bluuebunny/crossref_metadata_2025 huggingface dataset:
Subcutaneous Histamine versus Topiramate in Migraine Prophylaxis: A Double-Blind Study
Authors: Millán-Guerrero R.O. , Isais-Millán R. , Barreto-Vizcaíno S. , Gutiérrez I. , Rivera-Castaño L. , Trujillo-Hernández B. , Baltazar L.M.
Published: February 2008

Background: Histamine has a selective affinity for H3 receptors and it may specifically inhibit the neurogenic edema response involved in migraine pathophysiology. Objective: To evaluate the therapeutic potential of subcutaneous administration of histamine in migraine prophylaxis, compared with oral administration of topiramate. Methods: Ninety patients with migraine were selected in a 12-week double-blind controlled clinical trial to evaluate the efficacy of subcutaneous administration of histamine (1–10 ng twice a week) compared with oral administration of topiramate (100 mg daily dose). The variables studied were: headache intensity, frequency, duration, analgesic intake and Migraine Disability Assessment. Results: The data collected during the 12 weeks of treatment revealed that headache symptoms improved in both the histamine and topiramate groups, which was evident within the first month after the initiation of treatment, with statistically significant (p < 0.001) reductions in headache frequency (50%), Migraine Disability Assessment score (75%), intensity of pain (51%), duration of migraine attacks (45%), as well as in the use of rescue medication (52%). Conclusion: The present study provides evidence of the efficacy of subcutaneously applied histamine and orally administered topiramate in migraine prophylaxis. Subcutaneously applied histamine may represent a novel and effective therapeutic alternative in resistant migraine patients.
Cerebrospinal Fluid Amino Acids in Pathological Gamblers and Healthy Controls
Authors: Nordin Conny , Gupta Ramesh C. , Sjödin Ingemar
Published: February 2008

Amino acids, such as valine, isoleucine and leucine compete with tyrosine and tryptophan for transport into the brain and might thus affect the central serotonin and catecholamine patterns. Furthermore, the excitatory amino acids glutamic acid, aspartic acid and glycine are known to act on the N-methyl-D-aspartate receptor, which is part of the reward system. Based on these facts, we have explored the role of cerebrospinal fluid (CSF) amino acids in pathological gambling. Concentrations of amino acids were determined in CSF obtained from one female and 11 pathological male gamblers and 11 healthy male controls. In an ANCOVA with best subset regression, pathological male gamblers had higher CSF levels of the excitatory glutamic and aspartic acids, as well as of phenylalanine, isoleucine, citrulline and glycine. A negative contribution of glycine in interaction with the neuraxis distance might mirror a reduced spinal supply or an altered elimination of glycine in pathological gamblers. A decreasing CSF gradient from the first (0–6 ml) to the third (13–18 ml) CSF fraction was found for glutamic acid, glycine, leucine, isoleucine, lysine, ornithine and glutamine in both pathological gamblers and healthy controls. A decreasing gradient was found, however, for aspartic acid and phenylalanine in pathological male gamblers. The altered pattern of CSF amino acids in pathological gamblers might exert an influence on central monoamines as well as on N-methyl-D-aspartate receptor function.
No Effect of 5-Day Treatment with Acetylsalicylic Acid (Aspirin) or the Beta-Blocker Propranolol (Inderal) on Free Cortisol Responses to Acute Psychosocial Stress: A Randomized Double-Blind, Placebo-Controlled Study
Authors: Kudielka Brigitte M. , Fischer Joachim E. , Metzenthin Petra , Helfricht Susanne , Preckel Daniel , von Känel Roland
Published: February 2008

Background: The characterization of an individual’s hypothalamic-pituitary-adrenal axis stress response is a main research topic in neuropsychobiology since alterations have been causally linked to several disease states. Over the last years, several studies focused on the identification of sources of inter- and intraindividual variability, but there is still a paucity of experimental data on the effect of different pharmaceuticals on cortisol responses to acute psychological stress. Therefore, in this randomized double-blind placebo-controlled study, we investigated the effect of treatment with two popular and clinically used pharmaceuticals on stress-related cortisol responses, namely acetylsalicylic acid (aspirin), a known prostaglandin synthesis inhibitor, and the beta-blocker propranolol (Inderal), a nonselective beta-receptor antagonist. Methods: For 5 days, 73 healthy subjects (50 men, 23 women; mean age 47.3 ± 7.7 years) received either a daily oral dose of 100 mg aspirin, 80 mg propranolol (Inderal), aspirin + propranolol, or placebo. After treatment, subjects were confronted with the Trier Social Stress Test, a widely-used standardized psychosocial stress protocol. Cortisol responses were measured by six saliva samples taken before and after the stress exposure. Results: Subjects showed a significant cortisol increase after stress (p < 0.0001). The four treatment groups did not differ in their cortisol responses (group effect p > 0.44; interaction p > 0.97). Additionally, controlling for gender, age, smoking status, body mass index, mean arterial blood pressure or pre-stress cortisol levels yielded similar results in the total sample as well as in the male or female subgroups, respectively. Conclusion: Neither short-term treatment with aspirin nor propranolol altered the acute free cortisol response to psychological stress in healthy adults.
Gastrointestinal Symptoms and Helicobacter pylori Infection in Early Pregnancy
Authors: Karaer Abdullah , Ozkan Ovgu , Ozer Serdar , Bayir Betul , Kilic Selcuk , Babur Cahit , Danişman Nuri
Published: February 2008

Background: To investigate the relationship of Helicobacter pylori infection with gastrointestinal symptoms in early pregnancy. Methods:H. pylori seropositivity was determined in 296 pregnant women at 7–12 weeks’ gestation by ELISA between January 2004 and April 2007. Sociodemographic characteristics and gastrointestinal symptoms were recorded at this time. Results: The prevalence of H. pylori infection in our population was 56.8% (168 of 296). 76% of the women with H. pylori and 68% of the women who tested negative for H. pylori infection reported at least one of the evaluated gastrointestinal symptoms. Although morning sickness and morning vomiting were not associated with H. pylori infection, sickness and vomiting during the whole day were more frequently noted with H. pylori infection (OR 2.5, 95% CI 1.2–4.9, p = 0.01). Conclusions: Of the evaluated gastrointestinal symptoms, H. pylori infection is significantly associated with sickness and vomiting during the whole day.
Increased Incidence of Acute Kidney Injury with Aprotinin Use during Cardiac Surgery Detected with Urinary NGAL
Authors: Wagener Gebhard , Gubitosa Gina , Wang Shuang , Borregaard Niels , Kim Mihwa , Lee H. Thomas
Published: February 2008

Background: Use of aprotinin has been associated with acute kidney injury after cardiac surgery. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel, very sensitive marker for renal injury. Urinary NGAL may be able to detect renal injury caused by aprotinin. This study determined if the use of aprotinin is associated with an increased incidence of acute kidney injury and increased levels of urinary NGAL. Methods: In this prospective, observational study 369 patients undergoing cardiac surgery were enrolled. 205 patients received aprotinin and 164 received epsilon amino-caproic acid intraoperatively. Urinary NGAL was measured before and immediately after cardiac surgery and 3, 18 and 24 h later. The association of aprotinin use with the incidence of acute kidney injury (increase of serum creatinine >0.5 mg/dl) and NGAL levels was determined using logistic and linear regression models. Results: 51 of 205 patients (25%) who received aprotinin developed acute kidney injury compared to 19 of 164 patients (12%) who received epsilon amino-caproic acid (p = 0.0013). Aprotinin use was associated with a two-fold higher risk of acute kidney injury when adjusted for potential confounders (age, Parsonnet score, preoperative serum creatinine, cardiopulmonary bypass and cross-clamp times; multiple logistic regression: OR = 2.164; CI (95%) = 1.102 to 4.249; p = 0.0249. Urinary NGAL was 19 times higher immediately after cardiopulmonary bypass and 18 times higher 3 h later in patients who had received aprotinin (postoperative: 19.23; CI (95%) = 12.60 to 29.33; p < 0.0001; 3 h post-cardiopulmonary bypass 18.67; CI (95%) = 11.45 to 30.43; p < 0.0001). Conclusions: Postoperative urinary NGAL – a novel marker for renal injury – is increased in cardiac surgical patients receiving aprotinin compared to patients receiving epsilon amino-caproic acid. These results further support the hypothesis that aprotinin may cause renal injury. The substantial rise of urinary NGAL associated with aprotinin use may in part be due to aprotinin blocking the uptake of NGAL by megalin/gp330 receptors in the proximal tubules.
Angiopoietin-Related Growth Factor Enhances Blood Flow Via Activation of the ERK1/2-eNOS-NO Pathway in a Mouse Hind-Limb Ischemia Model
Authors: Urano Takashi , Ito Yasuhiro , Akao Masaki , Sawa Tomohiro , Miyata Keishi , Tabata Mitsuhisa , Morisada Tohru , Hato Tai , Yano Masato , Kadomatsu Tsuyoshi , Yasunaga Kunio , Shibata Rei , Murohara Toyoaki , Akaike Takaaki , Tanihara Hidenobu , Suda Toshio , Oike Yuichi
Published: February 2008

Objective—

Transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis, suggesting that AGF may be a useful drug target in ischemic disease. Our goal was to determine whether AGF enhances blood flow in a mouse hind-limb ischemia model and to define molecular mechanisms underlying AGF signaling in endothelial cells.

Methods and Results—

Intramuscular injection of adenovirus harboring AGF into the ischemic limb increased AGF production, which increased blood flow through induction of angiogenesis and arteriogenesis, thereby reducing the necessity for limb amputation. In vitro analysis showed that exposing human umbilical venous endothelial cells to AGF increased nitric oxide (NO) production through activation of an ERK1/2-endothelial NO synthetase (eNOS) signaling pathway. AGF-stimulated eNOS phosphorylation, NO production, and endothelial cell migration were all abolished by specific MEK1/2 inhibitors. Moreover, AGF did not restore blood flow to ischemic hind-limbs of either mice receiving NOS inhibitor L-NAME or eNOS knockout mice.

Conclusion—

Activation of an ERK1/2-eNOS-NO pathway is a crucial signaling mechanism by which AGF increases blood flow through induction of angiogenesis and arteriogenesis. Further investigation of the regulation underlying AGF signaling pathway may contribute to develop a new clinical strategy for ischemic vascular diseases.
High Glucose Enhances Transient Receptor Potential Channel Canonical Type 6–Dependent Calcium Influx in Human Platelets via Phosphatidylinositol 3-Kinase–Dependent Pathway
Authors: Liu Daoyan , Maier Alexandra , Scholze Alexandra , Rauch Ursula , Boltzen Ulrike , Zhao Zhigang , Zhu Zhiming , Tepel Martin
Published: February 2008

Background—

Transient receptor potential canonical type 6 (TRPC6) channels mediating 1-oleoyl-2-acetyl-sn-glycerol (OAG)–induced calcium entry have been identified on human platelets. In the present study we tested the hypothesis that hyperglycemia increases the expression of TRPC6 channels.

Methods and Results—

Platelets from healthy control subjects and patients with type 2 diabetes mellitus were incubated with glucose and calcium influx was measured using the fluorescent dye technique. TRPC channel protein expression was investigated using immunofluorescence and fluorescence microscopy of single platelets. Administration of 25 mmol/L glucose significantly enhanced the OAG-induced calcium influx, which was attenuated by inhibitors of the phosphatidylinositol 3-kinase, wortmannin or LY294002. The glucose-enhanced and OAG-induced calcium influx was concentration- and time-dependent. Glucose significantly increased the TRPC6 protein expression in platelets to 131±12% (n=33;
P
<0.05), whereas the expression of TRPC1, TRPC3, TRPC4, or TRPC5 were unchanged. The glucose-induced TRPC6 expression was significantly attenuated in the presence of wortmannin or LY294002. Platelets from patients with type 2 diabetes mellitus showed increased TRPC6 expression compared to nondiabetic individuals (
P
<0.05).

Conclusion—

The study indicates that high glucose increases TRPC6 channel protein expression on the platelet surface which is mediated by a phosphatidylinositol 3-kinase–dependent pathway.
Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate
Authors: Venkataraman Krishnan , Lee Yong-Moon , Michaud Jason , Thangada Shobha , Ai Youxi , Bonkovsky Herbert L. , Parikh Nehal S. , Habrukowich Cheryl , Hla Timothy
Published: February 2008

Sphingosine 1-phosphate (S1P), an abundant lipid mediator in plasma, regulates vascular and immune cells by activating S1P receptors. In this report, we investigated the mechanisms by which high plasma S1P levels are maintained in mice. We found that plasma S1P turns over rapidly with a half-life of ≈15 minutes, suggesting the existence of a high-capacity biosynthetic source(s). Transplantation of bone marrow from wild-type to
Sphk1
−/−
Sphk2
+/−
mice restored plasma S1P levels, suggesting that hematopoietic cells are capable of secreting S1P into plasma. However, plasma S1P levels were not appreciably altered in mice that were thrombocytopenic, anemic, or leukopenic. Surprisingly, reconstitution of
Sphk1
−/−
Sphk2
+/−
bone marrow cells into wild-type hosts failed to reduce plasma S1P, suggesting the existence of an additional, nonhematopoietic source for plasma S1P. Adenoviral expression of
Sphk1
in the liver of
Sphk1
−/−
mice restored plasma S1P levels. In vitro, vascular endothelial cells, but not hepatocytes, secreted S1P in a constitutive manner. Interestingly, laminar shear stress downregulated the expression of S1P lyase (
Sgpl
) and S1P phosphatase-1 (
Sgpp
1) while concomitantly stimulating S1P release from endothelial cells in vitro. Modulation of expression of endothelial S1P lyase with small interfering RNA and adenoviral expression altered S1P secretion, suggesting an important role played by this enzyme. These data suggest that the vascular endothelium, in addition to the hematopoietic system, is a major contributor of plasma S1P.
Angiotensin-Converting Enzyme 2 Overexpression in the Subfornical Organ Prevents the Angiotensin II–Mediated Pressor and Drinking Responses and Is Associated With Angiotensin II Type 1 Receptor Downregulation
Authors: Feng Yumei , Yue Xinping , Xia Huijing , Bindom Sharell M. , Hickman Peter J. , Filipeanu Catalin M. , Wu Guangyu , Lazartigues Eric
Published: February 2008

We recently reported the presence of angiotensin-converting enzyme (ACE)2 in brain regions controlling cardiovascular function; however, the role of ACE2 in blood pressure regulation remains unclear because of the lack of specific tools to investigate its function. We hypothesized that ACE2 could play a pivotal role in the central regulation of cardiovascular function by regulating other renin–angiotensin system components. To test this hypothesis, we generated an adenovirus expressing the human ACE2 cDNA upstream of an enhanced green fluorescent protein (eGFP) reporter gene (Ad-hACE2-eGFP). In vitro characterization shows that neuronal cells infected with Ad-hACE2-eGFP (10 to 100 multiplicities of infection), but not Ad-eGFP (100 multiplicities of infection), exhibit dose-dependent ACE2 expression and activity. In addition, an active secreted form was detected in the conditioned medium. In vivo, Ad-hACE2-eGFP infection (2×10
6
plaque-forming units intracerebroventricularly) produced time-dependent expression and activity (with a peak at 7 days) in the mouse subfornical organ. More importantly, 7 days after virus infection, the pressor response to angiotensin (Ang) II (200 pmol intracerebroventricularly) was significantly reduced in Ad-hACE2-eGFP–treated mice compared with controls. Furthermore, subfornical organ–targeted ACE2 overexpression dramatically reduced the Ang II–mediated drinking response. Interestingly, ACE2 overexpression was associated with downregulation of the Ang II type 1 receptor expression both in vitro and in vivo. These data suggest that ACE2 overexpression in the subfornical organ impairs Ang II–mediated pressor and drinking responses at least by inhibiting the Ang II type 1 receptor expression. Taken together, our results show that ACE2 plays a pivotal role in the central regulation of blood pressure and volume homeostasis, offering a new target for the treatment of hypertension and other cardiovascular diseases.
Measurement of Walking Distance and Speed in Patients With Peripheral Arterial Disease
Authors: Le Faucheur Alexis , Abraham Pierre , Jaquinandi Vincent , Bouyé Philippe , Saumet Jean Louis , Noury-Desvaux Bénédicte
Published: February 2008

Background—

The maximal walking distance (MWD) performed on a treadmill test remains the “gold standard” in estimating the walking capacity of patients who have peripheral arterial disease with intermittent claudication, although treadmills are not accessible to most physicians. We hypothesized that global positioning system (GPS) recordings could monitor community-based outdoor walking and provide valid information on walking capacity in patients with peripheral arterial disease.

Methods and Results—

We studied 24 patients (6 women) with arterial claudication (median [25th to 75th percentile] values: 57 years old [48 to 67 years], 169 cm tall [164 to 172 cm], weight 81 kg [71 to 86 kg], and ankle-brachial index 0.64 [0.56 to 0.74]). MWD on the treadmill was 184 m (144 to 246 m), which was compared with the results of self-reported MWD, the distance score from the Walking Impairment Questionnaire, MWD observed during a 6-minute walking test, and MWD measured over a GPS-recorded unconstrained outdoor walk in a public park. Self-reported MWD, Walking Impairment Questionnaire distance score, 6-minute walking test score, and GPS-measured MWD were 300 m (163 to 500 m), 28% (15% to 47%), 405 m (338 to 441 m), and 609 m (283 to 1287 m), respectively. The best correlation with MWD on the treadmill test was obtained with the MWD measured by the GPS (Spearman
r
=0.81,
P
<0.001).

Conclusions—

Outdoor walking capacity measured by a low-cost GPS is a potentially innovative way to study the walking capacity of patients with peripheral arterial disease. It opens new perspectives in the study of walking capacity for vascular patients with claudication under free-living conditions or for physicians who do not have a treadmill.
Clinical Characteristics and In-Hospital Outcomes of Patients With Cardiogenic Shock Undergoing Coronary Artery Bypass Surgery
Authors: Mehta Rajendra H. , Grab Joshua D. , O’Brien Sean M. , Glower Donald D. , Haan Constance K. , Gammie James S. , Peterson Eric D.
Published: February 2008

Background—

There exist few studies that characterize contemporary clinical features and outcomes or risk factors for operative mortality in cardiogenic shock (CS) patients undergoing coronary artery bypass grafting (CABG).

Methods and Results—

We evaluated data of 708 593 patients with and without CS undergoing CABG enrolled in the Society of Thoracic Surgeons National Cardiac Database (2002–2005). Clinical, angiographic, and operative features and in-hospital outcomes were evaluated in patients with and without CS. Logistic regression was used to identify predictors of operative mortality and to estimate weights for an additive risk score. Patients with preoperative CS constituted 14 956 (2.1%) of patients undergoing CABG yet accounted for 14% of all CABG deaths. Operative mortality in CS patients was high and surgery specific, rising from 20% for isolated CABG to 33% for CABG plus valve surgery and 58% for CABG plus ventricular septal repair. Although mortality for CABG surgery overall declined significantly over time (
P
for trend <0.0001), mortality for CS patients undergoing CABG did not change significantly during the 4-year study period (
P
=0.07). Factors associated with higher death risk for CS patients undergoing CABG were identified by multivariable analysis and summarized into a simple bedside risk score (c statistic=0.74) that accurately stratified those with low (<10%) to very high (>60%) mortality risk.

Conclusions—

Patients with CS represent a minority of those undergoing CABG yet have persistently high operative risks, accounting for 14% of deaths in CABG patients. Estimation of patient-specific risk of mortality is feasible with the simplified additive risk tool developed in our study with the use of routinely available preprocedural data.
Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling
Authors: Zhou Cissy Chenyi , Ahmad Shakil , Mi Tiejuan , Abbasi Shahrzad , Xia Lingwei , Day Mary-Clare , Ramin Susan M. , Ahmed Asif , Kellems Rodney E. , Xia Yang
Published: February 2008

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Recent evidence indicates that maternal endothelial dysfunction in preeclampsia results from increased soluble Fms-like tyrosine kinase-1 (sFlt-1), a circulating antiangiogenic protein. Factors responsible for excessive production of sFlt-1 in preeclampsia have not been identified. We tested the hypothesis that angiotensin II type 1 (AT
1
) receptor activating autoantibodies, which occur in women with preeclampsia, contribute to increased production of sFlt-1. IgG from women with preeclampsia stimulates the synthesis and secretion of sFlt-1 via AT
1
receptor activation in pregnant mice, human placental villous explants, and human trophoblast cells. Using FK506 or short-interfering RNA targeted to the calcineurin catalytic subunit mRNA, we determined that calcineurin/nuclear factor of activated T-cells signaling functions downstream of the AT
1
receptor to induce sFlt-1 synthesis and secretion by AT
1
-receptor activating autoantibodies. AT
1
-receptor activating autoantibody–induced sFlt-1 secretion resulted in inhibition of endothelial cell migration and capillary tube formation in vitro. Overall, our studies demonstrate that an autoantibody from women with preeclampsia induces sFlt-1 production via angiotensin receptor activation and downstream calcineurin/nuclear factor of activated T-cells signaling. These autoantibodies represent potentially important targets for diagnosis and therapeutic intervention.
Shared Constitutional Risks for Maternal Vascular-Related Pregnancy Complications and Future Cardiovascular Disease
Authors: Berends Anne L. , de Groot Christianne J.M. , Sijbrands Eric J. , Sie Mark P.S. , Benneheij Sofie H. , Pal Richard , Heydanus Roger , Oostra Ben A. , van Duijn Cornelia M. , Steegers Eric A.P.
Published: February 2008

Maternal predisposition to vascular and metabolic disease may underlie both vascular-related pregnancy complications, such as preeclampsia and intrauterine growth restriction, as well as future maternal cardiovascular disease. We aimed to substantiate this hypothesis with biochemical and anthropometric evidence by conducting an intergenerational case-control study in a Dutch isolated population including 106 women after preeclampsia or intrauterine growth restriction (median follow-up: 7.1 years) and their fathers (n=43) and mothers (n=64), as well as 106 control subjects after uncomplicated pregnancies with their fathers (n=51) and mothers (n=68). Cardiovascular risk profiles were assessed, including fasting glucose, lipids, anthropometrics, blood pressure, intima-media thickness, and metabolic syndrome. We found significantly higher fasting glucose levels, larger waist circumferences, and a 5-fold increased prevalence of hypertension in women with a history of preeclampsia as compared with control subjects (
P
<0.001). Likewise, their parents had higher glucose levels than control parents (
P
<0.05). Their mothers had larger waist circumferences and higher blood pressures (
P
<0.05). Also, women after pregnancies complicated by intrauterine growth restriction had higher glucose levels and increased prevalence of hypertension (
P
<0.01). Their fathers showed higher glucose levels as well (
P
<0.05). Mean carotid intima-media thickness was increased in a subset of women after preeclampsia diagnosed with chronic hypertension as compared with those without hypertension (
P
<0.01). Metabolic syndrome was more prevalent both in women with a history of preeclampsia and their mothers (
P
<0.05). We demonstrated intergenerational similarities in cardiovascular risk profiles between women after preeclampsia or intrauterine growth restriction and their parents. These findings suggest shared constitutional risks for vascular-related pregnancy complications and future cardiovascular disease.
Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite
Authors: Webb Andrew J. , Patel Nakul , Loukogeorgakis Stavros , Okorie Mike , Aboud Zainab , Misra Shivani , Rashid Rahim , Miall Philip , Deanfield John , Benjamin Nigel , MacAllister Raymond , Hobbs Adrian J. , Ahluwalia Amrita
Published: February 2008

Diets rich in fruits and vegetables reduce blood pressure (BP) and the risk of adverse cardiovascular events. However, the mechanisms of this effect have not been elucidated. Certain vegetables possess a high nitrate content, and we hypothesized that this might represent a source of vasoprotective nitric oxide via bioactivation. In healthy volunteers, approximately 3 hours after ingestion of a dietary nitrate load (beetroot juice 500 mL), BP was substantially reduced (Δ
max
−10.4/8 mm Hg); an effect that correlated with peak increases in plasma nitrite concentration. The dietary nitrate load also prevented endothelial dysfunction induced by an acute ischemic insult in the human forearm and significantly attenuated ex vivo platelet aggregation in response to collagen and ADP. Interruption of the enterosalivary conversion of nitrate to nitrite (facilitated by bacterial anaerobes situated on the surface of the tongue) prevented the rise in plasma nitrite, blocked the decrease in BP, and abolished the inhibitory effects on platelet aggregation, confirming that these vasoprotective effects were attributable to the activity of nitrite converted from the ingested nitrate. These findings suggest that dietary nitrate underlies the beneficial effects of a vegetable-rich diet and highlights the potential of a “natural” low cost approach for the treatment of cardiovascular disease.
Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia
Authors: Anton Lauren , Merrill David C. , Neves Liomar A.A. , Stovall Kathryn , Gallagher Patricia E. , Diz Debra I. , Moorefield Cheryl , Gruver Courtney , Ferrario Carlos M. , Brosnihan K. Bridget
Published: February 2008

The chorionic villi in the placenta are responsible for the regulation of fetal oxygen and nutrient transport. Although the peripheral renin-angiotensin system is activated during normal pregnancy, the regulation of the local chorionic villi renin-angiotensin system remains unknown. Therefore, placental chorionic villous tissue was collected from nulliparous third-trimester normotensive or preeclamptic subjects and was analyzed for angiotensin peptide content, angiotensinogen, renin, angiotensin-converting enzyme (ACE), ACE2, neprilysin, angiotensin II type 1 (AT
1
), angiotensin II type 2,
Mas
receptor mRNAs, and angiotensin receptor density and subtype. Angiotensin II in chorionic villi was significantly higher in preeclamptic subjects, whereas angiotensin (1-7) was not different. Angiotensinogen and AT
1
receptor gene expression was significantly higher in preeclamptic subjects. No differences were observed in renin, ACE, ACE2, or neprilysin gene expression.
Mas
receptor mRNA in preeclamptic subjects was decreased. The AT
1
receptor was the predominant receptor subtype in normal and preeclamptic chorionic villi. There was no difference in the density of the AT
1,
angiotensin II type 2, and angiotensin (1-7) receptors. These results indicate that enhanced chorionic villous expression of angiotensin II may result from increased angiotensinogen. Elevated angiotensin II, acting through the AT
1
receptor, may favor vasoconstriction in placental chorionic villi and contribute to impaired fetal blood flow and decreased fetal nutrition observed during preeclampsia.
Mean Arterial Pressure at 11
+0
to 13
+6
Weeks in the Prediction of Preeclampsia
Authors: Poon Leona C.Y. , Kametas Nikos A. , Pandeva Ivilina , Valencia Catalina , Nicolaides Kypros H.
Published: February 2008

This study aimed to determine the performance of screening for preeclampsia (PE) by maternal medical history and mean arterial pressure (MAP) at 11
+0
to 13
+6
weeks. In 5590 women with singleton pregnancies attending for routine care at 11
+0
to 13
+6
week’s gestation we recorded maternal variables and measured the MAP. We excluded 397 because they had missing outcome data or the pregnancies resulted in miscarriage or termination. In 104 patients there was subsequent development of PE, 97 developed gestational hypertension, 574 delivered small-for-gestational-age newborns, and 4418 were unaffected by PE, gestational hypertension, or small for gestational age. A multivariate Gaussian model was fitted to the distribution of log multiple of the median MAP in the PE and unaffected groups. Likelihood ratios for log multiple of the median MAP were computed and used together with maternal variables to produce patient-specific risks for each case. Detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold. In the unaffected group, log MAP was influenced by maternal age, ethnic origin, smoking, family and personal history of PE, and fetal crown-rump length. In the prediction of PE, significant contributions were provided by log multiple of the median MAP, ethnic origin, body mass index, and personal history of PE. The detection rate of PE by log multiple of the median MAP and maternal variables was 62.5% for a false-positive rate of 10%. Maternal variables, together with MAP, at 11
+0
to 13
+6
weeks identify a group at high risk for development of PE.
Spironolactone Suppresses Peritubular Capillary Loss and Prevents Deoxycorticosterone Acetate/Salt-Induced Tubulointerstitial Fibrosis
Authors: Iwazu Yoshitaka , Muto Shigeaki , Fujisawa Genro , Nakazawa Eiko , Okada Koji , Ishibashi Shun , Kusano Eiji
Published: February 2008

We examined whether and how peritubular capillary (PTC) loss in the renal cortex contributes to the development of deoxycorticosterone acetate (DOCA)/salt-induced tubulointerstitial fibrosis. Uninephrectomized rats provided with 0.9% NaCl/0.3% KCl drinking solution ad libitum were divided into control, DOCA, and spironolactone groups, which were administered vehicle, DOCA alone, and DOCA plus spironolactone for 1 (initial phase) and 4 weeks (delayed phase), respectively. Exposure to DOCA initiated a sequence of events that initially involved reduced PTC density, followed by a delayed response that involved further reduced PTC density, development of tubulointerstitial fibrosis and hypertension, enhanced expression of transforming growth factor-β1 and connective tissue growth factor, and impaired renal function. Concomitant with the reduced PTC density, the 2 hypoxia-responsive angiogenic factors (vascular endothelial growth factor and hypoxia-inducible factor-1α) and the antiangiogenic factor (thrombospondin-1) were upregulated in cortical tubular cells of the DOCA group during the 2 phases and only in the delayed phase, respectively. In the DOCA group, PTC endothelial cell apoptosis was enhanced during the 2 phases, and PTC endothelial cell proliferation was inhibited in the delayed phase. In accordance with upregulation of thrombospondin-1, p53 expression was enhanced in the DOCA group in the delayed phase. The initial and delayed effects of DOCA were blocked in the spironolactone group. We conclude that exposure to DOCA initially caused the reduced PTC density associated with enhanced apoptosis independent of thrombospondin-1, which induced tubulointerstitial fibrosis via p53-mediated thrombospondin-1 activation, and spironolactone conversely corrected the effects of DOCA to prevent fibrosis.
Maternal Wave Reflections and Arterial Stiffness in Normal Pregnancy as Assessed by Applanation Tonometry
Authors: Macedo Maria L. , Luminoso Daniele , Savvidou Makrina D. , McEniery Carmel M. , Nicolaides Kypros H.
Published: February 2008

Normal pregnancy is associated with profound alterations in the maternal cardiovascular system. The aim of the present study was to assess noninvasively, using applanation tonometry, the maternal central aortic blood pressures (BP), effects of wave reflection and arterial stiffness (aortic and brachial pulse wave velocity) in normal pregnancy. This was a cross sectional study including 193 women with normal singleton pregnancies at 11 to 41 weeks of gestation and 23 nonpregnant controls, matched for age and height. Compared to nonpregnant controls, pregnant women had lower mean arterial pressure (85±8.9 mm Hg versus 81.1±7.2 mm Hg;
P
=0.01), central systolic BP (103±11 mm Hg versus 96±8 mm Hg,
P
=0.001), central diastolic BP (71±9 mm Hg versus 67±7 mm Hg,
P
=0.008), and augmentation index (AIx) (19±11% versus 4±12%,
P
<0.001). The AIx changed significantly with gestation reaching its nadir at midpregnancy (
R
2
=0.05,
P
=0.007). This change was present even after adjusting for maternal age (
P
<0.001), heart rate (
P
<0.001), and mean arterial BP (
P
<0.001); known determinants of AIx. The pulse wave velocity (carotid-radial and carotid-femoral) did not change significantly with gestation and was marginally different between pregnant and nonpregnant women (
P
=0.03 and
P
=0.05 for carotid-radial and carotid-femoral respectively). However, adjustments for maternal age and mean arterial pressure rendered these differences nonsignificant (
P
=0.2 for carotid-radial,
P
=0.5 for carotid-femoral). In summary, we found that normal pregnancy is associated with a reduction in central BP and wave reflection.
Prenatal Gender-Related Nicotine Exposure Increases Blood Pressure Response to Angiotensin II in Adult Offspring
Authors: Xiao DaLiao , Xu Zhice , Huang Xiaohui , Longo Lawrence D. , Yang Shumei , Zhang Lubo
Published: February 2008

Epidemiological studies suggest that maternal cigarette smoking is associated with an increased risk of elevated blood pressure (BP) in postnatal life. The present study tested the hypothesis that prenatal nicotine exposure causes an increase in BP response to angiotensin II (Ang II) in adult offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps throughout the gestation. BP and vascular responses to Ang II were measured in 5-month–old adult offspring. Prenatal nicotine had no effect on baseline BP but significantly increased Ang II–stimulated BP in male but not female offspring. The baroreflex sensitivity was significantly decreased in both male and female offspring. Prenatal nicotine significantly increased arterial media thickness in male but not female offspring. In male offspring, nicotine exposure significantly increased Ang II–induced contractions of aortas and mesenteric arteries. These responses were not affected by inhibition of endothelial NO synthase activity. Losartan blocked Ang II–induced contractions in both control and nicotine-treated animals. In contrast, PD123319 had no effect on Ang II–induced contractions in control but inhibited them in nicotine-treated animals. Nicotine significantly increased Ang II type 1 receptor but decreased Ang II type 2 receptor protein levels, resulting in a significant increase in the ratio of Ang II type 1 receptor/Ang II type 2 receptor in the aorta. Furthermore, the increased contractions of mesenteric arteries were mediated by increases in intracellular Ca2+concentrations and Ca2+sensitivity. These results suggest that prenatal nicotine exposure alters vascular function via changes in Ang II receptor–mediated signaling pathways in adult offspring in a gender-specific manner, which may lead to an increased risk of hypertension in male offspring.
Gender-Related Difference in Arterial Elastance During Exercise in Patients With Hypertension
Authors: Park Sungha , Ha Jong-Won , Shim Chi Young , Choi Eui-Young , Kim Jin-Mi , Ahn Jeong-Ah , Lee Se-Wha , Rim Se-Joong , Chung Namsik
Published: February 2008

Exercise intolerance and heart failure with preserved ejection fraction are common in females. Recently, arterial stiffness has been suggested to be a significant contributor in the development of heart failure. How gender difference affects arterial stiffening and its response to exercise is not well known. We hypothesized that arterial elastance index during exercise would be more abnormal in females with hypertension than males. Arterial elastance index was estimated as arterial end systolic pressure/stroke volume controlled for body surface area and was measured at rest and during graded supine bicycle exercise (25 watts, 3-minute increments) in 298 patients with hypertension (149 males; 149 females; mean age, 59). The subjects were divided into 2 groups by gender. Exercise duration was significantly shorter in females compared to males (692±222 versus 483±128 seconds,
P
<0.001). Although arterial elastance index at baseline was significantly higher in males, the magnitude of increase was steeper in females with the magnitude of change at 75 W of exercise being significantly higher in females compared to males (0.69±0.83 versus 0.43±0.69,
P
=0.018). Arterial elastance index at each stage of exercise up to 75 W was independently associated with decreased exercise duration. In conclusion, despite lower arterial elastance index at rest, the increase during exercise was steeper in women with hypertension, suggesting a gender-related difference in dynamic arterial stiffness. The arterial elastance index during exercise was significantly associated with exercise duration in patients with hypertension.
Adverse Perinatal Outcomes and Risk Factors for Preeclampsia in Women With Chronic Hypertension
Authors: Chappell Lucy C. , Enye Stephen , Seed Paul , Briley Annette L. , Poston Lucilla , Shennan Andrew H.
Published: February 2008

Prospective contemporaneous data on the outcome of pregnancies in women with chronic hypertension are sparse. Indices of maternal and perinatal morbidity and mortality were determined in 822 women with chronic hypertension with data prospectively collected and rigorously validated. The incidence of superimposed preeclampsia was 22% (n=180) with early-onset preeclampsia (≤34 weeks gestation) accounting for nearly half of these cases. Delivering an infant <10th customized birthweight centile complicated 48% (87/180) of those with superimposed preeclampsia and 21% (137/642) in those without (relative risk [RR] 2.30; 95% confidence intervals [CI] 1.85 to 2.84). Delivery at <37 weeks gestation occurred in 51% of those with superimposed preeclampsia (98% of these iatrogenic) and 15% without (66% iatrogenic) (RR 3.52; 95% CI 2.79 to 4.45). Using multiple logistic regression, black ethnic origin, raised body mass index, present smoking, booking systolic blood pressure of 130 to 139 mm Hg, and diastolic blood pressure of 80 to 89 mm Hg, a previous history of preeclampsia or eclampsia and chronic renal disease were identified as risk factors for superimposed preeclampsia. Adverse maternal and perinatal outcomes occur in women with chronic hypertension; the prevalence of infants born small for gestational age and preterm is considerably higher than background rates, and is increased further in women with superimposed preeclampsia. Use of customized birthweight centiles provides more accurate determination of fetal growth restriction and highlights the need for greater fetal surveillance in these women. Paradoxically, smoking is an independent risk factor for superimposed preeclampsia in chronic hypertension, in contrast to the protective effect in low-risk pregnant women.
Deoxycorticosterone Acetate-Salt Mice Exhibit Blood Pressure–Independent Sexual Dimorphism
Authors: Karatas Aysun , Hegner Björn , de Windt Leon J. , Luft Friedrich C. , Schubert Carola , Gross Volkmar , Akashi Yoshihiro J. , Gürgen Dennis , Kintscher Ulrich , da Costa Goncalves Andrey C. , Regitz-Zagrosek Vera , Dragun Duska
Published: February 2008

We tested the hypothesis that female and male mice differ in terms of cardiac hypertrophy after deoxycorticosterone acetate (DOCA)+salt hypertension (uninephrectomy and 1% saline in drinking water) and focused on calcineurin signaling. We excluded confounding effects of blood pressure elevation or sex-related blood pressure differences by treating DOCA-salt mice with hydralazine (250 mg/L in drinking water). We found that directly measured mean arterial blood pressure was lowered to control values with hydralazine and corroborated this finding in separate mouse groups with radiotelemetry. Male mice were more responsive to DOCA-salt–related effects. They developed more left ventricular hypertrophy and more renal hypertrophy after 6 weeks of DOCA-salt+hydralazine compared with female mice. In hearts, transcripts for calcineurin Aβ and for myocyte-enriched calcineurin interacting protein 1 were upregulated in male but not in female mice. Enhanced activity of calcineurin Aβ, as indicated by diminished phosphorylation of NFATc2 in male mice, accounted for this sex-specific difference. Stretch-related, inflammatory, and profibrotic responses were also accentuated in male mice, as shown by higher transcript levels of atrial natriuretic peptide, monocyte chemoattractant protein-1, and transforming growth factor-β. Our results support sex-specific regulation of the calcineurin pathway in response to largely blood pressure–independent mineralocorticoid action. We suggest that sex-specific calcineurin activation determines the maladaptive cardiac and renal hypertrophic responses and accompanying organ injury in male mice.
Hemodynamics of Increased Pulse Pressure in Older Women in the Community-Based Age, Gene/Environment Susceptibility–Reykjavik Study
Authors: Mitchell Gary F. , Gudnason Vilmundur , Launer Lenore J. , Aspelund Thor , Harris Tamara B.
Published: February 2008

Pulse pressure increases with advancing age particularly in women. As a result, women have a higher pulse pressure than men from midlife onward. Higher pulse pressure in older women as compared to men is often attributed to increased aortic wall stiffness and premature wave reflection. To evaluate this hypothesis, we measured central aortic input impedance, pulse wave velocity, and wave reflection in 408 older men and women (age range, 69 to 94 yr, mean 75 yr) participating in the community-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik). Women as compared to men had higher pulse pressure (75.8±18.7 versus 69.5±16.8 mm Hg,
P
<0.001) and smaller aortic diameters (2.74±0.24 versus 2.97±0.28 cm,
P
<0.001). Augmentation index (AI) was higher (11.0±15.9 versus 7.9±12.9%,
P
=0.032) in women whereas proximal aortic elastance-wall thickness product (Eh) did not differ (
P
=0.61). In a stepwise model for pulse pressure that included age and sex and offered aortic diameter, Eh, mean pressure, AI, pulse wave velocity, height, weight, and body surface area as additional covariates, higher pulse pressure was associated with increased wall stiffness, smaller aortic diameter, higher mean pressure, and increased AI (Model
R
2
=0.59,
P
<0.001). The sex difference in pulse pressure (6.6±1.7 mm Hg,
P
<0.001) persisted after Eh entered the model (6.9±1.5 mm Hg,
P
<0.001) but not after aortic diameter entered the model (−0.4±1.4 mm Hg,
P
=0.75). Thus, reduced aortic diameter and impaired matching between diameter and flow accounts for the sex difference in pulse pressure in an unselected community-based cohort of older people.
White Matter Hyperintensities and Subclinical Infarction
Authors: Wright Clinton B. , Festa Joanne R. , Paik Myunghee C. , Schmiedigen Alexis , Brown Truman R. , Yoshita Mitsuhiro , DeCarli Charles , Sacco Ralph , Stern Yaakov
Published: February 2008

Background and Purpose—

We examined white matter hyperintensity volume (WMHV) and subclinical infarction (no history of clinical stroke; SI) in relation to performance on tests of sequencing, cognitive flexibility, and sensorimotor ability.

Methods—

The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, Black, and White participants. A subsample (n=656) has undergone measurement of WMHV, SI, and neuropsychological testing. Linear regression was used to examine WMHV and SI in relation to performance on tests of sequencing as measured by Color Trails 1, cognitive flexibility as measured by Color Trails 2, and sensorimotor ability as measured by Grooved Pegboard, using generalized estimating equations (GEE) to account for the correlation among the cognitive tests and other covariates.

Results—

Considering performance on the tests of sequencing, cognitive flexibility, and sensorimotor ability simultaneously using GEE, WMHV and subclinical infarction were each associated with worse cognitive performance globally. There was a threshold effect for WMHV with those in the upper quartile performing significantly worse on the tests of cognitive flexibility and sensorimotor ability. Those with frontal SI performed worse on the test of cognitive flexibility and those with deep SI, worse on the test of sequencing.

Conclusions—

Both SI and WMHV were associated with globally worse cognitive performance. Participants with WMH affecting more than 0.75% of cranial volume had significantly slower performance on a task of cognitive flexibility and sensorimotor ability than those in the lowest quartile. The effects of SI on cognitive performance varied by location.