bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of ATP-Sensitive Potassium Channel Inhibition on Coronary Metabolic Vasodilation in Humans
Authors: Farouque H. M. Omar , Worthley Stephen G. , Meredith Ian T.
Published: March 2004

Objective—

Experimental evidence indicates that ATP-sensitive potassium (K
ATP
) channels regulate coronary blood flow (CBF). However, their contribution to human coronary metabolic vasodilation is unknown.

Methods and Results—

Seventeen patients (12 male, age 58±10 years) were studied. Coronary hemodynamics were assessed before and after K
ATP
channel inhibition with subselective intracoronary glibenclamide infused at 40 μg/min in an angiographically smooth coronary artery after successful percutaneous coronary intervention to another vessel. Metabolic vasodilation was induced by 2 minutes of rapid right ventricular pacing. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. The time course of hyperemia was recorded for 2 minutes after pacing, and hyperemic volume was estimated from the area under the flow-versus-time curve (AUC). Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting CBF by 9% (
P
=0.04) and increased resting coronary vascular resistance (CVR) by 15% (
P
=0.03). Glibenclamide reduced pacing-induced peak CBF (50.8±6.8 versus 42.0±5.4 mL/min,
P
=0.001), peak CBF corrected for baseline flow (25.1±4.6 versus 17.6±3.1 mL/min,
P
=0.01), and increased minimum CVR (2.6±0.3 versus 3.1±0.3 mm Hg/mL per minute,
P
=0.002). Compared with vehicle, glibenclamide reduced total AUC at 2 minutes (3535±397 versus 3027±326 mL,
P
=0.001).

Conclusions—

Vascular K
ATP
channels appear to be involved in functional coronary hyperemia after metabolic stimulation.
Regional Body Composition Changes Exhibit Opposing Effects on Coronary Heart Disease Risk Factors
Authors: Okura Tomohiro , Nakata Yoshio , Yamabuki Keisuke , Tanaka Kiyoji
Published: March 2004

Objective—

We investigated how regional body composition measured by dual-energy X-ray absorptiometry (DXA) is associated with risk factors for coronary heart disease (CHD) during weight reduction in obese women.

Methods and Results—

Data were gathered from 128 overweight and obese women, aged 34 to 66 years, during a 14-week intervention study with diet and exercise. Regional (arms, legs, and trunk) fat tissue (FT) and lean soft tissue (LST) were measured by DXA. The FT change in legs correlated negatively with changes in diastolic blood pressure, low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and the number of CHD risk factors per subject (
r
=−0.17,
P
<0.05 to −0.26,
P
<0.01) in response to weight reduction, whereas truncal FT change had positive correlations with changes in triglycerides, LDL-C, FPG, and the number of CHD risk factors per subject (
r
=0.17,
P
<0.05 to 0.25,
P
<0.01). LST change in legs correlated negatively with changes in systolic blood pressure, FPG, and the number of risk factors (
r
=−0.20 to −0.21,
P
<0.05).

Conclusions—

Regional body composition information is important for evaluating improvement of CHD risk factors during weight-reduction treatment for obesity; differential FTs had opposing effects on CHD risk factors during weight reduction in obese women.
Ceramide Synthesis Correlates with the Posttranscriptional Regulation of the Sterol-Regulatory Element-Binding Protein
Authors: Worgall Tilla S. , Juliano Rebecca A. , Seo Toru , Deckelbaum Richard J.
Published: March 2004

Objective—

Sterol-regulatory element-binding proteins (SREBPs) regulate transcription of genes of lipid metabolism. Ceramide decreases transcriptionally active SREBP levels independently of intracellular cholesterol levels. Mechanisms of the ceramide-mediated decrease of SREBP levels were investigated.

Methods and Results—

Experiments were performed in Chinese hamster ovary cells. Inhibition of ceramide synthesis with myriocin, cycloserine, or fumonisin decreases levels of transcriptionally active SREBP and reduces SRE-mediated gene transcription. When ceramide synthesis is increased through exogenous sphingosine or inhibition of sphingosine kinase, SRE-mediated gene transcription is increased. The important role of ceramide synthesis in SRE-mediated gene transcription is confirmed in LY-B cells that do not synthesize ceramide de novo. LY-B cells fail to increase SRE-mediated gene transcription in sterol depletion.

Conclusions—

Ceramide synthesis correlates with the generation of transcriptionally active SREBP and SRE-mediated gene transcription. Inhibition of ceramide synthesis decreases levels of transcriptionally active SREBP and SRE-mediated gene transcription. It is hypothesized that the process of ongoing ceramide synthesis contributes to the physiological processing of SREBP, perhaps affecting ER-to-Golgi trafficking. Taken together, modification of ceramide synthesis could be a novel target for drug development in the pharmacologic modification of SRE-dependent pathways.
Cell Cycle–Dependent Regulation of Smooth Muscle Cell Activation
Authors: Braun-Dullaeus Ruediger C. , Mann Michael J. , Sedding Daniel G. , Sherwood Steven W. , von der Leyen Heiko E. , Dzau Victor J.
Published: March 2004

Objective—

Although numerous diseases involving cellular proliferation are also associated with phenotypic changes, there has been little direct evidence that cell phenotype and the cell’s response to external stimuli are modified during passage through different phases of the cell cycle. In this study, we demonstrate that an association exists between cell cycle progression and the expression of genes involved in cellular activation.

Methods and Results—

Early cell cycle arrest of aortic smooth muscle cells was found to inhibit the tumor necrosis factor α (TNFα)-induced upregulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, important markers of vascular cell activation in diseases such as atherosclerosis. A combination of immunocytochemistry and flow cytometry were used to document that TNFα-induced adhesion molecule upregulation was inhibited during G1-phase and S-phase, but not in G0-phase or G2/M-phase cells. The inhibition of adhesion molecule expression occurred at the level of transcription, as demonstrated by changes in the patterns of mRNA and protein accumulation in cycling and arrested cells.

Conclusions—

Early cell cycle phases may represent states in which the responses to a variety of stimuli that influence cell fate can be modulated, and these observations may have novel implications for the prevention and/or therapy of vascular proliferative, neoplastic, and inflammatory diseases.
Overexpression of Uncoupling Protein 2 in THP1 Monocytes Inhibits β2Integrin-Mediated Firm Adhesion and Transendothelial Migration
Authors: Ryu Je-Won , Hong Kyung Hee , Maeng Jin Hee , Kim Jae-Bum , Ko Jesang , Park Joong Yeol , Lee Ki-Up , Hong Myeong Ki , Park Seong Wook , Kim You Ho , Han Ki Hoon
Published: March 2004

Objective—Uncoupling protein 2 (UCP2) belongs to the mitochondrial anion carrier family and regulates production of reactive oxygen species in macrophages. Previous studies have shown that selective genetic disruption of UCP2 in bone marrow cells results in excess accumulation of monocytes/macrophages in the vascular wall of hypercholesterolemic low-density lipoprotein receptor-deficient (LDLR−/−) mice. Here we investigated whether UCP2 regulates expression of genes involved in monocyte recruitment.

Methods and Results—UCP2 overexpression in THP1 monocytes, which induced a 10-fold increase in mitochondrial UCP2 protein levels, reduced steady-state level of intracellular reactive oxygen species (ROS) and H2O2-induced ROS production. THP1 monocytes with UCP2 overexpression showed lower intracellular calcium levels and less H2O2-triggered intracellular calcium mobilization, and less protein and mRNA levels of β2integrins, most notably CD11b. UCP2 overexpression reduced β2integrin-mediated firm adhesion of monocytes to either tumor necrosis factor-α (TNF-α)–stimulated human aortic endothelial cell (HAEC) monolayers or to plates coated with intercellular adhesion molecule-1, not vascular cell adhesion molecule-1. UCP2 overexpression also inhibited cell spreading and actin polymerization in monocytes treated with TNF-α and monocyte chemoattractant protein-1 (MCP-1), and reduced MCP-1–induced transmigration of monocytes through HAEC monolayers.

Conclusions—Mitochondrial UCP2 in circulating monocytes may prevent excessive accumulation of monocytes/macrophages in the arterial wall, thereby reducing atherosclerotic plaque formation.
Endothelial Cell Markers and the Risk of Coronary Heart Disease
Authors: Morange P.E. , Simon C. , Alessi M.C. , Luc G. , Arveiler D. , Ferrieres J. , Amouyel P. , Evans A. , Ducimetiere P. , Juhan-Vague I.
Published: March 2004

Background—

Tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), and thrombomodulin (TM) are 3 major hemostatic regulatory molecules synthesized by endothelium. Data from epidemiological studies aiming to evaluate the relation between plasma levels of these molecules and the development of coronary heart disease (CHD) are sparse or contradictory.

Methods and Results—

We examined the association between these endothelial-cell markers and the incidence of fatal or nonfatal myocardial infarction (hard CHD) and stable or unstable angina (angina pectoris) in a prospective cohort (the PRIME Study) of nearly 10 000 healthy men recruited in France and Northern Ireland. We measured baseline plasma concentration of the free form of TFPI (f-TFPI), vWF, and the soluble form of TM (sTM) among 296 participants who subsequently developed CHD over the 5-year follow-up (158 with hard CHD and 142 with angina pectoris) and in 563 control subjects by use of a nested case-control design. Individuals with plasma vWF levels in the highest quartile showed a 3.04-fold increase in the risk of hard CHD compared with those in the lowest quartile (95% CI, 1.59 to 5.80). Individuals with f-TFPI levels below the 10th percentile had a 2.13-fold increased risk of hard CHD compared with those with levels above it (95% CI, 1.08 to 4.18). The risk for both molecules persisted after control for inflammatory parameters. Individuals with vWF levels in the highest quartile and f-TFPI levels below the 10th percentile presented a 6.9-fold increased risk of hard CHD compared with those with vWF levels in the lowest quartile and f-TFPI levels above the 10th percentile (95% CI, 1.3 to 37.8).

Conclusions—

vWF and f-TFPI plasma levels were independent risk factors for hard CHD events.
C-Reactive Protein Modulates Risk Prediction Based on the Framingham Score
Authors: Koenig Wolfgang , Löwel Hannelore , Baumert Jens , Meisinger Christa
Published: March 2004

Background—

The Framingham Coronary Heart Disease (CHD) prediction score is recommended for global risk assessment in subjects prone to CHD. Recently, C-reactive protein (CRP) has emerged as an independent predictor of CHD. We sought to assess the potential of CRP measurements to enhance risk prediction based on the Framingham Risk Score (FRS) in a large cohort of middle-aged men from the general population.

Methods and Results—

We measured CRP and traditional cardiovascular risk factors at baseline in 3435 white men of German nationality, 45 to 74 years of age. All men were drawn from 3 random samples of the general population in the Augsburg area located in Southern Germany in 1984 to 1985, 1989 to 1990, and 1994 to 1995 (response rate, 80%), and the FRS was calculated in all of them. Outcome was defined as nonfatal and fatal coronary events, including sudden cardiac death. During an average follow-up of 6.6 years, a total of 191 coronary events occurred. Cox regression showed a significant contribution of CRP to coronary event risk prediction independent of the FRS (
P
=0.0002). In stratified analysis for 5 categories of FRS, CRP significantly added prognostic information to the FRS in subjects in 2 intermediate risk categories (
P
=0.03 and
P
=0.02).

Conclusions—

Our results suggest that CRP enhances global coronary risk as assessed by the FRS, especially in intermediate risk groups. This might have implications for future risk assessment.
Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure
Authors: Delgado Reynolds M. , Nawar Mohamad A. , Zewail Aly M. , Kar Biswajit , Vaughn William K. , Wu Kenneth K. , Aleksic Nena , Sivasubramanian Natarajan , McKay Kathleen , Mann Douglas L. , Willerson James T.
Published: March 2004

Background—

Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression.

Methods and Results—

Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg · kg
−1
· wk
−1
for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor–containing mice chow (n=50) or plain mice chow (controls; n=50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography (with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor–treated mice decreased significantly less than in control mice (9% versus 29%,
P
<0.01). Mortality was significantly lower for COX-2 inhibitor–treated mice than for control mice (18% versus 38%,
P
<0.01). These results were confirmed in a revalidation study in COX-2 inhibitor–treated mice (n=25) and controls (n=25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor–treated mice but showed more extensive signs of cardiomyopathy (as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting [6442±1635 versus 4300±2408 arbitrary units,
P
<0.022]).

Conclusions—

COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.
Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia
Authors: Kuang Michael , Febbraio Maria , Wagg Cory , Lopaschuk Gary D. , Dyck Jason R.B.
Published: March 2004

Background—

Evidence from humans suggests that fatty acid translocase (FAT)/CD36 deficiency can lead to functionally and/or energetically compromised hearts, but the data are equivocal, and the subject remains controversial. In this report we assessed the contribution of FAT/CD36 to overall fatty acid oxidation rates in the intact heart and determined the effect of FAT/CD36 on energy metabolism during reperfusion of ischemic hearts.

Methods and Results—

Isolated working hearts from wild-type and FAT/CD36-knockout (KO) mice were perfused with Krebs-Henseleit solution containing 0.4 or 1.2 mmol/L [U-
3
H]palmitate, 5 mmol/L [U-
14
C]glucose, 2.5 mmol/L calcium, and 100 μU/mL insulin at a preload pressure of 11.5 mm Hg and afterload pressure of 50 mm Hg. Hearts were aerobically perfused for 30 minutes or aerobically perfused for 30 minutes, followed by 18 minutes of global no-flow ischemia and 40 minutes of aerobic reperfusion. Rates of fatty acid oxidation in FAT/CD36-KO hearts were significantly lower than in wild-type hearts at both concentrations of palmitate (0.4 or 1.2 mmol/L). In addition, hearts from FAT/CD36-KO mice displayed a compensatory increase in glucose oxidation rates. On aerobic reperfusion after ischemia, cardiac work of FAT/CD36-KO hearts recovered to the same extent as wild-type hearts.

Conclusions—

FAT/CD36-deficient hearts are not energetically or functionally compromised and are not more sensitive to ischemic injury because glucose oxidation can compensate for the loss of fatty acid–derived ATP.
Improved Survival With Radial Artery Versus Vein Conduits in Coronary Bypass Surgery With Left Internal Thoracic Artery to Left Anterior Descending Artery Grafting
Authors: Zacharias Anoar , Habib Robert H. , Schwann Thomas A. , Riordan Christopher J. , Durham Samuel J. , Shah Aamir
Published: March 2004

Background—

Given its proven survival benefit, left internal thoracic artery to left anterior descending (LITA-LAD) grafting has become a fundamental part of CABG. This grafting also led to increased use of other arterial conduits, of which the radial artery is most popular. Whether radial grafting improves survival beyond that achieved by LITA-LAD alone is not known.

Methods and Results—

We compared 6-year outcomes in propensity-matched CABG-LITA-LAD patients (925 each) divided into those with ≥1 radial grafts and those with vein-only grafting. Matched patients had essentially identical demographics, comorbidities, coronary disease, and operative data. Perioperative outcomes, including death (radial, 11 [1.2%]; vein, 10 [1.1%]), were similar for the 2 groups. Cumulative 0- to 6-year survival was better for radial patients (risk ratio, 0.675), particularly after 3 years (
P
<0.03). Six-year survival in vein (86.8%) and radial (92.1%) patients indicated 67% greater overall vein mortality. Incidence rates of radial and vein repeated catheterization (190 of 925 [20.5%] versus 199 of 925 [21.5%]) and revascularization (8.8% versus 8.5%) were similar. Angiography data in restudied symptomatic patients showed a trend for greater radial patency. Vein failure (66 of 161 [41%]) was significantly worse than radial failure (46 of 157 [29.3%]) in patients receiving both types of grafts (
P
=0.039).

Conclusions—

Using radial as a second arterial conduit in CABG-LITA-LAD as opposed to vein grafting improves long-term outcomes as a result of decreased late deaths, especially after the third postoperative year.
Relation Between Pulmonary Vein Firing and Extent of Left Atrial–Pulmonary Vein Connection in Patients With Atrial Fibrillation
Authors: Nakagawa Hiroshi , Aoyama Hiroshi , Beckman Karen J. , Po Sunny S. , Wu Richard , Lockwood Deborah , Spector Peter , Calame James D. , Lustgarten Daniel L. , Herring Lisa , Hasdemir Can , Singh Dalip , Lazzara Ralph , Jackman Warren M.
Published: March 2004

Background—

The purpose of this study was to measure the extent of left atrial–pulmonary vein (LA-PV) connections and determine the relation to PV firing in patients with atrial fibrillation (AF).

Methods and Results—

Ten close-bipolar (1 mm-spacing) Lasso electrograms were recorded circumferentially around 210 PVs (excluding 2 right middle PVs and 4 left common trunks) in 62 patients with AF. PV firing was provoked by isoproterenol (4 μg/min) and cardioversion of pacing-induced AF. The width of each LA-PV connection was measured in tenths of PV circumference, based on number of continuous close-bipolar Lasso electrode sites required for ablation (10% for each close-bipolar electrode site). One, 2, or 3 to 4 discrete LA-PV connections (discrete connection defined by ablation along 10% to 30% of PV circumference) were present in 18 (9%), 31 (14%), and 32 (15%) of 210 PVs, respectively: 1 broad connection (ablation along continuous 40% to 80% circumference) in 46 (22%) PVs; 1 broad plus other broad or discrete connections in 54 (26%) PVs; and a circumferential connection (ablation along 90% to 100%) in 29 (14%) PVs. Circumferential LA-PV connections were more common in superior than in inferior PVs (20% versus 7%,
P
<0.01). There was no major difference in distribution of the other types of LA-PV connections between the four PVs. PV firing occurred in 27%, 47%, and 72% of PVs with discrete only, broad and circumferential connections, respectively (
P
<0.01). Dissociated PV potentials after isolation were more common in arrhythmogenic (firing) PVs (32% versus 8%,
P
<0.01).

Conclusions—

The extent of LA-PV connections corresponds with arrhythmognesis. The incidence of PV firing increases with progressively wider LA-PV connections (discrete versus broad versus circumferential).
Repetitive 4-Week Periods of Atrial Electrical Remodeling Promote Stability of Atrial Fibrillation
Authors: Todd Derick M. , Fynn Simon P. , Walden Andrew P. , Hobbs W. Julian , Arya Sanjay , Garratt Clifford J.
Published: March 2004

Background—

Episodes of atrial fibrillation (AF) are known to cause both a rapid reduction in atrial refractoriness (atrial electrical remodeling) and a more delayed increase in AF stability thought to be due to a so-called “second factor.” The aim of this study was to quantify the effects and time course of such a factor on AF stability in the chronic goat model.

Methods and Results—

AF was maintained in 6 goats by burst atrial pacing for 3 consecutive 4-week periods separated a mean of 6±2.1 days of sinus rhythm. Six days of sinus rhythm was just sufficient for refractoriness changes to reverse fully in all goats. Atrial effective refractory period, AF inducibility, and duration of individual episodes of AF were assessed at regular intervals. There was a progressive reduction from month 1 to 2 to 3 in the mean duration of burst pacing required to induce individual episodes of AF of 60 seconds (178±251, 110±102, and 21±30 hours), 1 hour (229±224, 136±104, and 68±51 hours), and 24 hours (277±218, 192±190, and 102±75 hours;
P
<0.03). The frequency with which AF was induced during extrastimulus pacing increased progressively from 16.7% in month 1 to 31.7% in month 2 and 46.9% in month 3 (
P
<0.001).

Conclusions—

Sequential 4-week periods of atrial fibrillation result in a progressive increase in AF stability independent of baseline atrial refractory period. This finding suggests the presence of a second factor in the self-perpetuation of AF with a time course comparable to that of AF-induced ultrastructural changes in the atria.
Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis
Authors: Candido Riccardo , Allen Terri J. , Lassila Markus , Cao Zemin , Thallas Vicki , Cooper Mark E. , Jandeleit-Dahm Karin A.
Published: March 2004

Background—

It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT
1
) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)–null mouse and to explore molecular and cellular mechanisms linked to vascular protection.

Methods and Results—

Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT
1
receptor expression, cellular proliferation, collagen content, macrophage- and α-smooth muscle actin–positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT
1
receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments.

Conclusions—

Diabetes-associated atherosclerosis is ameliorated by AT
1
receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.
Local Delivery of Marrow-Derived Stromal Cells Augments Collateral Perfusion Through Paracrine Mechanisms
Authors: Kinnaird T. , Stabile E. , Burnett M.S. , Shou M. , Lee C.W. , Barr S. , Fuchs S. , Epstein S.E.
Published: March 2004

Background—

Bone marrow cell therapy is reported to contribute to collateral formation through cell incorporation into new or remodeling vessels. However, the possible role of a paracrine contribution to this effect is less well characterized.

Methods and Results—

Murine marrow-derived stromal cells (MSCs) were purified by magnetic bead separation of cultured bone marrow. The release of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1) was demonstrated by analysis of MSC conditioned media (MSC-CM). MSC-CM enhanced proliferation of endothelial cells and smooth muscle cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partly attenuated these effects. Balb/C mice (n=10) underwent distal femoral artery ligation, followed by adductor muscle injection of 1×10
6
MSCs 24 hours later. Compared with controls injected with media (n=10) or mature endothelial cells (n=8), distal limb perfusion improved, and mid-thigh conductance vessels increased in number and total cross-sectional area. MSC injection improved limb function and appearance, reduced the incidence of auto-amputation, and attenuated muscle atrophy and fibrosis. After injection, labeled MSCs were seen dispersed between muscle fibers but were not seen incorporated into mature collaterals. Injection of MSCs increased adductor muscle levels of bFGF and VEGF protein compared with controls. Finally, colocalization of VEGF and transplanted MSCs within adductor tissue was demonstrated.

Conclusions—

MSCs secrete a wide array of arteriogenic cytokines. MSCs can contribute to collateral remodeling through paracrine mechanisms.
Brain Natriuretic Peptide Enhances Renal Actions of Furosemide and Suppresses Furosemide-Induced Aldosterone Activation in Experimental Heart Failure
Authors: Cataliotti Alessandro , Boerrigter Guido , Costello-Boerrigter Lisa C. , Schirger John A. , Tsuruda Toshihiro , Heublein Denise M. , Chen Horng H. , Malatino Lorenzo S. , Burnett John C.
Published: March 2004

Background—

The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF.

Methods and Results—

CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg
−1
· h
−1
). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg
−1
· h
−1
) and low-dose (2 pmol · kg
−1
· min
−1
) BNP followed by 45-minute coinfusion of Fs (1 mg · kg
−1
· h
−1
) and high-dose (10 pmol · kg
−1
· min
−1
) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35±3 to 56±4*) (* indicates
P
<0.05 versus baseline) (
P
<0.0001 between groups). Plasma aldosterone increased with Fs (41±10 to 100±11* ng/dL) but was attenuated in the Fs+BNP group (44±11 to 54±9 ng/dL low-dose and to 47±7 ng/dL high-dose) (
P
=0.0007 between groups).

Conclusions—

Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.
Shed Membrane Particles From T Lymphocytes Impair Endothelial Function and Regulate Endothelial Protein Expression
Authors: Martin Sophie , Tesse Angela , Hugel Bénédicte , Martínez M. Carmen , Morel Olivier , Freyssinet Jean-Marie , Andriantsitohaina Ramaroson
Published: March 2004

Background—

Microparticles (MPs) are membrane vesicles with procoagulant and proinflammatory properties released during cell activation. The present study was designed to dissect the effects evoked by T lymphocyte–derived MPs on vascular function.

Methods and Results—

MPs were produced by treatment of the human lymphoid CEM T cell line with actinomycin D or phytohemagglutinin. Incubation of mouse aortic rings with 30 nmol/L MPs resulted in a time-dependent impairment of acetylcholine-induced relaxation of precontracted vessels, with a maximal reduction after 24 hours. MPs also impaired shear stress–induced dilatation of mouse small mesenteric arteries by affecting the nitric oxide (NO) and prostacyclin but not the endothelium-derived hyperpolarizing factor components of the response. However, neither alteration of calcium signaling in response to agonists nor reduction of cyclooxygenase-1 expression accounted for the impairment of the NO and prostacyclin components of the endothelial response. The effect of MPs was rather because of a decrease in expression of endothelial NO synthase and an overexpression of caveolin-1. Furthermore, lymphocyte-derived MPs from diabetic patients or in vivo circulating MPs from either diabetic or HIV-infected patients reduced endothelial NO synthase expression. Finally, the effects of MPs on endothelial cells were not driven through CD11a/CD18 adhesion molecules or the Fas/FasL pathway.

Conclusions—

MPs from T cells induce endothelial dysfunction in both conductance and resistance arteries by alteration of NO and prostacyclin pathways. MPs regulate protein expression for endothelial NO synthase and caveolin-1. These data contribute to a better understanding of the deleterious effects of enhanced circulating MPs observed in disorders with cardiovascular or immune complications.
CD44 Regulates Arteriogenesis in Mice and Is Differentially Expressed in Patients With Poor and Good Collateralization
Authors: van Royen N. , Voskuil M. , Hoefer I. , Jost M. , de Graaf S. , Hedwig F. , Andert J.-P. , Wormhoudt T.A.M. , Hua J. , Hartmann S. , Bode C. , Buschmann I. , Schaper W. , van der Neut R. , Piek J.J. , Pals S.T.
Published: March 2004

Background—

Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis.

Methods and Results—

CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44
−/−
mice (wild-type, 54.5±14.9% versus CD44
−/−
, 24.1±9.2%,
P
<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29±12% versus CD44
−/−
, 18±7% CD11b-positive cells/square,
P
<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764±572 versus good collateralization, 2817±1029 AU,
P
<0.05).

Conclusions—

For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.
PR39 Inhibits Apoptosis in Hypoxic Endothelial Cells
Authors: Wu Jiaping , Parungo Cherie , Wu Guifu , Kang Peter M. , Laham Roger J. , Sellke Frank W. , Simons Michael , Li Jian
Published: March 2004

Background—

PR39 is a proline- and arginine-rich peptide implicated in wound healing and myocardial ischemia protection. To determine the potential mechanisms of PR39 in ischemia, we examined the role of PR39 in hypoxia-induced apoptosis in vascular endothelial cells.

Methods and Results—

Hypoxia results in an increase of apoptosis in bovine aortic endothelial cells (BAECs), as determined by terminal deoxynucleotidyl transferase–mediated dUTP biotin nick-end labeling (TUNEL) analysis and caspase-3 activity. Hypoxia induced 66.2±2.7% TUNEL-positive cells, whereas in the presence of synthesized PR39 peptide, TUNEL-positive cells were reduced to 29.6±1.9% (
P
<0.05). After 24 hours of hypoxia, the addition of PR39 reduced caspase-3 activity to 3.17±0.47 pMol/min from 10.52±0.55 pMol/min in hypoxic BAECs. Moreover, PR39 increased inhibitor of apoptosis protein-2 (IAP-2) gene and protein expression by 3-fold in a time- and dose-dependent manner. The induction of IAP-2 by PR39 conferred an increase in IAP-2 gene transcription and IAP-2 mRNA stability. Furthermore, inhibiting IAP-2 with second mitochondria-derived activator of caspase (Smac) and with small interfering RNA targeting IAP-2 abrogated the ability of PR39 to reduce caspase-3 activity.

Conclusions—

We provide the first direct evidence for PR39 as an antiapoptotic factor in endothelial cells during hypoxia. These data suggest that PR39 inhibits hypoxia-induced apoptosis and decreases caspase-3 activity in endothelial cells through an increase of IAP-2 expression.
Human Mesenchymal Stem Cells Form Purkinje Fibers in Fetal Sheep Heart
Authors: Airey Judith A. , Almeida-Porada Graça , Colletti Evan J. , Porada Christopher D. , Chamberlain Jason , Movsesian Matthew , Sutko John L. , Zanjani Esmail D.
Published: March 2004

Background—

We have investigated the usefulness of a model of cardiac development in a large mammal, sheep, for studies of engraftment of human stem cells in the heart.

Methods and Results—

Adult and fetal human mesenchymal stem cells were injected intraperitoneally into sheep fetuses in utero. Hearts at late fetal development were analyzed for engraftment of human cells. The majority of the engrafted cells of human origin formed segments of Purkinje fibers containing exclusively human cells. There were no differences in engraftment of human mesenchymal stem cells from adult bone marrow, fetal brain, and fetal liver. On average, 43.2% of the total Purkinje fibers in random areas (n=11) of both ventricles were of human origin. In contrast, ≈0.01% of cardiomyocytes were of human origin.

Conclusions—

Human mesenchymal stem cells preferentially engraft at high levels in the ventricular conduction system during fetal development in sheep. These findings raise the possibility that stem cells contribute to normal development of the fetal heart.
Red Blood Cell Nitric Oxide as an Endocrine Vasoregulator
Authors: Datta Borunendra , Tufnell-Barrett Timothy , Bleasdale Robert A. , Jones Christopher J.H. , Beeton Ian , Paul Vincent , Frenneaux Michael , James Philip
Published: March 2004

Background—

A respiratory cycle for nitric oxide (NO) would involve the formation of vasoactive metabolites between NO and hemoglobin during pulmonary oxygenation. We investigated the role of these metabolites in hypoxic tissue in vitro and in vivo in healthy subjects and patients with congestive heart failure (CHF).

Methods and Results—

We investigated the capacity for red blood cells (RBCs) to dilate preconstricted aortic rings under various O
2
tensions. RBCs induced cyclic guanylyl monophosphate–dependent vasorelaxation during hypoxia (35±4% at 1% O
2
, 4.7±1.6% at 95% O
2
;
P
<0.05). RBC-induced relaxations during hypoxia correlated with
S
-nitrosohemoglobin (SNO-Hb) (
R
2
=0.88) but not iron nitrosylhemoglobin (HbFeNO) content. Relaxation responses for RBCs were compared with
S
-nitrosoglutathione across a range of O
2
tensions. The fold increases in relaxation evoked by RBCs were significantly greater at 1% and 2% O
2
compared with relaxations induced at 95% (
P
<0.05), consistent with an allosteric mechanism of hypoxic vasodilation. We also measured transpulmonary gradients of NO metabolites in healthy control subjects and in patients with CHF. In CHF patients but not control subjects, levels of SNO-Hb increase from 0.00293±0.00089 to 0.00585±0.00137 mol NO/mol hemoglobin tetramer (
P
=0.005), whereas HbFeNO decreases from 0.00361±0.00109 to 0.00081±0.00040 mol NO/mol hemoglobin tetramer (
P
=0.03) as hemoglobin is oxygenated in the pulmonary circulation. These metabolite gradients correlated with the hemoglobin O
2
saturation gradient (
P
<0.05) and inversely with cardiac index (
P
<0.05) for both CHF patients and control subjects.

Conclusions—

We confirm that RBC-bound NO mediates hypoxic vasodilation in vitro. Transpulmonary gradients of hemoglobin-bound NO are evident in CHF patients and are inversely dependent on cardiac index. Hemoglobin may transport and release NO bioactivity to areas of tissue hypoxia or during increased peripheral oxygen extraction via an allosteric mechanism.
Catheter-Based Cryoablation Permanently Cures Patients With Common Atrial Flutter
Authors: Manusama Randy , Timmermans Carl , Limon Froylan , Philippens Suzanne , Crijns Harry J.G.M. , Rodriguez Luz-Maria
Published: March 2004

Background—

Cryoablation (cryo) has a high success rate in the short-term treatment of atrial flutter (AFL), but evidence of long-term efficacy is lacking. The present study reports the long-term effect of cryo of the cavotricuspid isthmus (CTI) in patients with common AFL.

Methods and Results—

Thirty-five consecutive patients (28 men; mean age, 53 years) underwent cryo of the CTI. In 34 patients, the AFL had a counterclockwise rotation (cycle length, 242±43 ms). Eleven patients had structural heart disease. Cryo was performed with a 10F catheter with a 6-mm-tip electrode (CryoCor). Applications (3 to 5 minutes each) were delivered by use of a point-by-point technique to create the ablation line. The acute end point of the procedure was creation of bidirectional isthmus conduction block and noninducibility of AFL. A median of 14 applications (range, 4 to 30) at 10 sites (range, 4 to 19) was given along the CTI with a mean temperature of −80.0±5.0°C. Mean fluoroscopy and procedure times were 40±26 minutes and 3.2±1.3 hours, respectively. Of the 35 patients, 34 were acutely successfully ablated (97%). After a mean follow-up of 17.6±6.2 months (range, 9.6 to 26.1 months), 31 patients (89%) did not have recurrence of AFL. Three of the 4 patients with recurrence had a second successful procedure. One patient had transient ST elevation in the inferior leads during cryoapplication.

Conclusions—

Cryo produces permanent bidirectional isthmus conduction block of the CTI. Short- and long-term success rates are comparable to those for radiofrequency ablation.
Midterm Benefits of Left Univentricular Pacing in Patients With Congestive Heart Failure
Authors: Blanc Jean-Jacques , Bertault-Valls Valérie , Fatemi Marjaneh , Gilard Martine , Pennec Pierre-Yves , Etienne Yves
Published: March 2004

Background—

Resynchronization therapy by simultaneous pacing of the right and left ventricles has gained wide acceptance as a useful treatment for patients with severe congestive heart failure. Several short-term hemodynamic studies in humans and animals failed to demonstrate any benefit of biventricular pacing over left univentricular pacing, but long-term studies on this pacing mode are lacking. The objective of this study was to assess the outcome over a 1-year period of patients paced exclusively in the left ventricle.

Methods and Results—

Clinical, angiographic, echocardiographic, and ergometric data were collected at baseline and after 12 months in 22 patients (age, 69.3±6.5 years) with NYHA class III or IV (10 patients), sinus rhythm, left bundle-branch block, and no bradycardia indication for pacing. After 12 months, compared with baseline values, NYHA class improved significantly by 40% (
P
<0.0001), 6-minute walk distance by 30% (
P
=0.01), peak V̇
o
2
by 26% (
P
=0.01), left ventricular end-diastolic diameter by 5% (
P
=0.02), ejection fraction by 22% (
P
=0.07), mitral regurgitation area by 40% (
P
=0.01), and norepinephrine level by 37% (
P
=0.04).

Conclusions—

In patients with severe congestive heart failure, sinus rhythm, and left bundle-branch block despite optimal pharmacological treatment, left univentricular pacing is feasible and results in significant midterm benefit in exercise tolerance and left ventricular function.
Progression of Atherosclerosis as Assessed by Carotid Intima-Media Thickness in Patients With HIV Infection
Authors: Hsue Priscilla Y. , Lo Joan C. , Franklin Arlana , Bolger Ann F. , Martin Jeffrey N. , Deeks Steven G. , Waters David D.
Published: March 2004

Background—

HIV-infected patients may be at increased risk for coronary events. The purpose of this study was to identify predictors of carotid intima-media thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1 year.

Methods and Results—

We measured blood lipids, inflammatory markers, and IMT in 148 HIV-infected adults (mean age, 45±8 years) and in 63 age- and sex-matched HIV-uninfected control subjects. The mean duration of HIV infection was 11 years, and the median duration of protease inhibitor treatment was 3.3 years. Mean baseline IMT was 0.91±0.33 mm in HIV patients and 0.74±0.17 mm in control subjects (
P
=0.0001). Multivariable predictors of baseline IMT in HIV patients were age (
P
<0.001), LDL cholesterol (
P
<0.001), cigarette pack-years (
P
=0.005), Latino race (
P
=0.062), and hypertension (
P
=0.074). When the control group was added to the analysis, HIV infection was an independent predictor of IMT (
P
=0.001). The rate of progression among the 121 HIV patients with a repeated IMT measurement at 1 year was 0.074±0.13 mm, compared with −0.006±0.05 mm in 27 control subjects (
P
=0.002). Age (
P
<0.001), Latino race (
P
=0.02), and nadir CD4 count ≤200 (
P
=0.082) were multivariable predictors of IMT progression.

Conclusions—

Carotid IMT is higher in HIV patients than in age-matched control subjects and progresses much more rapidly than previously reported rates in non-HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary risk factors and with nadir CD4 count ≤200, suggesting that immunodeficiency and traditional coronary risk factors may contribute to atherosclerosis.
Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation
Authors: Tsai Chia-Ti , Lai Ling-Ping , Lin Jiunn-Lee , Chiang Fu-Tien , Hwang Juey-Jen , Ritchie Marylyn D. , Moore Jason H. , Hsu Kuan-Lih , Tseng Chuen-Den , Liau Chiau-Suong , Tseng Yung-Zu
Published: March 2004

Background—

The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this.

Methods and Results—

A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls (χ
2
=62.5,
P
=0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (
P
=0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests.

Conclusions—

This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.
Blood Pressure and Risk of Secondary Cardiovascular Events in Women
Authors: Mason Peter J. , Manson JoAnn E. , Sesso Howard D. , Albert Christine M. , Chown Marilyn J. , Cook Nancy R. , Greenland Philip , Ridker Paul M , Glynn Robert J.
Published: March 2004

Background—

In apparently healthy people, the relation between blood pressure and risk of subsequent cardiovascular disease (CVD) is linear. In persons with CVD, the relation is uncertain.

Methods and Results—

We conducted a prospective study of 5218 older women with CVD who reported their blood pressure at baseline in the Women’s Antioxidant Cardiovascular Study (WACS), an ongoing double-blind, placebo-controlled secondary prevention trial of the benefits and risks of antioxidant vitamins, folic acid, vitamin B
6
, and vitamin B
12
among women with CVD or ≥3 coronary risk factors. A total of 661 confirmed CVD events (nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass graft procedure, percutaneous coronary angioplasty, or CVD death) occurred during a median follow-up of 6.5 years. After controlling for age, randomized treatment assignment, antihypertensive medication use, and coronary risk factors, we found that systolic blood pressure (SBP) was a strong predictor of CVD events and that the relation between SBP and CVD risk was positive, continuous, and linear (
P
for linear trend=0.001). For each 10-mm Hg increment in SBP, there was a 9% (95% CI 4% to 15%) increase in risk of secondary CVD events. Diastolic blood pressure, mean arterial pressure, and pulse pressure were weaker predictors of CVD risk in this cohort, and joint consideration of SBP and diastolic blood pressure found that only SBP significantly predicted risk. Use of antihypertensive medication did not modify the relationship of SBP with CVD events.

Conclusions—

In this population of women with CVD, we observed a strong, continuous, and linear association between SBP and risk of secondary CVD events. SBP was the blood pressure measure most strongly related to CVD risk.