bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrical Remodeling of the Atria in Congestive Heart Failure
Authors: Sanders Prashanthan , Morton Joseph B. , Davidson Neil C. , Spence Steven J. , Vohra Jitendra K. , Sparks Paul B. , Kalman Jonathan M.
Published: September 2003

Background—

Atrial fibrillation (AF) frequently complicates congestive heart failure (CHF). However, the electrophysiological substrate for AF in humans with CHF remains unknown. We evaluated the electrophysiological and electroanatomic characteristics of the atria in patients with CHF.

Methods and Results—

Twenty-one patients (aged 53.7±13.6 years) with symptomatic CHF (left ventricular ejection fraction 25.5±6.0%) and 21 age-matched controls were studied. The following were evaluated: effective refractory periods (ERPs) from the high and low lateral right atrium (LRA), high septal right atrium, and distal coronary sinus (CS); conduction time along the CS and LRA; corrected sinus node recovery times; P-wave duration; and conduction at the crista terminalis. In a subset, electroanatomic mapping was performed to determine atrial activation, regional conduction velocity, double potentials, fractionated electrograms, regional voltage, and areas of electrical silence. Patients with CHF demonstrated an increase in atrial ERP with no change in the heterogeneity of refractoriness, an increase of atrial conduction time along the LRA and the CS, prolongation of the P-wave duration and corrected sinus node recovery times, and greater number and duration of double potentials along the crista terminalis. Electroanatomic mapping demonstrated regional conduction slowing with a greater number of electrograms with fractionation or double potentials, associated with areas of low voltage and electrical silence (scar). Patients with CHF demonstrated an increased propensity for AF with single extrastimuli, and induced AF was more often sustained.

Conclusions—

Atrial remodeling due to CHF is characterized by structural changes, abnormalities of conduction, sinus node dysfunction, and increased refractoriness. These abnormalities may be responsible in part for the increased propensity for AF in CHF.
Matrix Metalloproteinases as Novel Disease Markers in Takayasu Arteritis
Authors: Matsuyama Akifumi , Sakai Naohiko , Ishigami Masato , Hiraoka Hisatoyo , Kashine Susumu , Hirata Ayumu , Nakamura Tadashi , Yamashita Shizuya , Matsuzawa Yuji
Published: September 2003

Background—

Takayasu arteritis (TA) is a chronic vasculitis that primarily affects large elastic arteries. Monitoring of disease activity is crucial because the disease tends to progress despite treatment with glucocorticoid and/or immunosuppressive agents. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have generally been used as disease activity markers, but these are nonspecific inflammatory markers and lack the sensitivity and specificity to accurately monitor the disease status. Given the histological findings characterized by destruction of elastic fibers, we hypothesized that matrix metalloproteinases (MMPs) could be useful as markers of disease activity in TA.

Methods and Results—

A consecutive series of 25 patients with TA were enrolled in this study. According to the National Institutes of Health criteria of disease activity, 11 were in an active phase and the remaining 14 were in remission. Circulating levels of MMP-2, MMP-3, and MMP-9 were determined by ELISA in all patients with TA and controls. MMP-2 levels were higher in patients with TA than in controls, but no correlation was found between serum MMP-2 and disease activity score. In contrast, MMP-3 and MMP-9 levels in patients with active disease were higher than in patients in remission and controls, and a positive correlation was demonstrated between circulating levels of MMP-3 or MMP-9 and disease activity score. The high levels of MMP-3 and MMP-9 improved when patients underwent remission.

Conclusions—

The present results indicate that MMP-2 can be helpful in diagnosing TA and that MMP-3 and MMP-9 can be used as activity markers for TA.
Myeloperoxidase Serum Levels Predict Risk in Patients With Acute Coronary Syndromes
Authors: Baldus Stephan , Heeschen Christopher , Meinertz Thomas , Zeiher Andreas M. , Eiserich Jason P. , Münzel Thomas , Simoons Maarten L. , Hamm Christian W.
Published: September 2003

Background—

Polymorphonuclear neutrophils (PMNs) have gained attention as critical mediators of acute coronary syndromes (ACS). Myeloperoxidase (MPO), a hemoprotein abundantly expressed by PMNs and secreted during activation, possesses potent proinflammatory properties and may contribute directly to tissue injury. However, whether MPO also provides prognostic information in patients with ACS remains unknown.

Methods and Results—

MPO serum levels were assessed in 1090 patients with ACS. We recorded death and myocardial infarctions during 6 months of follow-up. MPO levels did not correlate with troponin T, soluble CD40 ligand, or C-reactive protein levels or with ST-segment changes. However, patients with elevated MPO levels (>350 μg/L; 31.3%) experienced a markedly increased cardiac risk (adjusted hazard ratio [HR] 2.25 [1.32 to 3.82];
P
=0.003). In particular, MPO serum levels identified patients at risk who had troponin T levels below 0.01 μg/L (adjusted HR 7.48 [95% CI 1.98 to 28.29];
P
=0.001). In a multivariate model that included other biochemical markers, troponin T (HR 1.99;
P
=0.023), C-reactive protein (1.25;
P
=0.044), vascular endothelial growth factor (HR 1.87;
P
=0.041), soluble CD40 ligand (HR 2.78;
P
<0.001), and MPO (HR 2.11;
P
=0.008) were all independent predictors of the patient’s 6-month outcome.

Conclusions—

In patients with ACS, MPO serum levels powerfully predict an increased risk for subsequent cardiovascular events and extend the prognostic information gained from traditional biochemical markers. Given its proinflammatory properties, MPO may serve as both a marker and mediator of vascular inflammation and further points toward the significance of PMN activation in the pathophysiology of ACS.
Estrogen Stimulates Dimethylarginine Dimethylaminohydrolase Activity and the Metabolism of Asymmetric Dimethylarginine
Authors: Holden Desmond P. , Cartwright Judith E. , Nussey Stephen S. , Whitley Guy St J.
Published: September 2003

Background—

Experimental evidence suggests that estrogens stimulate the production of nitric oxide (NO) by vascular endothelial cells. This effect has been attributed to increased expression and enzymatic activity of both the constitutive and inducible isoforms of NO synthase. In this study, we have investigated whether estrogens regulate the metabolism or release of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase.

Methods and Results—

The concentration of ADMA in the plasma of 15 postmenopausal women was 0.722±0.04 μmol/L (mean±SEM). Two weeks after subcutaneous implantation with estradiol, there was an increase in plasma estradiol concentration from 0.693±0.075 to 0.81±87 nmol/L, which was accompanied by a significant fall in plasma ADMA concentration to 0.588±0.03 μmol/L (
P
=0.006). Human and murine endothelial cell lines previously cultured in estrogen-free medium and then exposed to 17β-estradiol showed a dose-dependent decrease in the release of ADMA. This reached statistical significance at 10
−14
mol/L 17β-estradiol and was accompanied by a corresponding increase in the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catalyzes the metabolism of ADMA.

Conclusions—

We have demonstrated that estrogens can alter the catabolism and release of ADMA in vitro and reduce the circulating concentration in vivo. We therefore propose that increased DDAH activity and the subsequent fall in ADMA could contribute to the positive effect of estrogen on NO synthesis.
Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment
Authors: Maack Christoph , Kartes Tanja , Kilter Heiko , Schäfers Hans-Joachim , Nickenig Georg , Böhm Michael , Laufs Ulrich
Published: September 2003

Background—

Reactive oxygen species (ROS) contribute to the development of heart failure. A potential source of myocardial ROS is the NADPH oxidase, which is regulated by the small GTP-binding protein rac1. Isoprenylation of rac1 can be inhibited by statin therapy. Thus, we examined ROS and rac1 in human failing myocardium and tested their regulation by statins in vivo.

Methods and Results—

In human left ventricular myocardium from patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), NADPH oxidase activity was increased 1.5-fold compared with nonfailing controls (
P
<0.05, n=8). In failing myocardium, increased oxidative stress determined by measurements of lipid peroxidation and aconitase activity was associated with increased translocation of rac1 from the cytosol to the membrane. Pull-down assays revealed a 3-fold increase of rac1-GTPase activity in ICM and DCM. In parallel, membrane expression of the NADPH oxidase subunit p47

phox

, but not p67

phox

, was upregulated in failing compared with nonfailing myocardium. In right atrial myocardium from patients undergoing cardiac surgery who were prospectively treated with atorvastatin or pravastatin (40 mg/d, 4 weeks), rac1-GTPase activity was decreased to 67.9±12% and 65.6±13.8% compared with patients without statin (
P
<0.05, n=8). Both atorvastatin and pravastatin significantly reduced angiotensin II–stimulated but not basal NADPH oxidase activity.

Conclusions—

Failing myocardium of patients with DCM and ICM is characterized by upregulation of NADPH oxidase–mediated ROS release associated with increased rac1 activity. Oral statin treatment inhibits myocardial rac1-GTPase activity. These data suggest that extrahepatic effects of statins can be observed in humans and may be beneficial for patients with chronic heart failure.
Impaired VE-Cadherin/β-Catenin Expression Mediates Endothelial Cell Degeneration in Dilated Cardiomyopathy
Authors: Schäfer Romana , Abraham Dietmar , Paulus Patrick , Blumer Roland , Grimm Michael , Wojta Johann , Aharinejad Seyedhossein
Published: September 2003

Background—

The cross-talk between vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang), and VE-cadherin coregulates endothelial cell (EC) survival. Cardiac expression of VEGF-A but not its receptor KDR is blunted in dilated cardiomyopathy (DCM). Whether VE-cadherin/Ang function is affected in DCM is unknown.

Methods and Results—

The myocardial expression of VE-cadherin/β-catenin, Ang-1, Ang-2, and their receptor Tie-2 was examined in DCM, ischemic cardiomyopathy (ICM), and in control subjects through the use of real-time RT-PCR, Western blotting, and immunocytochemistry. EC degeneration was quantified by TEM. RNA interference against VE-cadherin and VEGF deprivation and stimulation were applied to cultured DCM myocardium and human microvascular ECs to examine the interplay between VEGF, VE-cadherin/β-catenin, and Ang-2. Analysis of tissue sections with similar rates of EC degeneration in both patient groups showed that VE-cadherin/β-catenin expression was downregulated in DCM only (
P
<0.05). Although Ang-1 was not changed, Ang-2 expression was downregulated and Tie-2 protein expression was upregulated both in DCM and ICM (
P
<0.05). The ratio of degenerated to normal ECs was significantly higher in DCM versus ICM (
P
<0.05). Targeted VE-cadherin gene silencing in cultured human ECs resulted in similar degenerative effects observed in myocardial ECs of DCM patients. In vitro experiments indicated that VE-cadherin/β-catenin expression is independent of VEGF.

Conclusions—

These results indicate for the first time that the EC survival is impaired in myocardium of patients with DCM involving VE-cadherin/β-catenin, probably independent of VEGF. Targeting VE-cadherin might be of benefit to counteract the selective EC pathology in DCM.
Simultaneous Assessment of Fractional and Coronary Flow Reserves in Cardiac Transplant Recipients
Authors: Fearon William F. , Nakamura Mamoo , Lee David P. , Rezaee Mehrdad , Vagelos Randall H. , Hunt Sharon A. , Fitzgerald Peter J. , Yock Paul G. , Yeung Alan C.
Published: September 2003

Background—

The utility of measuring fractional flow reserve (FFR) to assess cardiac transplant arteriopathy has not been evaluated. Measuring coronary flow reserve (CFR) as well as FFR could add information about the microcirculation, but until recently, this has required two coronary wires. We evaluated a new method for simultaneously measuring FFR and CFR with a single wire to investigate transplant arteriopathy.

Methods and Results—

In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFR
thermo
) were measured simultaneously with the same coronary pressure wire in the left anterior descending artery and compared with volumetric intravascular ultrasound (IVUS) imaging. The average FFR was 0.88±0.07; in 75% of cases, the FFR was less than the normal threshold of 0.94; and in 15% of cases, the FFR was ≤0.80, the upper boundary of the gray zone of the ischemic threshold. There was a significant inverse correlation between FFR and IVUS-derived measures of plaque burden, including percent plaque volume (
r
=0.55,
P
<0.0001). The average CFR
thermo
was 2.5±1.2; in 47% of cases, CFR
thermo
was ≤2.0. In 14%, the FFR was normal (≥0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction.

Conclusions—

FFR correlates with IVUS findings and is abnormal in a significant proportion of asymptomatic cardiac transplant patients with normal angiograms. Simultaneous measurement of CFR with the same pressure wire, with the use of a novel coronary thermodilution technique, is feasible and adds information to the physiological evaluation of these patients.
Molecular Imaging of Cardiac Cell Transplantation in Living Animals Using Optical Bioluminescence and Positron Emission Tomography
Authors: Wu Joseph C. , Chen Ian Y. , Sundaresan Gobalakrishnan , Min Jung-Joon , De Abhijit , Qiao Jian-Hua , Fishbein Michael C. , Gambhir Sanjiv S.
Published: September 2003

Background—

The current method of analyzing myocardial cell transplantation relies on postmortem histology. We sought to demonstrate the feasibility of monitoring transplanted cell survival in living animals using molecular imaging techniques.

Methods and Results—

For optical bioluminescence charged-coupled device imaging, rats (n=20) underwent intramyocardial injection of embryonic rat H9c2 cardiomyoblasts (3×10
6
to 5×10
5
) expressing firefly luciferase (Fluc) reporter gene. Cardiac bioluminescence signals were present for more than 2 weeks with 3×10
6
cells: day 1 (627 000±15%), day 2 (346 100±21%), day 4 (112 800±20%), day 8 (78 860±24%), day 12 (67 780±12%), and day 16 (62 200±5% p · s
−1
· cm
2
−1
· sr
−1
). For micro–positron emission tomography imaging, rats (n=20) received cardiomyoblasts (3×10
6
) expressing mutant herpes simplex type 1 thymidine kinase (HSV1-sr39tk) reporter gene. Detailed tomography of transplanted cells is shown by 9-(4-[
18
F]-fluoro-3hydroxymethylbutyl)guanine ([
18
F]-FHBG) reporter probe and nitrogen-13 ammonia ([
13
N]-NH
3
) perfusion images. Within the transplanted region, there was a 4.48±0.71-fold increase of in vivo [
18
F]-FHBG activity and a 4.01±0.51-fold increase of ex vivo gamma counting compared with control animals. Finally, the in vivo images of cell survival were confirmed by ex vivo autoradiography, histology, immunohistochemistry, and reporter protein assays.

Conclusions—

The location(s), magnitude, and survival duration of embryonic cardiomyoblasts were monitored noninvasively. With further development, molecular imaging studies should add critical insights into cardiac cell transplantation biology.
Improvement of Cardiac Function During Enzyme Replacement Therapy in Patients With Fabry Disease
Authors: Weidemann Frank , Breunig Frank , Beer Meinrad , Sandstede Joern , Turschner Oliver , Voelker Wolfram , Ertl Georg , Knoll Anita , Wanner Christoph , Strotmann Jörg M.
Published: September 2003

Background—

Enzyme replacement therapy (ERT) has been shown to enhance microvascular endothelial globotriaosylceramide clearance in the hearts of patients with Fabry disease. Whether these results can be translated into an improvement of myocardial function has yet to be demonstrated.

Methods and Results—

Sixteen patients with Fabry disease who were treated in an open-label study with 1.0 mg/kg body weight of recombinant α-Gal A (agalsidase β, Fabrazyme) were followed up for 12 months. Myocardial function was quantified by ultrasonic strain rate imaging to assess radial and longitudinal myocardial deformation. End-diastolic thickness of the left ventricular posterior wall and myocardial mass (assessed by magnetic resonance imaging, n=10) was measured at baseline and after 12 months of ERT. Data were compared with 16 age-matched healthy controls. At baseline, both peak systolic strain rate and systolic strain were significantly reduced in the radial and longitudinal direction in patients compared with controls. Peak systolic strain rate increased significantly in the posterior wall (radial function) after one year of treatment (baseline, 2.8±0.2 s
−1
; 12 months, 3.7±0.3 s
−1
;
P
<0.05). In addition, end-systolic strain of the posterior wall increased significantly (baseline, 34±3%; 12 months, 45±4%;
P
<0.05). This enhancement in radial function was accompanied by an improvement in longitudinal function. End-diastolic thickness of the posterior wall decreased significantly after 12 months of treatment (baseline, 13.8±0.6 mm; 12 months, 11.8±0.6 mm;
P
<0.05). In parallel, myocardial mass decreased significantly from 201±18 to 180±21 g (
P
<0.05).

Conclusions—

These results suggest that ERT can decrease left ventricular hypertrophy and improve regional myocardial function.
Impact of Preinterventional Arterial Remodeling on Neointimal Hyperplasia After Implantation of (Non–Polymer-Encapsulated) Paclitaxel-Coated Stents
Authors: Mintz Gary S. , Tinana Adrienne , Hong Myeong-Ki , Lee Cheol Whan , Kim Jae-Joong , Fearnot Neal E. , Park Seong-Wook , Park Seung-Jung , Weissman Neil J.
Published: September 2003

Background—

This study used serial volumetric intravascular ultrasound (IVUS) to evaluate the effect of preinterventional arterial remodeling on in-stent intimal hyperplasia (IH) after implantation of non–polymer-encapsulated paclitaxel-coated stents.

Methods and Results—

Patients were randomized to placebo or one of two doses of paclitaxel (low dose, 1.28 μg/mm
2
; high dose, 3.10 μg/mm
2
). Complete preinterventional, post–stent implantation, and follow-up IVUS were available in 18 low-dose and 21 high-dose patients. IH volumes were similar in low-dose and high-dose patients: 17.6±15.1 mm
3
in low-dose patients and 13.1±13.3 mm
3
in high-dose patients (
P
=0.3). Therefore, IVUS findings in low- and high-dose patients were combined. Preinterventional remodeling was assessed by comparing lesion site to proximal and distal reference arterial area: positive remodeling (lesion>proximal reference, n=13), intermediate remodeling (distal reference<lesion<proximal reference, n=13), and negative remodeling (lesion<distal reference, n=13). During follow-up, there was a decrease in lumen volume in positive remodeling lesions (from 106±30 to 90±27 mm
3
;
P
=0.0067) and in intermediate remodeling lesions (from 97±28 to 76±31 mm
3
;
P
=0.0004), but not in negative remodeling lesions (99±27 versus 92±32 mm
3
;
P
=0.15). The follow-up IH volume was lower in negative remodeling lesions (5±7 mm
3
) compared with positive remodeling (20±14 mm
3
;
P
=0.0051) and intermediate remodeling lesions (20±15 mm
3
;
P
=0.0043); however, IH volume was virtually identical in positive and intermediate remodeling lesions. Multivariate linear regression analysis determined that remodeling and inflation pressure were independent predictors of IH volume; variables tested in the model included diabetes, acute coronary syndromes, dose, remodeling, and preinterventional plaque burden.

Conclusions—

Preinterventional arterial remodeling, especially negative remodeling, influences neointimal hyperplasia suppression after implantation of non–polymer-encapsulated paclitaxel-coated stents.
Phosphoinositide 3-Kinase γ–Deficient Mice Are Protected From Isoproterenol-Induced Heart Failure
Authors: Oudit Gavin Y. , Crackower Michael A. , Eriksson Urs , Sarao Renu , Kozieradzki Ivona , Sasaki Takehiko , Irie-Sasaki Junko , Gidrewicz Dominica , Rybin Vitalyi O. , Wada Teiji , Steinberg Susan F. , Backx Peter H. , Penninger Josef M.
Published: September 2003

Background—

We have recently shown that genetic inactivation of phosphoinositide 3-kinase γ (PI3Kγ), the isoform linked to G-protein–coupled receptors, results in increased cardiac contractility with no effect on basal cell size. Signaling via the G-protein–coupled β-adrenergic receptors has been implicated in cardiac hypertrophy and heart failure, suggesting that PI3Kγ might play a role in the pathogenesis of heart disease.

Methods and Results—

To determine the role for PI3Kγ in hypertrophy induced by G-protein–coupled receptors and cardiomyopathy, we infused isoproterenol, a β-adrenergic receptor agonist, into PI3Kγ-deficient mice. Compared with controls, isoproterenol infusion in PI3Kγ-deficient mice resulted in an attenuated cardiac hypertrophic response and markedly reduced interstitial fibrosis. Intriguingly, chronic β-adrenergic receptor stimulation triggered impaired heart functions in wild-type mice, whereas PI3Kγ-deficient mice retained their increased heart function and did not develop heart failure. The lack of PI3Kγ attenuated the activation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 signaling pathways in cardiac myocytes in response to isoproterenol. β
1
- and β
2
-adrenergic receptor densities were decreased by similar amounts in PI3Kγ-deficient and control mice, suggesting that PI3Kγ isoform plays no role in the downregulation of β-adrenergic receptors after chronic β-adrenergic stimulation.

Conclusions—

Our data show that PI3Kγ is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction function in response to β-adrenergic receptor stimulation in vivo. Thus, PI3Kγ may represent a novel therapeutic target for the treatment of decreased cardiac function in heart failure.
Dual Inhibition of β-Adrenergic and Angiotensin II Receptors by a Single Antagonist
Authors: Barki-Harrington Liza , Luttrell Louis M. , Rockman Howard A.
Published: September 2003

Background—

Although the renin–angiotensin and the β-adrenergic systems are interrelated, a direct interaction between β-adrenergic receptors (βARs) and angiotensin II type 1 receptors (AT
1
Rs) has not been identified.

Methods and Results—

Here, we provide evidence for a functional and physiological interaction between 2 G protein–coupled receptors: the βAR and the AT
1
R. Selective blockade of βARs in mouse cardiomyocytes inhibits angiotensin-induced contractility with an IC
50
that is similar to its inhibition of isoproterenol-mediated contractility. Furthermore, administration of the angiotensin receptor blocker valsartan to intact mice results in a significant reduction in the maximal response to catecholamine-induced elevation of heart rate. The mechanism for this transinhibitory effect of β-blockers and angiotensin receptor blockers is through receptor–G protein uncoupling; ie, β-blockers interfere with AT
1
R-G
q
coupling, and valsartan interferes with βAR-G
s
coupling. Finally, we demonstrate that AT
1
Rs and βARs form constitutive complexes that are not affected by ligand stimulation. As a result of these interactions, a single receptor antagonist effectively blocks downstream signaling and trafficking of both receptors simultaneously.

Conclusions—

We show that direct interactions between βARs and AT
1
Rs may have profound consequences on the overall response to drugs that antagonize these receptors.
Relation Between Left Ventricular Midwall Function and Coronary Vasodilator Capacity in Arterial Hypertension
Authors: Kozàkovà Michaela , Ferrannini Ele , Palombo Carlo
Published: September 2003

In systemic hypertension, depressed left ventricular midwall shortening predicts an adverse outcome and is associated with increased left ventricular relative wall thickness, which has been proposed as an independent predictor of cardiovascular risk and reduced coronary reserve. This study was designed to investigate whether depressed midwall shortening is associated with more critical impairment of coronary function and with exercise-induced myocardial ischemia. Sixty untreated hypertensive patients without coronary artery stenosis and 20 normotensive volunteers underwent exercise ECG testing, standard and transesophageal echocardiography to assess the occurrence of exercise-induced myocardial ischemia, left ventricular mass, geometry, and midwall shortening, and coronary vasodilator capacity. Compared with hypertensive patients with normal midwall shortening, those with depressed function (n=15) had higher minimum coronary resistance (1.19±0.27 versus 1.39±0.20 mm Hg/cm per second,
P
<0.01) and prevalence of exercise-induced myocardial ischemia (36 versus 67%,
P
<0.05). Within the hypertensive group, midwall shortening was inversely related to minimum coronary resistance (
r
=−0.42,
P
<0.01). Compared with patients with an exercise ECG test negative for myocardial ischemia, those with a positive test result (n=26) had higher minimum coronary resistance (1.13±0.21 versus 1.38±0.27 mm Hg/cm per second,
P
<0.01) and lower midwall shortening (104±16 versus 93±14%,
P
<0.01). We conclude that hypertensive patients with depressed midwall shortening have more severe impairment of coronary function and a higher prevalence of exercise-induced myocardial ischemia as compared with hypertensive patients with normal midwall shortening. These findings suggest that a decrease in myocardial performance may be related, at least in part, to chronic intermittent myocardial ischemia caused by a critical impairment of coronary vasodilator capacity.
Molecular Mechanisms of Inhibition of Vascular Growth by Angiotensin-(1-7)
Authors: Tallant E. Ann , Clark Michelle A.
Published: September 2003

Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9±25.2% of basal values (
P
<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3′,5′-cyclic monophosphorothioate attenuated the Ang-(1-7)–mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 μmol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II–stimulated ERK1/2 activities. Ang-(1-7) (1 μmol/L) reduced 100 nmol/L Ang II–stimulated ERK1 and ERK2 activation by 42.3±6.2% and 41.2±4.2%, respectively (
P
<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
Endothelin-1 Gene LYS198ASN Polymorphism and Blood Pressure Reactivity
Authors: Treiber Frank A. , Barbeau Paule , Harshfield Gregory , Kang Hyun-Sik , Pollock David M. , Pollock Jennifer S. , Snieder Harold
Published: September 2003

The Lys198Asn polymorphism of the endothelin-1 gene has been associated with increased blood pressure levels in several studies involving European and Australian adults. The purpose of the present study was to examine the potential moderating influence of ethnicity, obesity, and socioeconomic status on associations between the ET-1/Lys198Asn polymorphism and hemodynamic function at rest and during two laboratory stressors (video game, forehead cold) in a sample of 161 black and 213 white American normotensive young adults (mean age, 18.5±2.7 years). Carrier status of the T allele was not associated with resting blood pressure or total peripheral resistance index. However, carriers of the T allele showed greater diastolic blood pressure increases to the video game (
P
<0.04), particularly among those who were obese (
P
<0.02). Carrier status also interacted with socioeconomic status such that T allele carriers who came from lower socioeconomic status backgrounds exhibited the greatest increases in systolic blood pressure to the video game challenge (
P
<0.05). In conclusion, the findings point out the importance of examining the impact of genetic polymorphisms on blood pressure control phenotypes within the context of potentiating environmental factors.
Individual Blood Pressure Responses to Changes in Salt Intake
Authors: Obarzanek Eva , Proschan Michael A. , Vollmer William M. , Moore Thomas J. , Sacks Frank M. , Appel Lawrence J. , Svetkey Laura P. , Most-Windhauser Marlene M. , Cutler Jeffrey A.
Published: September 2003

Although group characteristics are known to influence average blood pressure response to changes in salt intake, predictability of individual responses is less clear. We examined variability and consistency of individual systolic blood pressure responses to changes in salt intake in 188 participants who ate the same diet at higher, medium, and lower (140, 104, 62 mmol/d) sodium levels for 30 days each, in random order, after 2 weeks of run-in at the higher sodium level. Regarding variability in systolic blood pressure changes over time, changes from run-in to higher sodium (no sodium level change) ranged from −24 to +25 mm Hg; 8.0% of participants decreased ≥10 mm Hg. Regarding variability in systolic blood pressure response to change in sodium intake, with higher versus lower sodium levels (78-mmol sodium difference), the range of systolic blood pressure change was −32 to +17 mm Hg; 33.5% decreased ≥10 mm Hg. Regarding consistency of response, systolic blood pressure change with run-in versus lower sodium was modestly correlated with systolic blood pressure change with higher versus medium sodium; systolic blood pressure change with higher versus lower sodium was similarly correlated with run-in versus medium sodium (combined Spearman
r
=0.27,
P
=0.002). These results show low-order consistency of response and confirm that identifying individuals as sodium responders is difficult. They support current recommendations for lower salt intake directed at the general public rather than “susceptible” individuals as one of several strategies to prevent and control adverse blood pressures widely prevalent in the adult population.
Serum Uric Acid and Plasma Norepinephrine Concentrations Predict Subsequent Weight Gain and Blood Pressure Elevation
Authors: Masuo Kazuko , Kawaguchi Hideki , Mikami Hiroshi , Ogihara Toshio , Tuck Michael L.
Published: September 2003

It has been reported that hypertension and obesity often coexist with hyperuricemia. To clarify the relations between serum uric acid, plasma norepinephrine, and insulin or leptin levels in subjects with weight gain–induced blood pressure elevation, we conducted the present longitudinal study. In 433 young, nonobese, normotensive men, body mass index, blood pressure, and levels of serum uric acid, fasting plasma norepinephrine, insulin, and leptin were measured every year for 5 years. Subjects were stratified by significant weight gain and/or blood pressure elevation (>10% in body mass index or mean blood pressure) for 5 years. At entry, blood pressure, uric acid, and norepinephrine values in subjects with blood pressure elevation were greater than in those without it, although body mass index, insulin, and leptin were similar. At entry, body mass index, blood pressure, uric acid, and norepinephrine in subjects with weight gain were greater than in those without weight gain. The increases in body mass index, mean blood pressure, uric acid, norepinephrine, insulin, and leptin for 5 years were greater in subjects with blood pressure elevation and/or weight gain than in subjects without, and those increases were greatest in subjects with weight gain whose blood pressure was elevated. By multiple regression analysis, basal mean blood pressure, norepinephrine, and uric acid were significant determinant factors of changes in mean blood pressure over 5 years, and basal body mass index, norepinephrine, and uric acid were significant determinant factors of changes in body mass index. These results demonstrate that serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
Physiological Impact of Increased Expression of the AT
1
Angiotensin Receptor
Authors: Le Thu H. , Kim Hyung-Suk , Allen Andrew M. , Spurney Robert F. , Smithies Oliver , Coffman Thomas M.
Published: September 2003

To test the effect of increased AT
1
receptor expression on blood pressure, we used gene targeting to generate mouse lines with a tandem duplication of the AT
1A
receptor gene locus (
Agtr1a
) along with >10 kb of 5′ flanking DNA. By successive breeding, we generated mice with 3 and 4 copies of the
Agtr1a
gene locus on an inbred 129/Sv background. AT
1A
mRNA expression and AT
1
-specific binding of
125
I-angiotensin II were increased in proportion to
Agtr1a
gene copy number. These animals survived in expected numbers, and their body, heart, and kidney weights were similar to wild-type, 2-copy control mice. Pressor responses to angiotensin II were blunted in the 4-copy mice compared with control mice. In male mice, there was no correlation between resting blood pressure and
Agtr1a
gene copy number or AT
1A
mRNA levels. However, in female mice, there was a highly significant positive correlation between blood pressure and AT
1A
receptor expression, paralleled by significant increases in aldosterone synthase expression with increase in gene copy number. Furthermore, in female but not male mice, there was a positive correlation between kallikrein and AT
1A
receptor mRNA levels and an inverse correlation between renin mRNA and
Agtr1a
copy number. Thus, in female but not male mice, genetic variants that increase expression of AT
1
receptors affect blood pressure and gene expression programs. The impact of enhanced AT
1
receptor expression on blood pressure may be blunted by systemic compensatory responses and altered signal-effector coupling in the vasculature.
Important Role of Nitric Oxide in the Effect of Angiotensin-Converting Enzyme Inhibitor Imidapril on Vascular Injury
Authors: Chen Rui , Iwai Masaru , Wu Lan , Suzuki Jun , Min Li-Juan , Shiuchi Tetsuya , Sugaya Takashi , Liu Hong-Wei , Cui Tai-Xing , Horiuchi Masatsugu
Published: September 2003

To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT
1
a-receptor–deficient (AT
1
aKO) mice. A polyethylene cuff was placed around the femoral artery of AT
1
aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α was detected by immunohistochemical staining and reverse transcriptase–polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-α were attenuated in the injured artery in AT
1
aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-α in AT
1
aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT
1
aKO mice. Treatment with imidapril did not change AT
2
receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
Insulin-Stimulated Hydrogen Peroxide Increases Guanylate Cyclase Activity in Vascular Smooth Muscle
Authors: Yang Ming , Yang Yu , Zhang Sui , Kahn Andrew M.
Published: September 2003

Insulin resistance is associated with vascular disease. Physiological concentrations of insulin inhibit cultured vascular smooth muscle cell (VSMC) contraction and migration by increasing nitric oxide (NO)-stimulated cGMP accumulation. The failure to do so in insulin-resistant states may aggravate vascular disease. We sought to determine the mechanism of insulin’s increase in cGMP accumulation. Isobutylmethylxanthine, an inhibitor of phosphodiesterase activity, inhibited the decline in cGMP levels measured by immunoassay in cGMP-loaded cultured rat aortic VSMCs, but 1 nmol insulin did not. Thus, insulin’s increase in cGMP accumulation is due to stimulated production, not inhibited hydrolysis and/or efflux. Insulin, which increases the NADH/NAD
+
ratio in these cells, stimulated superoxide anion (O
2
−
) accumulation measured by lucigenin luminescence to 256±25% (
P
<0.05) by a process that was blocked by the NADH oxidase inhibitor diphenyliodonium (DPI) and enhanced by the superoxide dismutase inhibitor diethyldithiocarbonate (DETCA). Insulin also stimulated hydrogen peroxide (H
2
O
2
) accumulation measured by horseradish peroxidase/luminol luminescence to 221±22% (
P
<0.05) by a DETCA-sensitive mechanism. H
2
O
2
(100 μmol/L) in the absence of insulin increased NO-stimulated cGMP accumulation to 151±11% (
P
<0.05). Insulin alone increased NO-stimulated cGMP accumulation to 183±17% (
P
<0.05), and this was blocked by either DPI or DETCA. We conclude that insulin increases NADH oxidase-derived O
2
−
production in cultured rat VSMCs. This did not cause the expected scavenging of NO resulting in the reduction of NO-stimulated guanylate cyclase activity, but enough O
2
−
was metabolized to H
2
O
2
to increase overall NO-stimulated cGMP production.
Proton Permeation Through the Myocardial Gap Junction
Authors: Zaniboni Massimiliano , Rossini Alessandra , Swietach Pawel , Banger Nurindura , Spitzer Kenneth W. , Vaughan-Jones Richard D.
Published: September 2003

Although protons can directly or indirectly gate solute permeability of the myocardial gap junction, there is little information regarding their own permeation, despite their importance in the regulation of myocardial contractility and rhythm. By pipette-loading of acid into guinea pig isolated, ventricular myocyte pairs while imaging pH
i
confocally using SNARF fluorescence, we have observed that protons permeate the junctional region. Permeation is inhibited by glycyrrhetinic acid, an agent that also increases intercellular electrical resistance, suggesting H
+
permeation via gap junctions. The rate of spread of acid between cells appears to be limited by junctional permeation rather than by cytoplasmic diffusion. Mathematical analyses, combined with experiments using SNARF as a proton carrier, suggest that gap junctional H
+
transmission may be accomplished physiologically by the permeation of intrinsic “proton-porter” molecules. We propose that proton flux through gap junctions will contribute to the dissipation of regional acid loads within the myocardium. This represents a mechanism for the local control of myocardial pH
i
.
Left Ventricular Mass and Geometry and the Risk of Ischemic Stroke
Authors: Di Tullio Marco R. , Zwas Donna R. , Sacco Ralph L. , Sciacca Robert R. , Homma Shunichi
Published: September 2003

Background and Purpose—

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular events, but its effect on ischemic stroke risk is established mainly in whites. The effect of LV geometry on stroke risk has not been defined. The aim of the present study was to evaluate whether LVH and LV geometry are independently associated with increased ischemic stroke risk in a multiethnic population.

Methods—

A population-based case-control study was conducted on 394 patients with first ischemic stroke and 413 age-, sex-, and race-ethnicity-matched community control subjects. LV mass was measured by transthoracic echocardiography. LV geometric patterns (normal, concentric remodeling, concentric or eccentric hypertrophy) were identified. Stroke risk associated with LVH and different LV geometric patterns was assessed by conditional logistic regression analysis in the overall group and age, sex, and race-ethnic strata, with adjustment for established stroke risk factors.

Results—

Concentric hypertrophy carried the greatest stroke risk (adjusted odds ratio [OR], 3.5; 95% confidence interval [CI], 2.0 to 6.2), followed by eccentric hypertrophy (adjusted OR, 2.4; 95% CI, 2.0 to 4.3). Concentric remodeling carried slightly increased stroke risk (adjusted OR, 1.7; 95% CI, 1.0 to 2.9). Increased LV relative wall thickness was independently associated with stroke after adjustment for LV mass (OR, 1.6; 95% CI, 1.1 to 2.3).

Conclusions—

LVH and abnormal LV geometry are independently associated with increased stroke risk. LVH is strongly associated with ischemic stroke in all age, sex, and race-ethnic subgroups. Increased LV relative wall thickness imparts an increased stroke risk after adjustment for LV mass and is of additional value in stroke risk prediction.
Change in Perfusion in Acute Nondominant Hemisphere Stroke May Be Better Estimated by Tests of Hemispatial Neglect Than by the National Institutes of Health Stroke Scale
Authors: Hillis Argye E. , Wityk Robert J. , Barker Peter B. , Ulatowski John A. , Jacobs Michael A.
Published: September 2003

Background and Purpose—

It has been reported that National Institutes of Health Stroke Scale (NIHSS) scores correlate poorly with hypoperfused tissue measured by perfusion-weighted imaging (PWI) in nondominant hemisphere stroke. We conducted 2 studies to determine whether tests of hemispatial neglect provide a better measure of hypoperfusion and reperfusion than NIHSS in nondominant hemisphere stroke.

Methods—

In study 1, 74 patients with acute ischemic, supratentorial stroke were administered the NIHSS, tests of neglect or aphasia, and diffusion-weighted imaging (DWI) and PWI on day 1 (<24 hours from onset) of stroke. Pearson correlations between volumes of PWI/DWI abnormality and functional tests were calculated. In study 2, 10 patients with acute, nondominant hemisphere stroke who were candidates for intervention to restore perfusion underwent PWI, DWI, NIHSS, and a line cancellation test on days 1 and 3. Correlations between change in volumes of PWI/DWI abnormality and change in functional tests were calculated.

Results—

In study 1, in nondominant hemisphere stroke, volume of PWI abnormality correlated significantly with neglect scores (
r
=0.71;
P
<0.002) but not with NIHSS scores (
r
=0.39;
P
=NS). In dominant hemisphere stroke, volume of PWI abnormality correlated better with aphasia scores (
r
=0.50;
P
=0.0001) than with NIHSS scores (
r
=0.45;
P
=0.001). In study 2, change in volume of hypoperfused tissue on PWI correlated with change in line cancellation performance (
r
=0.83;
P
=0.003) but not with change in NIHSS score (
r
=0.26;
P
=NS).

Conclusions—

Tests of hemispatial neglect may better reflect dysfunction and reperfusion than NIHSS for patients with nondominant hemisphere stroke.
Dipyridamole in Stroke Prevention
Authors: De Schryver E.L.L.M.
Published: September 2003

Background and Purpose—

Trial data suggest that dipyridamole, with or without aspirin, is more efficacious in the secondary prevention of stroke than of coronary events. This selective effect might be attributed to blood pressure lowering by dipyridamole. Therefore, we aimed to assess the effect on blood pressure in the setting of a randomized clinical trial in patients with cerebral ischemia of presumed arterial origin.

Methods—

In this study, 591 patients with recent cerebral ischemia of arterial origin were randomly allocated to treatment with aspirin 30 to 325 mg/d or with the combination of aspirin and dipyridamole 400 mg/d in the European/Australian Stroke Prevention in Reversible Ischemia Trial. In an on-treatment analysis, the change in blood pressure measurements from baseline to values after at least 6 months of follow up was assessed with linear regression analysis.

Results—

After an average period of 15 months, systolic blood pressure dropped 6.2 mm Hg in the aspirin plus dipyridamole group (n=273) and 6.2 mm Hg in the aspirin group (n=318), for a difference of 0.0 mm Hg (95% confidence interval, −3.8 to 3.7). Diastolic blood pressure dropped 3.6 mm Hg in the aspirin plus dipyridamole group compared with 2.7 mm Hg in the aspirin group, for a difference of 0.9 mm Hg (95% confidence interval, −1.0 to 2.9).

Conclusions—

It is unlikely that dipyridamole leads to a permanent reduction in blood pressure and that this would explain why this drug might prevent strokes rather than coronary events.
Trends in the Incidence, Mortality, and Survival Rate of Cardiovascular Disease in a Japanese Community
Authors: Kubo Michiaki , Kiyohara Yutaka , Kato Isao , Tanizaki Yumihiro , Arima Hisatomi , Tanaka Keiichi , Nakamura Hidetoshi , Okubo Ken , Iida Mitsuo
Published: September 2003

Background and Purpose—

The slowdown of a steeply declining trend in cardiovascular mortality has been reported in Japan, but precise reasons for this trend are uncertain.

Methods—

We established 3 study cohorts of Hisayama residents aged ≥40 years without a history of stroke or myocardial infarction in 1961 (1618 subjects, first cohort), 1974 (2038 subjects, second cohort), and 1988 (2637 subjects, third cohort). We followed up with each cohort for 12 years, comparing the incidence, mortality, and survival rate of cardiovascular disease.

Results—

The age-adjusted incidence of cerebral infarction significantly declined by 37% for men and by 32% for women from the first to the second cohort. It continued to decline by 29% for men, but the decline decelerated for women in the third cohort. The incidence of cerebral hemorrhage steeply declined by 61% from the first to the second cohort in men only, while it was sustained for both sexes in the third cohort. Stroke mortality continuously declined as a result of these incidence changes and significant improvement of survival. In contrast, the incidence and mortality rate of coronary heart disease were unchanged except for the increasing incidence in the elderly. The prevalence of severe hypertension and current smoking significantly decreased, while that of glucose intolerance, hypercholesterolemia, and obesity greatly increased among the cohorts.

Conclusions—

Our data suggest that the decline in stroke incidence is slowing down and that the incidence of coronary heart disease has been increasing in the elderly in recent years. Insufficient control of hypertension and the increase in metabolic disorders may contribute to these trends.