP were much more prominent in the atria treated with CNP than in the atria treated with SIN-1. Increase in cAMP efflux concentration was blocked by milrinone but not changed by EHNA. BAY increased cGMP but not cAMP in a concentration-dependent manner. CNP and SIN-1 decreased atrial stroke volume and myocytic ANP release. The decreases in terms of cGMP efflux concentration were much more prominent in the atria treated with CNP than in the atria treated with SIN-1 or BAY. Milrinone accentuated GC agonist–induced decreases in atrial stroke volume and ANP release. In the presence of ODQ, SIN-1 or BAY induced effects were not observed. These data suggest that pGC and sGC activations have distinct roles via cGMP-PDE3-cAMP signaling in the cardiac atrium: high and low gain switches, respectively, for the regulation of cAMP levels and contractile and secretory functions.
Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers
Authors: Potapova Irina , Plotnikov Alexei , Lu Zhongju , Danilo Peter , Valiunas Virginijus , Qu Jihong , Doronin Sergey , Zuckerman Joan , Shlapakova Iryna N. , Gao Junyuan , Pan Zongming , Herron Alan J. , Robinson Richard B. , Brink Peter R. , Rosen Michael R. , Cohen Ira S.
Published: March 2004

We tested the ability of human mesenchymal stem cells (hMSCs) to deliver a biological pacemaker to the heart. hMSCs transfected with a cardiac pacemaker gene, mHCN2, by electroporation expressed high levels of Cs
+
-sensitive current (31.1±3.8 pA/pF at −150 mV) activating in the diastolic potential range with reversal potential of −37.5±1.0 mV, confirming the expressed current as
I
f
-like. The expressed current responded to isoproterenol with an 11-mV positive shift in activation. Acetylcholine had no direct effect, but in the presence of isoproterenol, shifted activation 15 mV negative. Transfected hMSCs influenced beating rate in vitro when plated onto a localized region of a coverslip and overlaid with neonatal rat ventricular myocytes. The coculture beating rate was 93±16 bpm when hMSCs were transfected with control plasmid (expressing only EGFP) and 161±4 bpm when hMSCs were expressing both EGFP+mHCN2 (
P
<0.05). We next injected 10
6
hMSCs transfected with either control plasmid or mHCN2 gene construct subepicardially in the canine left ventricular wall in situ. During sinus arrest, all control (EGFP) hearts had spontaneous rhythms (45±1 bpm, 2 of right-sided origin and 2 of left). In the EGFP+mHCN2 group, 5 of 6 animals developed spontaneous rhythms of left-sided origin (rate=61±5 bpm;
P
<0.05). Moreover, immunostaining of the injected regions demonstrated the presence of hMSCs forming gap junctions with adjacent myocytes. These findings demonstrate that genetically modified hMSCs can express functional HCN2 channels in vitro and in vivo, mimicking overexpression of HCN2 genes in cardiac myocytes, and represent a novel delivery system for pacemaker genes into the heart or other electrical syncytia.
Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation
Authors: Noseda Michela , McLean Graeme , Niessen Kyle , Chang Linda , Pollet Ingrid , Montpetit Rachel , Shahidi Réza , Dorovini-Zis Katerina , Li Linheng , Beckstead Benjamin , Durand Ralph E. , Hoodless Pamela A. , Karsan Aly
Published: March 2004

Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation. In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (α-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development.
Hemostatic Factors as Risk Markers for Intracerebral Hemorrhage
Authors: Johansson Lars , Jansson Jan-Håkan , Stegmayr Birgitta , Nilsson Torbjörn K. , Hallmans Göran , Boman Kurt
Published: March 2004

Background and Purpose—

Abnormalities in the hemostatic system may cause hemorrhagic complications. The aim of the present study was to examine whether total concentrations of tissue plasminogen activator (tPA), plasminogen inhibitor-1 (PAI-1), tPA/PAI-1 complex, von Willebrand factor (VWF), and soluble thrombomodulin were associated with a first-ever intracerebral hemorrhage (ICH).

Methods—

This prospective study was an incident case-referent study nested within the Västerbotten Intervention Program and the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) cohorts. By 2000, ≈74 000 subjects had been screened, and 39 ICH cases were defined according to the World Health Organization MONICA criteria. A total of 78 matched controls were selected from the same cohort.

Results—

The average time from screening to the ICH event was 5.1 years. tPA/PAI-1 complex, systolic and diastolic blood pressures, and hypertension were associated with ICH in the univariate analysis. In the multivariate model, only hypertension (odds ratio [OR], 3.96; 95% confidence interval [CI], 1.27 to 12.36) and the tertile with the highest level of VWF compared with the lowest tertile (OR, 0.27; 95% CI, 0.08 to 0.90) were independently associated with ICH. The OR for the combined exposure to hypertension and low levels of VWF was 8.95, indicating a possible synergistic interaction. No associations were observed for smoking, cholesterol, body mass index, PAI-1, tPA, and soluble thrombomodulin.

Conclusions—

This study showed that hypertension and low concentrations of VWF were independently associated with ICH. Furthermore, we observed a possible synergistic interaction between low levels of VWF and hypertension, suggesting 2 different pathways in the development of ICH.
Controlled Contrast Transcranial Doppler and Arterial Blood Gas Analysis to Quantify Shunt Through Patent Foramen Ovale
Authors: Devuyst Gérald , Piechowski-Jóźwiak Bartłomiej , Karapanayiotides Theodoros , Fitting Jean-William , Kémeny Vendel , Hirt Lorenz , Urbano Luis A. , Arnold Pierre , van Melle Guy , Despland Paul-Andre , Bogousslavsky Julien
Published: March 2004

Background and Purpose—

A right-to-left shunt can be identified by contrast transcranial Doppler ultrasonography (c-TCD) at rest and/or after a Valsalva maneuver (VM) or by arterial blood gas (ABG) measurement. We assessed the influence of controlled strain pressures and durations during VM on the right-to-left passage of microbubbles, on which depends the shunt classification by c-TCD, and correlated it with the right-to-left shunt evaluation by ABG measurements in stroke patients with patent foramen ovale (PFO).

Methods—

We evaluated 40 stroke patients with transesophageal echocardiography–documented PFO. The microbubbles were recorded with TCD at rest and after 4 different VM conditions with controlled duration and target strain pressures (duration in seconds and pressure in cm H
2
O, respectively): V5-20, V10-20, V5-40, and V10-40. The ABG analysis was performed after pure oxygen breathing in 34 patients, and the shunt was calculated as percentage of cardiac output.

Results—

Among all VM conditions, V5-40 and V10-40 yielded the greatest median number of microbubbles (84 and 95, respectively;
P
<0.01). A significantly larger number of microbubbles were detected in V5-40 than in V5-20 (
P
<0.001) and in V10-40 than in V10-20 (
P
<0.01). ABG was not sensitive enough to detect a shunt in 31 patients.

Conclusions—

The increase of VM expiratory pressure magnifies the number of microbubbles irrespective of the strain duration. Because the right-to-left shunt classification in PFO is based on the number of microbubbles, a controlled VM pressure is advised for a reproducible shunt assessment. The ABG measurement is not sensitive enough for shunt assessment in stroke patients with PFO.
Effect of Brain-Derived Neurotrophic Factor Treatment and Forced Arm Use on Functional Motor Recovery After Small Cortical Ischemia
Authors: Schäbitz W.-R. , Berger C. , Kollmar R. , Seitz M. , Tanay E. , Kiessling M. , Schwab S. , Sommer C.
Published: March 2004

Background and Purpose—

Both the administration of growth factors and physical therapy such as forced arm use (FAU) are promising approaches to enhance recovery after stroke. We explored the effects of these therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia.

Methods—

Rats were subjected to photothrombotic ischemia: sham (no ischemia), control (ischemia), brain-derived neurotrophic factor (BDNF; ischemia plus BDNF, 20 μg), and FAU (ischemia plus FAU, 1-sleeve plaster cast ipsilateral limb). Animals survived 1 or 6 weeks and underwent behavioral testing (Rotarod, beam balance, adhesive removal, plantar test, neuroscore). After the rats were killed, brain sections were immunostained for semiquantitative analysis of MAP1B, MAP2, synaptophysin, GFAP expression, and quantification of infarct volumes.

Results—

Infarct volumes were not different between the groups 1 or 6 weeks after ischemia. BDNF-treated animals had better functional motor recovery (Rotarod, beam balance, neuroscore) compared with all other groups (
P
<0.05). There was no significant adverse effect of early FAU treatment on motor recovery, although sensorimotor function (adhesive removal test) was impaired (
P
<0.05). There were no differences between groups as measured by nociception of the left and right forepaw (plantar test). BDNF treatment transiently induced MAP1B expression in the ischemic border zone and synaptophysin expression within the contralateral cortex 6 weeks after ischemia (
P
<0.05). Both BDNF and FAU reduced astrogliosis compared with controls (
P
<0.05).

Conclusions—

Postischemic intravenous BDNF treatment improves functional motor recovery after photothrombotic stroke and induces widespread neuronal remodeling. Early FAU treatment after stroke does not increase infarct size, impairs sensorimotor function, but leaves motor function unchanged. Postischemic astrogliosis was reduced by both treatments.
Imaging of Stem Cell Recruitment to Ischemic Infarcts in a Murine Model
Authors: Kim Dong-Eog , Schellingerhout Dawid , Ishii Ken , Shah Khalid , Weissleder Ralph
Published: March 2004

Background and Purpose—

Neural progenitor cells (NPC) have been reported to aid in the functional recovery from stroke and hold promise as a novel treatment for a variety of neurological diseases. There is a need for imaging tools to study the in vivo migratory behavior of these cells.

Methods—

C17.2 NPC, stably transfected with firefly luciferase, were serially imaged through intact skull and skin by bioluminescence imaging over 2 to 3 weeks in nu/nu mice with closed-vessel middle cerebral artery infarcts, followed by contralateral intraparenchymal or intraventricular injections of NPC.

Results—

NPC migrated to the site of infarct from the contraleral parenchyma, crossing the midline at 7 days. In control animals without infarcts, NPC remained at the site of administration. Intraventricular cell administration resulted in a wide distribution of cells, including the site of infarct. Within the infarct area, NPC colabeled with the neuronal marker NeuN and with astroglial marker glial fibrillary acidic protein. The time course and magnitude of NPC recruitment were longitudinally compared between the treatment groups.

Conclusions—

NPC recruitment to infarct can be assessed noninvasively by serial in vivo imaging. Images correlate well with histological cell distributions. NPC are recruited to infarcts with both parenchymal and cerebrospinal fluid administration, but higher initial photon counts suggest that cerebrospinal fluid administration is more efficient at early infarct seeding.
Flow Territory Mapping of the Cerebral Arteries With Regional Perfusion MRI
Authors: Hendrikse Jeroen , van der Grond Jeroen , Lu Hanzhang , van Zijl Peter C.M. , Golay Xavier
Published: March 2004

Background and Purpose—

Conventional contrast-enhanced angiography is the gold standard for visualization of the vascular tree supplied by the major cerebral arteries and assessment of collateral flow. Thus far, however, no methods are available to assess the actual flow territories of the individual cerebral arteries. In the present study, we evaluate a noninvasive arterial spin labeling MRI method for selective mapping of the flow territories of the left and right internal carotid arteries and posterior circulation (basilar artery and vertebral arteries).

Methods—

A spatially selective labeling approach, regional perfusion imaging, was developed on the basis of selective slab inversion of the arterial water with a pulsed arterial spin labeling sequence. The selectivity of this method was demonstrated.

Results—

Regional perfusion imaging enables assessment of the perfusion territories of the major cerebral arteries. With selective labeling of an internal carotid artery, signal is present in both the ipsilateral anterior cerebral artery and ipsilateral middle cerebral artery flow territory. With labeling of the basilar artery, perfusion-weighted signal is symmetrically present in both posterior cerebral artery flow territories. Cerebral blood flow values measured with regional perfusion imaging in the complete hemisphere (40.1 mL · min
−1
· 100 g
−1
tissue), white matter (22.1 mL · min
−1
· 100 g
−1
tissue), and gray matter (65.8 mL · min
−1
· 100 g
−1
tissue) are in agreement with data in the literature.

Conclusions—

We present the first imaging method capable of evaluating both quantitatively and qualitatively the flow territories of the individual brain-feeding arteries in vivo.
Contrast Enhancement and Contrast Extravasation on Computed Tomography After Intra-Arterial Thrombolysis in Patients With Acute Ischemic Stroke
Authors: Yoon Woong , Seo Jeong Jin , Kim Jae Kyu , Cho Ki Hyeon , Park Jin Gyoon , Kang Heoung Keun
Published: March 2004

Background and Purpose—

The goal of this study was to determine the CT findings and clinical consequences of contrast enhancement and contrast extravasation on CT scans obtained after intra-arterial thrombolytic therapy for treatment of acute ischemic stroke.

Methods—

Sixty-two patients were treated with intra-arterial thrombolysis. All patients underwent nonenhanced CT scans immediately and 24 hours after thrombolytic therapy. Contrast enhancement was defined as a hyperdense lesion that disappeared on a 24-hour follow-up CT scan. Contrast extravasation was defined as a hyperdense lesion with maximum Hounsfield unit >90 that persisted on a follow-up CT scan. We evaluated the differences in the clinical and radiological data between 3 groups: contrast enhancement, contrast extravasation, and control groups.

Results—

Contrast enhancement was found in 14 of 62 patients (22.6%); contrast extravasation was seen in 7 (11.3%). Compared with the control group, the contrast enhancement group had a lower recanalization grade (64.3% versus 34.1%,
P
=0.048) and a lower incidence of hemorrhagic transformation (14.3% versus 43.9%,
P
=0.047). The contrast extravasation group had a higher incidence of both hemorrhage (100% versus 43.9%,
P
=0.006) and symptomatic hemorrhage (100% versus 14.6%,
P
<0.001) than the control group. Poor outcomes were more frequent in the contrast extravasation group (100% versus 38.9%,
P
=0.003) than the control group.

Conclusions—

Contrast enhancement on CT scans obtained after intra-arterial thrombolysis is usually not associated with hemorrhagic complications. However, contrast extravasation is highly associated with parenchymatous hematoma and should be considered a negative prognostic sign.