bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial
Authors: Holmes David R. , Savage Michael , LaBlanche J.-M. , Grip Lars , Serruys P.W. , Fitzgerald Peter , Fischman David , Goldberg Sheldon , Brinker Jeffrey A. , Zeiher A.M. , Shapiro Leonard M. , Willerson James , Davis Barry R. , Ferguson James J. , Popma Jeffrey , King Spencer B. , Lincoff A. Michael , Tcheng James E. , Chan Robert , Granett Jeffrey R. , Poland Marcia
Published: September 2002

Background—

Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI.

Methods and Results—

In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (
P
=0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (
P
=0.061 for intent-to-treat population). The primary reason for not completing treatment was ≥1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo,
P
<0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76±0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78±0.76 to 80 mm,
P
=0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm
3
, respectively;
P
=0.16 to 0.72).

Conclusions—

Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.
Left Ventricular Systolic Unloading and Augmentation of Intracoronary Pressure and Doppler Flow During Enhanced External Counterpulsation
Authors: Michaels Andrew D. , Accad Michel , Ports Thomas A. , Grossman William
Published: September 2002

Background—

Enhanced external counterpulsation (EECP) is a noninvasive, pneumatic technique that provides beneficial effects for patients with chronic, symptomatic angina pectoris. However, the physiological effects of EECP have not been studied directly. We examined intracoronary and left ventricular hemodynamics in the cardiac catheterization laboratory during EECP.

Methods and Results—

Ten patients referred for diagnostic evaluation underwent left heart catheterization and coronary angiography from the radial artery. At baseline and then during EECP, central aortic pressure, intracoronary pressure, and intracoronary Doppler flow velocity were measured using a coronary catheter, a sensor-tipped high-fidelity pressure guidewire, and a Doppler flow guidewire, respectively. Similar to changes in aortic pressure, EECP resulted in a dramatic increase in diastolic (71±10 mm Hg at baseline to 137±21 mm Hg during EECP; +93%;
P
<0.0001) and mean intracoronary pressures (88±9 to 102±16 mm Hg; +16%;
P
=0.006) with a decrease in systolic pressure (116±20 to 99±26 mm Hg; −15%;
P
=0.002). The intracoronary Doppler measure of average peak velocity increased from 11±5 cm/s at baseline to 23±5 cm/s during EECP (+109%;
P
=0.001). The TIMI frame count, a quantitative angiographic measure of coronary flow, showed a 28% increase in coronary flow during EECP compared with baseline (
P
=0.001).

Conclusions—

EECP unequivocally and significantly increases diastolic and mean pressures and reduces systolic pressure in the central aorta and the coronary artery. Coronary artery flow, determined by both Doppler and angiographic techniques, is increased during EECP. The combined effects of systolic unloading and increased coronary perfusion pressure provide evidence that EECP may serve as a potential mechanical assist device.
Importance of Cardiac Troponins I and T in Risk Stratification of Patients With Acute Pulmonary Embolism
Authors: Konstantinides Stavros , Geibel Annette , Olschewski Manfred , Kasper Wolfgang , Hruska Nadine , Jäckle Sebastian , Binder Lutz
Published: September 2002

Background—

Assessment of risk and appropriate management of patients with acute pulmonary embolism (PE) remains a challenge. Cardiac troponins I (cTnI) and T (cTnT) are reliable indicators of myocardial injury and may be associated with right ventricular dysfunction in PE.

Methods and Results—

The present prospective study included 106 consecutive patients with confirmed acute PE. cTnI was elevated (≥0.07 ng/mL) in 43 patients (41%), and cTnT (≥0.04 ng/mL) was elevated in 39 (37%). Elevation of cTnI or cTnT was significantly associated with echocardiographically detected right ventricular dysfunction (
P
=0.001 and
P
<0.05, respectively). Moreover, a significant correlation was found between elevation of cTnI or cTnT and the two major end points overall mortality and complicated in-hospital course. The negative predictive value of cardiac troponins for major clinical events was 92% to 93%. Importantly, there was obvious escalation of in-hospital mortality, the rate of complications, and the incidence of recurrent PE, when patients with high troponin concentrations (cTnI >1.5; cTnT >0.1 ng/mL) were compared with those with only moderately elevated levels (cTnI, 0.07 to 1.5; cTnT, 0.04 to 0.1 ng/mL). Logistic regression analysis confirmed that the mortality risk (OR) was significantly elevated only in patients with high cTnI (
P
=0.019) or cTnT (
P
=0.038) levels. Furthermore, the risk of a complicated in-hospital course was almost 5 times higher (15.47 versus 3.16) in the high-cTnI group compared with patients with moderate cTnI elevation.

Conclusions—

Our results indicate that cTnI and cTnT may be a novel, particularly useful tool for optimizing the management strategy in patients with acute PE.
Effect of Transdermal Estradiol and Oral Conjugated Estrogen on C-Reactive Protein in Retinoid-Placebo Trial in Healthy Women
Authors: Decensi Andrea , Omodei Umberto , Robertson Chris , Bonanni Bernardo , Guerrieri-Gonzaga Aliana , Ramazzotto Francesca , Johansson Harriet , Mora Serena , Sandri Maria Teresa , Cazzaniga Massimiliano , Franchi Massimo , Pecorelli Sergio
Published: September 2002

Background—

The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2×2 retinoid-placebo trial.

Methods and Results—

A total of 189 postmenopausal women were randomized to 50 μg/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 μg/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo (n=49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI −9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI −14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE. Fenretinide did not change CRP levels at 6 and 12 months relative to placebo. Relative to oral CEE, the mean change in CRP after 12 months of transdermal E2 was −48% (95% CI −85% to −7%,
P
=0.012), whereas fenretinide was associated with a mean change of −1% (95% CI −34% to 40%,
P
=0.79) compared with placebo.

Conclusions—

In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.
Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease
Authors: Jono Shuichi , Ikari Yuji , Shioi Atsushi , Mori Katsuhito , Miki Takami , Hara Kazuhiro , Nishizawa Yoshiki
Published: September 2002

Background—

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD).

Methods and Results—

Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increase in serum OPG levels. Serum OPG levels were 0.94±0.34, 1.04±0.38, 1.19±0.38, and 1.44±0.54 ng/mL (medians 0.91, 0.99, 1.09, and 1.37) for the subjects with normal coronary arteries or luminal irregularities, 1-vessel disease, 2-vessel disease, and 3-vessel disease, respectively. Multivariate logistic regression analysis revealed that serum OPG levels were significantly associated with the presence of CAD [odds ratio, 5.2; 95% confidence interval, 1.7 to 16.0].

Conclusions—

Our data show that serum OPG levels are associated with the presence and severity of CAD, suggesting that OPG may be involved in the progression of CAD.
Smooth Muscle Progenitor Cells in Human Blood
Authors: Simper David , Stalboerger Paul G. , Panetta Carmelo J. , Wang Shaohua , Caplice Noel M.
Published: September 2002

Background—

Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells.

Methods and Results—

Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB–enriched medium caused rapid outgrowth and expansion of SOC to >40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell–specific α actin (αSMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle–specific markers. Integrin α
5
β
1
expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin (
P
<0.001), an effect that could be decreased using an α
5
β
1
antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage (
P
<0.001).

Conclusions—

This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing. (Circulation. 2002;106:1199–1204.)
C-Reactive Protein Is Associated With Subclinical Epicardial Coronary Calcification in Men and Women
Authors: Wang Thomas J. , Larson Martin G. , Levy Daniel , Benjamin Emelia J. , Kupka Michelle J. , Manning Warren J. , Clouse Melvin E. , D’Agostino Ralph B. , Wilson Peter W.F. , O’Donnell Christopher J.
Published: September 2002

Background—

High C-reactive protein (CRP) levels are associated with an increased risk of cardiovascular events, even in apparently healthy individuals. It has not been established whether elevated CRP reflects an increased burden of subclinical coronary atherosclerosis.

Methods and Results—

We studied a stratified random sample of 321 men and women (mean age 60 years) from the Framingham Heart Study who were free of clinically apparent cardiovascular disease. Subjects underwent electron-beam computed tomography to assess the number of coronary calcifications and the coronary artery calcification (CAC) Agatston score. Spearman correlation coefficients between CRP and CAC score were calculated and adjusted for age, age plus individual risk factors, and age plus the Framingham coronary heart disease risk score. For both sexes, CRP was significantly correlated with the Agatston score (age-adjusted Spearman correlation: 0.25 for men, 0.26 for women; both
P
<0.01). After adjustment for age and Framingham risk score, the correlation remained significant (
P
=0.01) for both sexes. Further adjustment for body mass index attenuated the correlation coefficient for women (0.14,
P
=0.09) but not for men (0.19,
P
<0.05).

Conclusions—

High CRP levels are associated with increased coronary calcification. Among individuals with elevated CRP, subclinical atherosclerosis may contribute to an increased risk for future cardiovascular events.
Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel
Authors: Kolodgie Frank D. , John Michael , Khurana Charanjit , Farb Andrew , Wilson Patricia S. , Acampado Eduardo , Desai Neil , Soon-Shiong Patrick , Virmani Renu
Published: September 2002

Background—

Paclitaxel (PXL)-eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth. The present study tested the efficacy of a novel systemic delivery nanoparticle PXL for reducing in-stent restenosis.

Methods and Results—

A saline-reconstituted formulation of PXL stabilized by albumin nanoparticles (nPXL) was tested in 38 New Zealand White rabbits receiving bilateral iliac artery stents. Doses of nPXL (1.0 to 5.0 mg/kg) were administered as a 10-minute intra-arterial infusion; control animals received vehicle (0.9% normal saline). In a follow-up chronic experiment, nPXL 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeat nPXL dose at 28 days; these studies were terminated at 3 months. At 28 days, mean neointimal thickness was reduced (
P
≤0.02) by doses of nPXL ≥2.5 mg/kg with evidence of delayed healing. The efficacy of a single dose of nPXL 5.0 mg/kg, however, was lost by 90 days. In contrast, a second repeat dose of nPXL 3.5 mg/kg given 28 days after stenting resulted in sustained suppression of neointimal thickness at 90 days (
P
≤0.009 versus single dose nPXL 5.0 mg/kg and controls) with nearly complete neointimal healing.

Conclusions—

Although systemic nPXL reduces neointimal growth at 28 days, a single repeat dose was required for sustained neointimal suppression. Thus, this novel systemic formulation of PXL may allow adjustment of dose at the stent treatment site and prove to be a useful adjunct for the clinical prevention of in-stent restenosis.
Ventricular Remodeling Does Not Accompany the Development of Heart Failure in Diabetic Patients After Myocardial Infarction
Authors: Solomon Scott D. , Sutton Martin St John , Lamas Gervasio A. , Plappert Ted , Rouleau Jean L. , Skali Hicham , Moyé Lemuel , Braunwald Eugene , Pfeffer Marc A.
Published: September 2002

Background—

Diabetic patients are at increased risk for heart failure (HF) and other adverse events after myocardial infarction (MI). Left ventricular (LV) enlargement after MI is also associated with the same increased risk. We used data from the Survival and Ventricular Enlargement (SAVE) echocardiographic substudy to test the hypothesis that diabetes was associated with increased LV enlargement after MI.

Methods and Results—

Four hundred twelve nondiabetic and 100 diabetic patients underwent echocardiographic assessment at baseline and 3 months, 1 year, and 2 years after MI. HF developed in 30% of diabetic and 17% of nondiabetic patients during follow-up (
P
<0.001). Baseline LV diastolic size, ejection fraction, and infarct segment length were similar between diabetic and nondiabetic patients. Diabetic patients demonstrated less LV enlargement between baseline and 2 years than nondiabetic patients (0.9±11.1 cm
2
versus 3.8±10.9 cm
2
,
P
=0.047). In patients who developed HF, LV diastolic dilatation (10.0±12.4 cm
2
versus 3.7±13.1 cm
2
,
P
=0.06) and systolic dilatation (4.6±11.8 versus 0.91±12.1,
P
=0.017) were greater in nondiabetic than in diabetic patients. LV dilatation between baseline and 2 years was a predictor of HF in nondiabetic patients, but not in diabetic patients, even after excluding patients with recurrent MI and adjusting for history of hypertension, prior MI, age, treatment group, and smoking. Diabetes modified the relationship between ventricular enlargement and the risk of HF (
P
=0.011).

Conclusions—

The increased incidence of HF after MI in diabetic patients is not explained by a greater propensity for LV remodeling.
Catecholamine-Related Gene Expression Correlates With Blood Pressures in SHR
Authors: Reja Valin , Goodchild Ann K. , Pilowsky Paul M.
Published: September 2002

In this study we aimed to determine whether the levels of gene expression for phenylethanolamine-N-methyltransferase (PNMT), noradrenaline transporter (NAT), α
1A
-receptor (α
1A
-R), and α
2A
-receptor (α
2A
-R) vary with resting systolic blood pressure in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. Sites examined included central and peripheral regions associated with the control of arterial pressure. Twenty week old SD (n=6), WKY (n=6), and SHR (n=6) were used. Systolic blood pressure was measured using tail cuff plethysmography 2 weeks before tissue extraction. RNA was isolated and reverse-transcribed into cDNA. Gene expression levels were measured, using quantitative real time PCR, relative to the expression of GAPDH. PNMT, NAT, and α
1A
-R mRNA expression was significantly greater in SHR tissue samples compared with normotensives. In the rostral ventrolateral medulla, PNMT mRNA in SHR was 3 times greater than that in WKY (SHR: 0.82±0.02%; WKY: 0.29±0.02%). The amount of α
2A
-R mRNA was significantly lower in SHR compared with normotensives. For example, the level of α
2A
-R mRNA in spinal cord of SHR was 3 times less than that found in WKY (SHR: 1.85±0.04%; WKY: 3.26±0.07%). PNMT, NAT, and α
1A
-R mRNA levels were
positively
correlated with systolic blood pressure in all central tissue investigated. Conversely, α
2A
-R mRNA levels in central sites were
negatively
correlated with systolic blood pressure. Clearly, a decrease in central α
2A
-R and an increase in α
1A
-R is consistent with the elevated blood pressure and sympathetic activity observed in SHR.
Selective Regulation of Blood Pressure by Heme Oxygenase-1 in Hypertension
Authors: Ndisang Joseph Fomusi , Zhao Weimin , Wang Rui
Published: September 2002

Heme oxygenase (HO) and carbon monoxide (CO) participate in the homeostatic control of cardiovascular functions, including the regulation of blood pressure (BP). Upregulation of the HO/CO system has been shown to lower BP in young (8 weeks) but not in adult (20 weeks) spontaneously hypertensive rats (SHR). The underlying mechanism for this selective effect, however, has been unknown and was investigated in the present study. The administration of hemin resulted in a marked decrease in BP (from 148.6±3.2 to 125.8±2.6 mm Hg,
P
<0.01) in young but not in prehypertensive (4 weeks) or adult SHR or Wistar-Kyoto rats at all ages. The inhibition of HO with chromium mesoporphyrin abrogated the BP-lowering effect of hemin. Significantly lower expression levels of HO-1 and soluble gyanylyl cyclase (sGC) as well as reduced cGMP content were detected in 8-week SHR but not in adult SHR or Wistar-Kyoto rats of all ages. These deficiencies were all corrected by hemin treatment. The expression of HO-2 protein was not different among all animal groups tested and not affected by hemin treatment. Desensitization of the sGC/cGMP pathway in adult SHR was demonstrated by the reduced vasorelaxant potency of the sGC activator 3-(5′ -hydroxymethyl-2-′furyl)-1-benzylindazole. Thus, in young and prehypertensive SHR, a defective HO/CO-sGC/cGMP system might constitute a pathogenic mechanism for the development of hypertension. The HO/CO-sGC/cGMP system appears normal in adult SHR, but desensitization of the downstream targets of the system to sGC/cGMP may endow SHR at this stage a persistent hypertension status.
Vascular Responses in Male and Female Hypertensive Rats With Hyperhomocysteinemia
Authors: Yen Chia-Hung , Lau Ying-Tung
Published: September 2002

We studied vascular responses in spontaneously hypertensive rats (SHR) of both genders after methionine (Met) loading to test whether or not there were gender differences. SHRs were divided into 5 groups: male control (MSHR), female control (FSHR), methionine-loaded (+Met) males (MSHR[+Met]) and females (FSHR[+Met]), and male SHR with both 17β-estradiol (E
2
) and Met administration (MSHR[+E
2
+Met]). Treated groups received Met (1g/kg body weight per day) in water for 6 weeks. Systolic blood pressure (SBP) was monitored weekly. Aortic contractile (phenylephrine-induced) and relaxant (acetylcholine-induced as endothelium-dependent relaxation, or EDR) responses as well as endothelial suppression (with nitric oxide synthase inhibitor) were evaluated at the end of experiments. Serum homocysteine (Hcy) level was also determined. Met overloading caused a nearly 3-fold increase in serum Hcy in each gender (moderate hyperhomocysteinemia, or HHcy). As age increased, SBP increased in all groups; FSHR(+Met) had the least elevation and significantly less increase of SBP than FSHR at the end of 6 weeks. There was also a significant increase of EDR in FSHR(+Met) compared with both FSHR and MSHR(+Met). FSHR(+Met) had the highest level of endothelium suppression. Furthermore, EDR in MSHR(+E
2
+Met) was significantly higher than that in MSHR(+Met). Direct Hcy feeding appeared to reduce the development of hypertension in female SHR in 3 weeks. Hence, SBP development was partially alleviated, whereas EDR and endothelium suppression were enhanced in female SHR with HHcy. E
2
could mimic the gender-dependent effect of HHcy on EDR enhancement in MSHR; moreover, reduction of SBP development occurred in Hcy-fed FSHR.
Association of GNAS1 Gene Variant With Hypertension Depending on Smoking Status
Authors: Abe Michiko , Nakura Jun , Yamamoto Miyuki , Jin Ji Jing , Wu Zhihong , Tabara Yasuharu , Yamamoto Yoshikuni , Igase Michiya , Kohara Katsuhiko , Miki Tetsuro
Published: September 2002

The β-adrenoceptor (β-AR) G
s
protein system has been shown to have important roles in the cardiovascular system. The gene encoding the α-subunit of G
s
proteins (GNAS1) is a candidate genetic determinant for hypertension. We studied the
GNAS1
T393C polymorphism in >2000 Japanese individuals. χ
2
test showed a marginally significant difference in the frequencies of the alleles (
P
=0.036) and genotypes (
P
=0.094) between hypertensives and normotensives. Because hypertension is considered to be a complex disorder resulting from interactions between genetic and environmental factors, we further analyzed the T393C polymorphism, with consideration of interactions between the polymorphism and confounding factors in regression models. These analyses showed a significant interaction between the polymorphism and cigarette smoking in the pathogenesis of hypertension (
P
=0.0005). The interaction was reflected in a significant association of the polymorphism with hypertension in nonheavy smokers (
P
=0.0028; odds ratio, 1.52; 95% confidence interval, 1.16 to 2.00). A significant interaction between the polymorphism and aging in the pathogenesis of hypertension was also shown in nonheavy smokers. These findings may be helpful in conducting further molecular and biological studies on the relationship among cigarette smoking, the β-AR-G
s
protein system, and hypertension.
Prognostic Value of Office and Ambulatory Blood Pressure Measurements in Pregnancy
Authors: Hermida Ramón C. , Ayala Diana E.
Published: September 2002

With the objective to assess the prognostic value of office values as compared with ambulatory monitoring in pregnancy, we analyzed 2430 blood pressure series systematically sampled from 403 untreated pregnant women for 48 consecutive hours every 4 weeks from the first visit to the hospital until delivery. Women were divided into 5 groups: “detected” gestational hypertension, women with office blood pressures >140/90 mm Hg after 20 weeks of gestation and hyperbaric index (area of blood pressure excess above the upper limit of a time-specified tolerance interval) consistently above the threshold for diagnosing hypertension in pregnancy; “undetected” gestational hypertension, office values <140/90 mm Hg but hyperbaric index above the threshold for diagnosis; normotension, both office values and hyperbaric index below the thresholds for diagnosis; white coat hypertension, women with recorded diagnosis of gestational hypertension but hyperbaric index consistently below the threshold for diagnosis; and preeclampsia, defined as gestational hypertension and proteinuria. Results indicate small and nonsignificant differences in 24-hour mean of ambulatory pressures between “detected” and “undetected” gestational hypertension at all stages of pregnancy, in contrast with highly significant differences between these two groups and normotensive pregnancies. Average office blood pressure values were similar for preeclampsia, “detected,” and “undetected” gestational hypertension. The hyperbaric index was, however, significantly higher for women with preeclampsia after 20 weeks of gestation as compared with all other groups and higher for women with either “detected” or “undetected” gestational hypertension as compared with normotensive pregnant women. The incidence of preterm delivery and intrauterine growth retardation were similar for “detected” and “undetected” gestational hypertension but significantly lower for normotensive women. In pregnancy, the hyperbaric index derived from ambulatory monitoring is markedly superior to office measurements for diagnosis of what should be truly considered gestational hypertension, as well as for prediction of the outcome of pregnancy.
ACE Inhibitor Improves Insulin Resistance in Diabetic Mouse Via Bradykinin and NO
Authors: Shiuchi Tetsuya , Cui Tai-Xing , Wu Lan , Nakagami Hironori , Takeda-Matsubara Yuko , Iwai Masaru , Horiuchi Masatsugu
Published: September 2002

Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[
3
H]-deoxy-
d
-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.
Neonatal Blood Pressure and Salt Taste Responsiveness
Authors: Zinner Stephen H. , McGarvey Stephen T. , Lipsitt Lewis P. , Rosner Bernard
Published: September 2002

To test the association between neonatal blood pressure (BP) and salt taste response, 283 healthy hospitalized neonates were administered small drops (0.06 mL) of water and 0.1 molar (mol/L) and 0.3 mol/L NaCl solutions by means of cannulas through a nipple with a pressure transducer to record sucking responses. Neonatal and 1-month BPs were recorded by ultrasound. Mean number of sucks per burst was scored as “aversive” if the 0.3 mol/L salt minus water difference score was ≤−10 mean sucks per burst, “preferential” if this difference was >0, and “neutral” otherwise. Babies with “preferential” responses had higher diastolic BPs than those with neutral (1.9 mm Hg) or aversive responses (3.1 mm Hg) (
P
trend=0.05). After adjustment for age, gender, birth weight, and activity for babies with at least one grandparent receiving antihypertensive medication, mean adjusted systolic pressure was 6.7 mm Hg higher (
P
=0.003) (
P
trend=0.003) and mean adjusted diastolic pressure was 5.0 mm Hg higher (
P
=0.010) (
P
trend=0.011) in neonates with preferential versus aversive salt taste responses. There was no relation of BP to sucking responses to sweet (sucrose) stimuli. Neonates can distinguish between dilute salt solutions and water. This response is related to BP and might be a potential risk factor for high BP later in life.
Serum- and Glucocorticoid-Regulated Kinase (SGK1) Gene and Blood Pressure
Authors: Busjahn Andreas , Aydin Atakan , Uhlmann Regina , Krasko Christine , Bähring Sylvia , Szelestei Tamas , Feng Yuxi , Dahm Stephan , Sharma Arya M. , Luft Friedrich C. , Lang Florian
Published: September 2002

The serum- and glucose-regulated kinase (SGK1) gene has recently been identified as an important aldosterone-induced protein kinase that mediates trafficking of the renal epithelial Na
+
channel (ENaC) to the cell membrane. Thus, SGK1 is an appealing candidate for blood pressure regulation and possibly essential hypertension. To test this hypothesis, we recruited monozygotic (126 pairs) and dizygotic (70 pairs) normotensive twin subjects and parents of dizygotic twins. Blood pressure was measured in a controlled fashion: recumbent, sitting, and upright. We documented genetic variance on blood pressure in all positions. We then relied on microsatellite markers at the SGK1 gene locus (D6S472, D6S1038, and D6S270) and 2 single nucleotide polymorphisms within the SGK1 gene. We found significant linkage of the SGK1 gene locus to diastolic blood pressure (
P
<0.0002) and suggestive evidence for linkage for systolic blood pressure (
P
<0.04), documenting the locus as a quantitative trait locus for blood pressure. We next performed association, using all dizygotic twins and a monozygotic member from each pair. We found significant associations between both single nucleotide polymorphism variants and blood pressure, as well as a significant interaction between the single nucleotide polymorphisms enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. We conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.
Ultrasonic Backscatter and Diastolic Function in Hypertensive Patients
Authors: Maceira Alicia M. , Barba Joaquín , Beloqui Oscar , Díez Javier
Published: September 2002

This study was designed to assess whether ultrasonic reflectivity, evaluated by a real-time integrated backscatter analysis, was related to the severity of diastolic dysfunction, as studied by Doppler echocardiography in patients with essential hypertension. One hundred nine subjects were included in the study. Diastolic function was assessed by mitral-inflow Doppler ultrasound recordings. Backscatter cyclic variation and maximal intensity were measured in 6 regions throughout the left ventricle. The subjects were classified in 5 groups according to blood pressure and diastolic function: 29 normotensives with normal diastolic function (group 1), 18 hypertensives with normal diastolic function (group 2), 47 hypertensives with a delayed relaxation pattern (group 3), 11 hypertensives with a pseudonormal filling pattern (group 4), and 4 hypertensives with a restrictive filling pattern (group 5). The highest cyclic variation was found in groups 1 and 2, the lowest in groups 4 and 5 (5.7±0.2 dB in group 1 and 5.7±0.2 dB in group 2 versus 2.9±0.3 dB in group 4 and 2.1±0.4 dB in group 5;
P
<0.001), with intermediate values in group 3 (5.2±0.2 dB). Cyclic variation was inversely correlated with left ventricular chamber stiffness (
P
<0.05) and directly correlated with midwall fractional shortening (
P
<0.02) in all hypertensives. No differences in maximal intensity were found among the 5 groups of subjects. These results show an association between diminished cyclic variation of backscatter and deterioration of diastolic function in hypertensive patients. Thus, alterations in this parameter may be useful for the assessment of diastolic dysfunction in hypertension.
Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men
Authors: Regamey Frédéric , Maillard Marc , Nussberger Jürg , Brunner Hans R. , Burnier Michel
Published: September 2002

This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (
P
<0.001 versus placebo;
P
<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (
P
<0.01). These hormonal effects were associated with a significant fall in blood pressure (
P
<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (
P
<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (
P
<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (
P
<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (
P
=NS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy.
Nitrolinoleate Inhibits Superoxide Generation, Degranulation, and Integrin Expression by Human Neutrophils
Authors: Coles Barbara , Bloodsworth Allison , Clark Stephen R. , Lewis Malcolm J. , Cross Andrew R. , Freeman Bruce A. , O’Donnell Valerie B.
Published: September 2002

Nitration of unsaturated fatty acids such as linoleate by NO-derived reactive species forms novel derivatives (including nitrolinoleate [LNO
2
]) that can stimulate smooth muscle relaxation and block platelet activation by either NO/cGMP or cAMP-dependent mechanisms. Here, LNO
2
was observed to inhibit human neutrophil function. LNO
2
, but not linoleic acid or the nitrated amino acid 3-nitrotyrosine, dose-dependently (0.2 to 1 μmol/L) inhibited superoxide (O
2
·−
) generation, Ca
2+
influx, elastase release, and CD11b expression in response to either phorbol 12-myristate 13-acetate or
N
-formyl-Met-Leu-Phe. LNO
2
did not elevate cGMP, and inhibition of guanylate cyclase by 1
H
-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one did not restore neutrophil responses, ruling out a role for NO. In contrast, LNO
2
caused elevations in intracellular cAMP in the presence and absence of phosphodiesterase inhibition, suggesting activation of adenylate cyclase. Compared with phorbol 12-myristate 13-acetate–activated neutrophils,
N
-formyl-Met-Leu-Phe–activated neutrophils were more susceptible to the inhibitory effects of LNO
2
, indicating that LNO
2
may inhibit signaling both upstream and downstream of protein kinase C. These data suggest novel signaling actions for LNO
2
in mediating its potent inhibitory actions. Thus, nitration of lipids by NO-derived reactive species yields products with antiinflammatory properties, revealing a novel mechanism by which NO-derived nitrated biomolecules can influence the progression of vascular disease.
Identification of Gating Modes in Single Native Na
+
Channels From Human Atrium and Ventricle
Authors: Böhle Thomas , Brandt Mathias C. , Lindner Michael , Beuckelmann Dirk J.
Published: September 2002

The aim of the present study was to investigate the single-channel properties of different gating modes in the native human cardiac Na
+
channel. Patch-clamp experiments were performed at low noise using ultrathick-walled pipettes. In 17 cell-attached patches containing only one channel, fast back and forth switching between five different Na
+
-channel gating modes (F-mode, M1-mode, M2-mode, S-mode, and P-mode) was identified, but no difference in the gating properties was found between normal and diseased cardiomyocytes from atrium or ventricle, respectively. Hodgkin-Huxley fits to the ensemble-averaged currents yielded the activation-time (τ
m
) and inactivation-time (τ
h
) constants. τ
m
was comparably fast in the F-mode, M1-mode, M2-mode, and S-mode (0.15 ms) and slow in the P-mode (0.3 ms). τ
h
ranged from 0.35 ms (F-mode) to 4.5 ms (S-mode and P-mode). The mean open-channel lifetime (τ
o
) was shortest in the F-mode and P-mode (0.15 ms) and longest in the S-mode (1.25 ms). The time before which half of the first channel openings occurred (t
0.5
) was comparably short in the F-mode, M1-mode, M2-mode, and S-mode (0.3 ms) and long in the P-mode (0.9 ms). It is concluded that (1) a single native human cardiac Na
+
channel can be recorded at low noise, (2) this channel can change its gating properties at a time scale of milliseconds, (3) lifetimes of the observed gating modes are short ranging from milliseconds to seconds only, and (4) the gating modes are characterized by specific activation and inactivation kinetics and differ at least in their mean open time and first latency.
Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Regulates Cardiac Contractility
Authors: Szokodi István , Tavi Pasi , Földes Gábor , Voutilainen-Myllylä Sari , Ilves Mika , Tokola Heikki , Pikkarainen Sampsa , Piuhola Jarkko , Rysä Jaana , Tóth Miklós , Ruskoaho Heikki
Published: September 2002

The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC
50
: 33.1±1.5 pmol/L). Moreover, preload-induced increase in dP/dt
max
was significantly augmented (
P
<0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect (
P
<0.001). In addition, zoniporide, a selective inhibitor of Na
+
-H
+
exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na
+
-Ca
2+
exchange (NCX), significantly suppressed the response to apelin (
P
<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca
2+
current or voltage-activated K
+
currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.
Angiotensin II Stimulation of NAD(P)H Oxidase Activity
Authors: Seshiah Puvi N. , Weber David S. , Rocic Petra , Valppu Liisa , Taniyama Yoshihiro , Griendling Kathy K.
Published: September 2002

Angiotensin II (Ang II)–stimulated hypertrophy of vascular smooth muscle cells is mediated by reactive oxygen species (ROS) derived from NAD(P)H oxidases. The upstream signaling mechanisms by which Ang II activates these oxidases are unclear but may include protein kinase C, tyrosine kinases, phosphatidylinositol-3-kinase, and Rac, a small molecular weight G protein. We found that Ang II–stimulated ROS production is biphasic. The first phase occurs rapidly (peak at 30 seconds) and is dependent on protein kinase C activation. The larger second phase of ROS generation (peak at 30 minutes) requires Rac activation, because inhibition of Rac by either
Clostridium difficile
toxin A or dominant-negative Rac significantly inhibits Ang II–induced ROS production. Phosphatidylinositol-3-kinase inhibitors (wortmannin or LY294002) and the epidermal growth factor (EGF) receptor kinase blocker AG1478 attenuate both Rac activation and ROS generation. The upstream activator of EGF receptor transactivation, c-Src, is also required for ROS generation, because PP1, an Src kinase inhibitor, abrogates the Ang II stimulation of both responses. These results suggest that c-Src, EGF receptor transactivation, phosphatidylinositol-3-kinase, and Rac play important roles in the sustained Ang II–mediated activation of vascular smooth muscle cell NAD(P)H oxidases and provide insight into the integrated signaling mechanisms whereby Ang II stimulation leads to activation of the growth-related NAD(P)H oxidases.
Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Ischemia-Induced Neovascularization in Mice Hindlimb
Authors: Mallat Ziad , Silvestre Jean-Sébastien , Le Ricousse-Roussanne Sophie , Lecomte-Raclet Laurence , Corbaz Anne , Clergue Michel , Duriez Micheline , Barateau Véronique , Akira Shizuo , Tedgui Alain , Tobelem Gérard , Chvatchko Yolande , Lévy Bernard I.
Published: September 2002

Identification of factors that may stimulate ischemia-induced neovascularization without increasing atherosclerotic plaque progression is of major therapeutic importance. We hypothesized that interleukin-18 binding protein (IL-18BP), a major antiinflammatory protein with plaque-stabilizing activities, may affect the neovascularization in mice ischemic hindlimb. Ischemia was produced by artery femoral occlusion in mice that were subjected to in vivo intramuscular electrotransfer of either an empty plasmid or a murine IL-18BP plasmid. Angiographic score, capillary density (CD31 staining), and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by respectively 1.6-, 1.4-, and 1.5-fold in IL-18BP–treated mice compared with controls (
P
<0.01). This was associated with a significant 2-fold increase in both vascular endothelial growth factor (VEGF) and phospho-Akt protein content in the ischemic hindlimb of IL-18BP–treated mice (
P
<0.05). Similar results were obtained in IL-18–deficient mice. Because bone marrow–derived endothelial progenitor cells (BM-EPCs) are involved in postnatal vasculogenesis, EPCs were isolated and cultivated from bone marrow mononuclear cells. IL-18BP treatment led to a significant 1.8-fold increase in the percentage of BM-EPCs characterized as cells positive for both AcLDL-Dil and von Willebrand factor (
P
<0.001). In conclusion, IL-18BP stimulates ischemia-induced neovascularization in association with an activation of VEGF/Akt signaling and an increase in BM-EPCs mobilization and differentiation. Our findings strongly suggest a major antiangiogenic role of endogenous IL-18 in postischemic injury.
Regulation of Smooth Muscle Cell Differentiation by AT-Rich Interaction Domain Transcription Factors Mrf2α and Mrf2β
Authors: Watanabe Masafumi , Layne Matthew D. , Hsieh Chung-Ming , Maemura Koji , Gray Susan , Lee Mu-En , Jain Mukesh K.
Published: September 2002

Despite the importance of vascular smooth muscle cells in the regulation of blood vessel function, the molecular mechanisms governing their development and differentiation remain poorly understood. Using an in vitro system whereby a pluripotent neural crest cell line (MONC-1) can be induced to differentiate into smooth muscle cells, we isolated a cDNA fragment that was robustly induced during this differentiation process. Sequence analysis revealed high homology to a partial cDNA termed modulator recognition factor 2 (Mrf2). Because the full-length cDNA has not been reported, we cloned the full-length Mrf2 cDNA by cDNA library screening and 5′ rapid amplification of cDNA ends and identified two isoforms of Mrf2 (α [3.0 kb] and β [3.7 kb]) that differ in the N-terminus but share the DNA-binding domain. Protein homology analysis suggests that Mrf2 is a member of the AT-rich interaction domain family of transcription factors, which are known to be critically involved in the regulation of development and cellular differentiation. Mrf2α and Mrf2β are highly induced during in vitro differentiation of MONC-1 cells into smooth muscle cells, and Mrf2α is expressed in adult mouse cardiac and vascular tissues. To define the function of Mrf2, we overexpressed both isoforms in 3T3 fibroblast cells and observed an induction of smooth muscle marker genes, including smooth muscle α-actin and smooth muscle 22α. Furthermore, Mrf2α and Mrf2β retarded cellular proliferation. These data implicate Mrf2 as a novel regulator of smooth muscle cell differentiation and proliferation.