bluuebunny/crossref_metadata_2025 huggingface dataset:
Chordal Cutting
Authors: Messas Emmanuel , Guerrero J. Luis , Handschumacher Mark D. , Conrad Chris , Chow Chi-Ming , Sullivan Suzanne , Yoganathan Ajit P. , Levine Robert A.
Published: September 2007

Background

Mitral regurgitation (MR) conveys adverse prognosis in ischemic heart disease. Because such MR is related to increased leaflet tethering by displaced attachments to the papillary muscles (PMs), it is incompletely treated by annular reduction. We therefore addressed the hypothesis that such MR can be reduced by cutting a limited number of critically positioned chordae to the leaflet base that most restrict closure but are not required to prevent prolapse. This was tested in 8 mitral valves: a porcine in vitro pilot with PM displacement and 7 sheep with acute inferobasal infarcts studied in vivo with three-dimensional (3D) echo to quantify MR in relation to 3D valve geometry.

Methods and Results

In all 8 valves, PM displacement restricted leaflet closure, with anterior leaflet angulation at the basal chord insertion, and mild-to-moderate MR. Cutting the 2 central basal chordae reversed this without prolapse. In vivo, MR increased from 0.8±0.2 to 7.1±0.5 mL/beat after infarction and then decreased to 0.9±0.1 mL/beat with chordal cutting (
P
<0.0001); this paralleled changes in the 3D leaflet area required to cover the orifice as dictated by chordal tethering (
r
2
=0.76).

Conclusions

Cutting a minimum number of basal chordae can improve coaptation and reduce ischemic MR. Such an approach also suggests the potential for future minimally invasive implementation.
Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension
Authors: Campbell Andrew I.M. , Zhao Yidan , Sandhu Reena , Stewart Duncan J.
Published: September 2007

Background

Pulmonary arterial hypertension is characterized by increased pulmonary vascular resistance secondary to a decrease in the caliber and number of pulmonary vascular channels. We hypothesized that the targeted overexpression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by preventing the loss of existing vessels or by inducing the development of new blood vessels within the lung.

Methods and Results

We used a cell-based method of gene transfer to the pulmonary microvasculature by delivering syngeneic smooth muscle cells overexpressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 rats in which pulmonary hypertension was induced with the pulmonary endothelial toxin monocrotaline. Four weeks after simultaneous endothelial injury and cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated animals. Four weeks after gene transfer, the plasmid VEGF transcript was still detectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent transgene expression. In addition, delay of cell-based gene transfer until after the development of pulmonary hypertension also resulted in a significant decrease in the progression of RV hypertension and hypertrophy.

Conclusions

These results indicate that cell-based VEGF gene transfer is an effective method of preventing the development and progression of pulmonary hypertension in the monocrotaline model and suggest a potential therapeutic role for angiogenic factors in the therapy of this devastating disease.
Sustained Suppression of Neointimal Proliferation by Sirolimus-Eluting Stents
Authors: Sousa J. Eduardo , Costa Marco A. , Abizaid Alexandre C. , Rensing Benno J. , Abizaid Andrea S. , Tanajura Luiz F. , Kozuma Ken , Van Langenhove Glenn , Sousa Amanda G.M.R. , Falotico Robert , Jaeger Judith , Popma Jeffrey J. , Serruys Patrick W.
Published: September 2007

Background

We have previously reported a virtual absence of neointimal hyperplasia 4 months after implantation of sirolimus-eluting stents. The aim of the present investigation was to determine whether these results are sustained over a period of 1 year.

Methods and Results

Forty-five patients with de novo coronary disease were successfully treated with the implantation of a single sirolimus-eluting Bx VELOCITY stent in São Paulo, Brazil (n=30, 15 fast release [group I, GI] and 15 slow release [GII]) and Rotterdam, The Netherlands (15 slow release, GIII). Angiographic and volumetric intravascular ultrasound (IVUS) follow-up was obtained at 4 and 12 months (GI and GII) and 6 months (GIII). In-stent minimal lumen diameter and percent diameter stenosis remained essentially unchanged in all groups (at 12 months, GI and GII; at 6 months, GIII). Follow-up in-lesion minimal lumen diameter was 2.28 mm (GIII), 2.32 mm (GI), and 2.48 mm (GII). No patient approached the ≥50% diameter stenosis at 1 year by angiography or IVUS assessment, and no edge restenosis was observed. Neointimal hyperplasia, as detected by IVUS, was virtually absent at 6 months (2±5% obstruction volume, GIII) and at 12 months (GI=2±5% and GII=2±3%).

Conclusions

This study demonstrates a sustained suppression of neointimal proliferation by sirolimus-eluting Bx VELOCITY stents 1 year after implantation.
Coronary Thermodilution to Assess Flow Reserve
Authors: De Bruyne Bernard , Pijls Nico H.J. , Smith Leif , Wievegg Maria , Heyndrickx Guy R.
Published: September 2007

Background

Fractional flow reserve (FFR) and coronary flow reserve (CFR) are indices of coronary stenosis severity that provide the clinician with complementary information on the contribution of epicardial arteries and microcirculation to total resistance to myocardial blood flow. At present, FFR and CFR can only be obtained by 2 separate guidewires. The present study tested the validity of the thermodilution principle in assessing CFR with one pressure-temperature sensor-tipped guidewire.

Methods and Results

In an in vitro model, absolute flow was compared with the inverse mean transit time (1/T
mn
) of a thermodilution curve obtained after a bolus injection of 3 mL of saline at room temperature. A very close correlation (
r
>0.95) was found between absolute flow and 1/T
mn
when the sensor was placed ≥6 cm from the injection site. In 6 chronically instrumented dogs (60 stenoses; FFR from 0.19 to 0.98), a significant linear relation was found between flow velocity and 1/T
mn
. A significant correlation was found between CFR
Doppler
, which was calculated from the ratio of hyperemic to resting flow velocities, and CFR
thermo
, which was calculated from the ratio of resting to hyperemic T
mn
(
r
=0.76; SEE=0.24;
P
<0.001).

Conclusion

The present findings demonstrate the validity of the thermodilution principle to assess CFR. Because the pressure-temperature sensor was mounted in a commercially available angioplasty guidewire, this technique permits simultaneous measurements of CFR and FFR.
An Iron-Binding Exochelin Prevents Restenosis Due to Coronary Artery Balloon Injury in a Porcine Model
Authors: Rosenthal Eli A. , Bohlmeyer Teri J. , Monnet Eric , MacPhail Catriona , Robertson Alastair D. , Horwitz Marcus A. , Burchenal J.E.B. , Horwitz Lawrence D.
Published: September 2007

Background

Vascular smooth muscle cell (VSMC) proliferation is a critical factor in the neointima formation that causes restenosis after coronary angioplasty (PTCA). Desferri-exochelin 772SM (D-EXO), a highly diffusible, lipophilic iron chelator secreted by
Mycobacterium tuberculosis
, inhibits proliferation of VSMCs in culture. We hypothesized that treatment with D-EXO would inhibit neointima formation in balloon-injured vessels in vivo.

Methods and Results

We subjected 24 pigs to overstretch coronary artery injury with standard PTCA balloons and then administered intramural injections of either D-EXO (n=14) or vehicle (n=10) through an Infiltrator catheter. Treatments were randomized, and the investigators were blinded with regard to treatment group until data analysis was completed. One month later, we euthanized the pigs, excised the injured coronary segments, made multiple sections of each segment, and identified the site of maximal neointima formation. An injury score based on the degree of disruption of the internal or external elastic lamina or media was assigned. D-EXO reduced stenosis index (neointima area divided by the area within the internal elastic lamina), adjusted for injury score, by 47%. Neointima thickness was also reduced.

Conclusions

D-EXO, injected intramurally, substantially inhibited formation of neointima in a porcine vascular injury model.
Perivascular Inflammation After Balloon Angioplasty of Porcine Coronary Arteries
Authors: Okamoto Ei-ichi , Couse Tracey , De Leon Hector , Vinten-Johansen Jakob , Goodman Richard B. , Scott Neal A. , Wilcox Josiah N.
Published: September 2007

Background

Inflammation has been suggested to play a role in vascular lesion formation after angioplasty. Whereas previous studies have focused on inflammatory reactions in the intima and media, less attention has been paid to adventitial and perivascular responses and their potential role in vascular remodeling.

Methods and Results

Balloon overstretch injury of porcine coronary arteries was performed with standard clinical angioplasty catheters. Vessels were examined from 0.5 hour to 14 days after injury by immunohistochemistry and in situ hybridization (ISH) for neutrophil and macrophage markers, cell adhesion molecules (P-selectin, E-selectin, and vascular cell adhesion molecule-1), and neutrophil-specific CXC chemokines (alveolar macrophage–derived neutrophil chemotactic factor [AMCF]-I/interleukin-8 and AMCF-II). Neutrophils accumulated in the adventitia surrounding the injury site from 2 hours to 3 days, followed by macrophages from 1 to 7 days after angioplasty. Inflammation was associated temporally with the expression of mRNAs encoding cell adhesion molecules and chemokines. The main inflammatory and proliferative foci were not limited to the adventitia but rather extended many millimeters away from the injured vessel throughout the surrounding adipose and myocardial tissues.

Conclusions

Inflammatory responses after angioplasty of porcine coronary arteries occurred throughout the entire perivascular tissue. We hypothesize that perivascular inflammatory cells play a role in the recruitment and/or proliferation of adventitial myofibroblasts, possibly through the release of reactive oxygen species and/or cytokines, and thus contribute to vascular remodeling associated with postangioplasty restenosis.
Benefit of Bilateral Over Single Internal Mammary Artery Grafts for Multiple Coronary Artery Bypass Grafting
Authors: Endo Masahiro , Nishida Hiroshi , Tomizawa Yasuko , Kasanuki Hiroshi
Published: September 2007

Background

The aim of this study was to evaluate the performance of bilateral internal mammary artery (BIMA) grafts in isolated CABG.

Methods and Results

Beginning in April 1985, elective primary multiple CABG for multivessel disease was performed in 1131 patients. The early and late results of 688 patients who received single internal mammary artery (SIMA) grafts and 443 patients who received BIMA grafts were compared (median follow-up, 6.15 years). Hospital mortality was not significantly different in the SIMA (0.9%) and BIMA (0.9%) groups. Graft patency was 97.3% in the BIMA group and 94.3% in the SIMA group (
P
<0.0001). The 7-year repeated CABG–free rate was significantly higher in the BIMA group (
P
=0.026). The 7-year new myocardial infarction–free rate in all patients tended to be higher in the BIMA group (
P
=0.06). The hazard ratio for all death or repeated CABG in patients with ejection fractions >0.4 and age <71 years was lower in the BIMA group (
P
=0.0499).

Conclusions

Our data suggest that the use of BIMA grafts in patients with in situ coronary artery anastomoses achieves a significantly higher repeated CABG–free rate in all patients compared with the use of SIMA.
Influence of Nitric Oxide Synthase and Adrenergic Inhibition on Adenosine-Induced Myocardial Hyperemia
Authors: Buus Niels H. , Bøttcher Morten , Hermansen Flemming , Sander Mikael , Nielsen Torsten T. , Mulvany Michael J.
Published: September 2007

BackgroundMyocardial perfusion during adenosine-induced hyperemia is used both in clinical diagnosis of coronary heart disease and for scientific investigations of the myocardial microcirculation. The objective of this study was to clarify whether adenosine-induced hyperemia is dependent on endothelial NO production or is influenced by adrenergic mechanisms.

Methods and ResultsIn 12 healthy men, myocardial perfusion was measured with PET in 2 protocols performed in random order, each including 3 perfusion measurements. First, perfusion was measured at rest. Second, either saline or the NO synthase inhibitorNG-nitro-l-arginine methyl ester (L-NAME, 4 mg/kg) was infused, and perfusion during adenosine-induced hyperemia was determined. Last, in both protocols, the α-receptor blocker phentolamine was infused, and perfusion during adenosine-induced hyperemia was determined again. Resting perfusion was similar in the 2 protocols (0.69±0.14 and 0.66±0.18 mL · min−1· g−1). L-NAME increased mean arterial blood pressure by 12±7 mm Hg (P<0.01) and reduced heart rate by 16±7 bpm (P<0.01). Adenosine-induced hyperemia (1.90±0.33 mL · min−1· g−1) was attenuated by L-NAME (1.50±0.55 mL · min−1· g−1,P<0.01). The addition of phentolamine had no effect on the adenosine-induced hyperemia (2.10±0.34 mL · min−1· g−1,P=NS). In the presence of L-NAME, however, when the adenosine response was attenuated, phentolamine was able to increase hyperemic perfusion (2.05±0.44 mL · min−1· g−1,P<0.05).

ConclusionsInhibition of endogenous NO synthesis attenuates myocardial perfusion during adenosine-induced hyperemia, indicating that coronary vasodilation by adenosine is partly endothelium dependent. α-Adrenergic blockade has no effect on adenosine-induced hyperemia unless NO synthesis is inhibited.
Quantification of Coronary Artery Lumen Volume by Digital Angiography
Authors: Molloi Sabee , Kassab Ghassan S. , Zhou Yifang
Published: September 2007

Background

Coronary artery lumen volume may potentially have several advantages over the commonly used variables, such as percent stenosis or minimal lumen diameter, in the assessment of coronary artery disease. The goal of this study is to validate a quantitative assessment of lumen volume using a video densitometry technique.

Methods and Results

Coronary arteriography was performed in 9 swine (body weight 20 to 55 kg) after power injection of contrast material (2 mL/s for 3 seconds) into the left main coronary artery. Phase-matched subtracted images were used to quantify regional lumen volume by a video densitometry technique. The in vivo volume measurements were validated by a polymer cast of the coronary arterial tree made at physiological pressure. The measured cast volume (V
C
) and video densitometric regional lumen volume (V
VD
) were related by V
VD
=1.06 V
C
−0.01 mL (
r
=0.99). The root mean square and systematic errors for these measurements were 17% and −3%, respectively.

Conclusions

A video densitometry technique for quantification of coronary lumen volume was validated both in vitro and in vivo in a swine animal model. The present results demonstrated the feasibility and potential utility of the video densitometry technique for accurate measurement of regional lumen volume in vivo. This study contributes to the understanding of the angiographic methods used for the assessment of coronary artery disease and indicates that this technique can potentially be used for quantification of diffuse coronary artery disease during routine coronary arteriography.
Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model
Authors: Taniyama Yoshiaki , Morishita Ryuichi , Hiraoka Kazuya , Aoki Motokuni , Nakagami Hironori , Yamasaki Keita , Matsumoto Kunio , Nakamura Toshikazu , Kaneda Yasufumi , Ogihara Toshio
Published: September 2007

Background

Because no study has documented the angiogenic properties of hepatocyte growth factor (HGF) in a diabetes model, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease in diabetes.

Methods and Results

Because intramuscular injection of luciferase plasmid by the hemagglutinating virus of Japan (HVJ)–liposome method had much higher efficiency than injection of naked plasmid, we used the HVJ-liposome method to transfect the human HGF gene into the rat diabetic hindlimb model. As expected, transfection of human HGF vector resulted in a significant increase in blood flow as assessed by laser Doppler imaging and capillary density, even in the diabetes model, accompanied by the detection of human HGF protein. Interestingly, the degree of natural recovery of blood flow was significantly greater in nondiabetic rats than in diabetic rats. Thus, in an in vitro culture system, we further studied the molecular mechanisms of how diabetes delayed angiogenesis. Importantly, high–
d
-glucose treatment of endothelial cells resulted in a significant decrease in matrix metalloproteinase (MMP)-1 protein and ets-1 expression in human aortic endothelial cells. Similarly, high
d
-glucose significantly decreased mRNA and protein of HGF in endothelial cells. Downregulation of MMP-1 and ets-1 by high
d
-glucose might be due to a significant decrease in HGF, because HGF stimulated MMP-1 production and activated ets-1.

Conclusions

Overall, intramuscular injection of human HGF plasmid induced therapeutic angiogenesis in a rat diabetic ischemic hindlimb model as a potential therapy for peripheral arterial disease. The delay of angiogenesis in diabetes might be due to downregulation of MMP-1 and ets-1 through a decrease in HGF by high
d
-glucose.
Oral Anticoagulation Thresholds
Authors: Brummel Kathleen E. , Paradis Sara G. , Branda Richard F. , Mann Kenneth G.
Published: September 2007

Background

Monitoring patients on oral anticoagulation is essential to prevent hemorrhage and recurrent thrombosis. We studied tissue factor–induced whole-blood coagulation in patients on warfarin therapy with similar international normalized ratios (INRs).

Methods and Results

Contact pathway–suppressed whole-blood coagulation initiated with tissue factor was studied in 8 male subjects (group W) and in 1 individual multiple times (subject A). Coagulation profiles for group W showed that subjects with similar INRs had widely varying clot times (6.2 to 23 minutes) and thrombin–antithrombin III (TAT) profiles with rates of 25 to 40 nmol · L
−1
· min
−1
and maximum levels varying from 192 to 349 nmol/L. The normal control group exhibited clot times of 5.7±0.3 minutes and TAT rates of 57±13 nmol · L
−1
· min
−1
, reaching maximum levels of 742±91 nmol/L. Subject A, who was stably anticoagulated at an INR of 2.1±0.4 for 6 months, had widely ranging profiles with clot times of 9.0 to 22.7 minutes, TAT maximums varying from 141 to 345 nmol/L, and TAT formation rates of 10 to 57 nmol · L
−1
· min
−1
. INR did not correlate with TAT formation. Platelet activation was decreased by anticoagulants but also displayed variability. Fibrinopeptide A generation showed threshold variability independent of the INR. Factor VIII levels were increased (
P
=0.03) in group W (204±34.4%) compared with normal control subjects (149.4±37.4%). A significant correlation was identified between increasing factor VIII levels and years on warfarin therapy (
r
=0.78,
P
=0.01), suggesting a possible factor VIII compensatory mechanism.

Conclusions

These results suggest that control of anticoagulation in patients to a set INR therapeutic range may be less secure than anticipated. Patients with similar INRs show significant individual variability in their tissue factor coagulation response, suggesting different risks to anticoagulation when confronted with underlying vascular anomalies.
Soluble CD40L and Cardiovascular Risk in Women
Authors: Schönbeck Uwe , Varo Nerea , Libby Peter , Buring Julie , Ridker Paul M.
Published: September 2007

Background

The immune-signaling dyad CD40/CD40L promotes atherogenesis, and patients with unstable angina have elevated plasma levels of soluble CD40L (sCD40L) and membrane-bound CD40L. It is unknown, however, whether elevations of circulating sCD40L precede the onset of acute cardiovascular symptoms.

Methods and Results

In a prospective, nested case-control evaluation of healthy middle-aged women, mean concentrations of sCD40L at baseline were significantly higher among 130 participants who subsequently developed myocardial infarction, stroke, or cardiovascular death (cases), compared with 130 age- and smoking-matched women who remained free of cardiovascular disease (controls) during a 4-year follow-up (2.86 ng/mL for cases versus 2.09 ng/mL for controls;
P
=0.02). Women with concentrations above the 95th percentile of the control distribution (>3.71 ng/mL) had a significantly increased relative risk (RR) of developing future cardiovascular events (RR, 3.3; 95% CI, 1.2 to 8.6;
P
=0.01) that remained after adjustment for usual cardiovascular risk factors (multivariate RR, 2.8; 95% CI, 0.9 to 8.0;
P
=0.05).

Conclusions

High plasma concentrations of sCD40L may be associated with increased vascular risk in apparently healthy women.
Heart Rate–Independent Vagal Effect on End-Systolic Elastance of the Canine Left Ventricle Under Various Levels of Sympathetic Tone
Authors: Nakayama Yasunori , Miyano Hiroshi , Shishido Toshiaki , Inagaki Masashi , Kawada Toru , Sugimachi Masaru , Sunagawa Kenji
Published: September 2007

Background

Although we have shown that in rabbits the direct (heart rate [HR]–independent) vagal effect on left ventricular end-systolic elastance (E
es
) was negligible under minimal sympathetic tone, how underlying sympathetic tone modulates the inotropic response to vagal stimulation remains unknown.

Methods and Results

We used an isolated canine heart preparation with functioning autonomic nerves. We examined the direct vagal inotropic effect by measuring E
es
under fixed-rate atrial pacing with or without concomitant sympathetic nerve stimulation. Right and left vagal stimulation at 20 Hz decreased HR by 27±3% and 14±2%, respectively, and decreased E
es
by 11±2% and 6±2%, respectively. When we fixed HR by atrial pacing, right and left vagal stimulation at 20 Hz did not decrease E
es
(0.01±0.3% and 0.3±0.4%; NS). Concomitant left sympathetic nerve stimulation at 4 Hz enhanced direct vagal negative inotropism to −19±3% and −34±5% for 20-Hz right and left vagal stimulation (interaction,
P
<0.01).

Conclusions

Direct vagal negative inotropism was unobservable with minimal sympathetic tone in dogs but was enhanced with concomitant sympathetic stimulation.
Differential Regulation of Mitogen-Activated Protein Kinases in the Failing Human Heart in Response to Mechanical Unloading
Authors: Flesch Markus , Margulies Kenneth B. , Mochmann Hans-Christian , Engel David , Sivasubramanian Natarajan , Mann Douglas L.
Published: September 2007

Background

Mechanical unloading of the heart with a left ventricular assist device (LVAD) leads to favorable changes in the biology of the failing cardiac myocyte. To determine a potential mechanism for these improvements, we examined the regulation of mitogen-activated protein kinases (MAPKs) in the failing heart in the presence and absence of LVAD support.

Methods and Results

We examined the degree of activation (ie, phosphorylation) of p44/42 extracellularly regulated kinase, p38 kinase, and c-Jun N-terminal kinase (JNK1/2), and the corresponding activity levels of these MAPKs in myocardial samples obtained from 11 patients with LVAD support and in 11 patients without LVAD support. MAPK activity was also examined in an additional 6 patients from whom paired samples were obtained before and after LVAD support. The activity of p44/42 and JNK1/2 were reduced significantly, whereas p38 activity levels were significantly increased after LVAD support. We examined functional parameters that are linked to MAPK activation, namely cardiac myocyte hypertrophy and apoptosis. Both cardiac myocyte cell size and the incidence of cardiac myocyte apoptosis were significantly reduced after LVAD support.

Conclusions

Mechanical unloading of the failing heart leads to differential regulation of MAPKs. These changes in MAPK activity are associated with changes in myocyte hypertrophy and viability, suggesting a potential mechanistic basis for some of the observed salutary changes after LVAD support.
Cardiovascular Thrombotic Events in Controlled, Clinical Trials of Rofecoxib
Authors: Konstam Marvin A. , Weir Matthew R. , Reicin Alise , Shapiro Deborah , Sperling Rhoda S. , Barr Eliav , Gertz Barry J.
Published: September 2007

BackgroundIn comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs.

Methods and ResultsCV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists’ Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen.

ConclusionsThis analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.
Expression of the Chemokine Receptor CXCR3 and Its Ligand IP-10 During Human Cardiac Allograft Rejection
Authors: Melter Michael , Exeni Andrea , Reinders Marlies E.J. , Fang James C. , McMahon Gearoid , Ganz Peter , Hancock Wayne W. , Briscoe David M.
Published: September 2007

BackgroundChemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of their expression or function after human cardiac transplantation.

Methods and ResultsWe analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3+T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-sectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3+T-cell infiltration. In particular, the expression of CXCR3 was temporally and spatially associated with CD3+T-cell infiltrates and correlated with the histopathological diagnosis of acute rejection (OR, 11.73 and 4.05, respectively;P<0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsies developed intimal thickening by intravascular ultrasound. In these patients, there was a trend for persistent expression of CD3- and CXCR3-expressing infiltrates in the later part of the first posttransplant year. The chemokines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were examined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, Mig, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43;P=0.01).

ConclusionsThe presence of CXCR3+T cells and the CXCR3 ligand IP-10 within endomyocardial biopsies is strongly associated with acute rejection. The CXCR3–IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.
Homocysteine Impairs the Nitric Oxide Synthase Pathway
Authors: Stühlinger Markus C. , Tsao Philip S. , Her Jeng-Horng , Kimoto Masumi , Balint Robert F. , Cooke John P.
Published: September 2007

Background

Hyperhomocysteinemia is a putative risk factor for cardiovascular disease, which also impairs endothelium-dependent vasodilatation. A number of other risk factors for cardiovascular disease may exert their adverse vascular effects in part by elevating plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Accordingly, we determined if homocysteine could increase ADMA levels.

Methods and Results

When endothelial or nonvascular cells were exposed to DL-homocysteine or to its precursor L-methionine, ADMA concentration in the cell culture medium increased in a dose- and time-dependent fashion. This effect was associated with the reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Furthermore, homocysteine-induced accumulation of ADMA was associated with reduced nitric oxide synthesis by endothelial cells and segments of pig aorta. The antioxidant pyrrollidine dithiocarbamate preserved DDAH activity and reduced ADMA accumulation. Moreover, homocysteine dose-dependently reduced the activity of recombinant human DDAH in a cell free system, an effect that was due to a direct interaction between homocysteine and DDAH.

Conclusion

Homocysteine post-translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium-mediated nitric oxide–dependent vasodilatation.
Atrial Electroanatomic Remodeling After Circumferential Radiofrequency Pulmonary Vein Ablation
Authors: Pappone Carlo , Oreto Giuseppe , Rosanio Salvatore , Vicedomini Gabriele , Tocchi Monica , Gugliotta Filippo , Salvati Adriano , Dicandia Cosimo , Calabrò Maria Pia , Mazzone Patrizio , Ficarra Eleonora , Di Gioia Claudio , Gulletta Simone , Nardi Stefano , Santinelli Vincenzo , Benussi Stefano , Alfieri Ottavio
Published: September 2007

Background

Circumferential radiofrequency ablation around pulmonary vein (PV) ostia has recently been described as a new anatomic approach for atrial fibrillation (AF).

Methods and Results

We treated 251 consecutive patients with paroxysmal (n=179) or permanent (n=72) AF. Circular PV lesions were deployed transseptally during sinus rhythm (n=124) or AF (n=127) using 3D electroanatomic guidance. Procedures lasted 148±26 minutes. Among 980 lesions surrounding individual PVs (n=956) or 2 ipsilateral veins with close openings or common ostium (n=24), 75% were defined as complete by a bipolar electrogram amplitude <0.1 mV inside the lesion and a delay >30 ms across the line. The amount of low-voltage encircled area was 3594±449 mm
2
, which accounted for 23±9% of the total left atrial (LA) map surface. Major complications (cardiac tamponade) occurred in 2 patients (0.8%). No PV stenoses were detected by transesophageal echocardiography. After 10.4±4.5 months, 152 patients with paroxysmal AF (85%) and 49 with permanent AF (68%) were AF-free. Patients with and without AF recurrence did not differ in age, AF duration, prevalence of heart disease, or ejection fraction, but the LA diameter was significantly higher (
P
<0.001) in permanent AF patients with recurrence. The proportion of PVs with complete lesions was similar between patients with and without recurrence, but the latter had larger low-voltage encircled areas after radiofrequency (expressed as percent of LA surface area;
P
<0.001).

Conclusions

Circumferential PV ablation is a safe and effective treatment for AF. Its success is likely due to both PV trigger isolation and electroanatomic remodeling of the area encompassing the PV ostia.
Vascular Hypertrophy and Increased P70S6 Kinase in Mice Lacking the Angiotensin II AT2Receptor
Authors: Brede Marc , Hadamek Kerstin , Meinel Lorenz , Wiesmann Frank , Peters Jörg , Engelhardt Stefan , Simm Andreas , Haase Axel , Lohse Martin J. , Hein Lutz
Published: September 2007

BackgroundAngiotensin II activates 2 distinct G protein–coupled receptors, the AT1and AT2receptors. Most of the known cardiovascular effects of angiotensin II are mediated by the AT1receptor subtype. The aim of the present study was to test whether deletion of the AT2receptor gene in mice (AT2-KO mice) leads to long-term functional or structural alterations in the cardiovascular system.

Methods and ResultsIn vivo pressure responses to angiotensin II or the α1-adrenergic receptor agonist phenylephrine were greatly enhanced in AT2-KO mice. Deletion of the angiotensin AT2receptor did not lead to a compensatory increase of the activity of the circulating renin-angiotensin system, and arterial blood pressure was identical in wild-type control mice (WT) and AT2-KO mice. Cardiac contractility as assessed by LV catheterization and by rapid MRI also did not differ between AT2-KO and WT mice. Isolated femoral arteries from AT2-KO mice, however, showed enhanced vasoconstriction to angiotensin II, norepinephrine, and K+depolarization compared with WT. Morphometric analysis of large and small femoral arteries revealed a significant hypertrophy of media smooth muscle cells. Phospho-P70S6 kinase levels were significantly increased in aortas from AT2-KO mice compared with WT mice. Treatment of mice with an ACE inhibitor for 8 weeks abolished the increased pressure responsiveness, vascular hypertrophy, and enhanced P70S6 kinase phosphorylation in AT2-KO mice.

ConclusionsThese results indicate that vascular AT2receptors inhibit the activity and, hence, hypertrophic signaling by the P70S6 kinase in vivo and thus are important regulators of vascular structure and function.
Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury
Authors: Wu Lan , Iwai Masaru , Nakagami Hironori , Li Zhen , Chen Rui , Suzuki Jun , Akishita Masahiro , de Gasparo Marc , Horiuchi Masatsugu
Published: September 2007

BackgroundTo investigate the effect of angiotensin (Ang) II type 1 receptor (AT1) blocker on vascular remodeling and explore the possibility of the involvement of Ang II type 2 receptor (AT2) stimulation in this process, we examined the effects of the selective AT1blocker valsartan on the vascular injury in wild-type (Agtr2+) and AT2-null (Agtr2−) mice.

Methods and ResultsNeointima formation and the proliferation of vascular smooth muscle cells (VSMCs) induced by cuff placement on the femoral artery were greater in Agtr2− mice than those in Agtr2+ mice. Treatment of mice with valsartan at a dose of 1 mg · kg−1· d−1, which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs, whereas the valsartan was less effective in Agtr2− mice. Moreover, cuff placement increased the expression of monocyte chemoattractant protein-1 (MCP-1); inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β; and infiltration of CD45-positive leukocytes and macrophages in the injured arteries and further enhanced them in Agtr2− mice, suggesting the antagonistic effects of AT1and AT2for vascular inflammation. Valsartan attenuated the expression of MCP-1, TNF-α, IL-6, IL-1β, and infiltration of leukocytes and macrophages in the injured arteries; however, these effects of valsartan were less prominent in Agtr2− mice.

ConclusionsThese results suggest that the stimulation of the AT2receptor after AT1blockade is important in the improvement of the inflammatory vascular injury.
Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition
Authors: Kingston Paul A. , Sinha Sanjay , David Anne , Castro Maria G. , Lowenstein Pedro R. , Heagerty Anthony M.
Published: September 2007

Background

Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-β1 (TGF-β1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-β1 on luminal loss after PTCA.

Methods and Results

Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-β type II receptor (Ad5-RIIs), an adenovirus expressing β-galactosidase (Ad5-
lacZ
), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs–injected arteries (1.71±0.12 mm
2
) than in the Ad5-
lacZ
(1.33±0.13 mm
2
) or vehicle-only (1.08±0.17 mm
2
;
P
=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (
P
=0.013) and external (
P
=0.031) elastic laminae in Ad5-RIIs–treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-
lacZ
and vehicle-only groups (
P
=0.004).

Conclusions

Adenovirus-mediated antagonism of TGF-β1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-β1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy–mediated antagonism of TGF-β1 as prophylactic therapy for restenosis.
Dispatcher-Assisted Cardiopulmonary Resuscitation and Survival in Cardiac Arrest
Authors: Rea Thomas D. , Eisenberg Mickey S. , Culley Linda L. , Becker Linda
Published: September 2007

Background—

Early cardiopulmonary resuscitation (CPR) improves survival in out-of-hospital cardiac arrest, and dispatcher-delivered instruction in CPR can increase the proportion of arrest victims who receive bystander CPR before emergency medical service (EMS) arrival. However, little is known about the survival effectiveness of dispatcher-delivered telephone CPR instruction.

Methods and Results

We evaluated a population-based cohort of EMS-attended adult cardiac arrests (n=7265) from 1983 through 2000 in King County, Washington, to assess the association between survival to hospital discharge and 3 distinct CPR groups: no bystander CPR before EMS arrival (no bystander CPR), bystander CPR before EMS arrival requiring dispatcher instruction (dispatcher-assisted bystander CPR), and bystander CPR before EMS arrival not requiring dispatcher instruction (bystander CPR without dispatcher assistance). In this cohort, 44.1% received no bystander CPR before EMS arrival, 25.7% received dispatcher-assisted bystander CPR, and 30.2% received bystander CPR without dispatcher assistance. Overall survival was 15.3%. Using no bystander CPR as the reference group, the multivariate adjusted odds ratio of survival was 1.45 (95% confidence interval [CI], 1.21, 1.73) for dispatcher-assisted bystander CPR and 1.69 (95% CI, 1.42, 2.01) for bystander CPR without dispatcher assistance.

Conclusion

Dispatcher-assisted bystander CPR seems to increase survival in cardiac arrest.
Global Burden of Cardiovascular Diseases
Authors: Yusuf Salim , Reddy Srinath , Ôunpuu Stephanie , Anand Sonia
Published: September 2007

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiologic transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.
Global Burden of Cardiovascular Diseases
Authors: Yusuf Salim , Reddy Srinath , Ôunpuu Stephanie , Anand Sonia
Published: September 2007

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiological transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.
Decrease in Coronary Blood Flow Reserve During Hyperlipidemia Is Secondary to an Increase in Blood Viscosity
Authors: Rim Se-Joong , Leong-Poi Howard , Lindner Jonathan R. , Wei Kevin , Fisher Nicholas G. , Kaul Sanjiv
Published: September 2007

Background

During maximal hyperemia, capillaries provide the greatest resistance to flow. A major determinant of capillary resistance is viscosity. We, therefore, hypothesized that abnormal coronary blood flow (CBF) reserve observed during hyperlipidemia is secondary to increased blood viscosity and not abnormal coronary vasomotion.

Methods and Results

Maximal hyperemia was induced in 9 dogs using adenosine. Serum triglyceride levels were increased by incremental doses of Intralipid. A good correlation was noted between serum triglyceride levels and blood viscosity (
r
=0.82). Neither total coronary blood volume nor myocardial blood volume changed with increasing serum triglyceride levels, indicating lack of vasomotion. Myocardial vascular resistance (MVR) increased with increasing triglyceride levels (
r
=0.84), while hyperemic myocardial blood flow (MBF) decreased (
r
=−0.64). The decrease in hyperemic MBF was associated with a decrease in blood velocity (
r
=−0.56). These findings were confirmed with direct intravital microscopic observations in the mice cremaster muscle.

Conclusions

Increasing lipid levels in a fully dilated normal coronary bed causes no change in large or small vessel dimensions. Instead, the increase in blood viscosity causes capillary resistance to rise, which attenuates hyperemic CBF. Therefore, the abnormal CBF reserve associated with hyperlipidemia is due to increase blood viscosity and not abnormal vascular function.
Ventricular Arrhythmia Vulnerability in Cardiomyopathic Mice With Homozygous Mutant Myosin-Binding Protein C Gene
Authors: Berul Charles I. , McConnell Bradley K. , Wakimoto Hiroko , Moskowitz Ivan P.G. , Maguire Colin T. , Semsarian Christopher , Vargas Marcel M. , Gehrmann Josef , Seidman Christine E. , Seidman Jonathan G.
Published: September 2007

Background

Homozygous mutant mice expressing a truncated form of myosin-binding protein C (MyBP-C
t/t
) develop severe dilated cardiomyopathy, whereas the heterozygous mutation (MyBP-C
t/+
) causes mild hypertrophic cardiomyopathy. Adult male MyBP-C
t/t
and MyBP-C
t/+
mice were evaluated for arrhythmia vulnerability with an in vivo electrophysiology study.

Methods and Results

Surface ECGs were obtained for heart rate, rhythm, and conduction intervals. Atrial, atrioventricular, and ventricular conduction parameters and refractoriness were assessed in 22 MyBP-C
t/t
, 10 MyBP-C
t/+
, and 17 wild-type MyBP-C
+/+
mice with endocardial pacing and intracardiac electrogram recording. Arrhythmia induction was attempted with standardized programmed stimulation at baseline and with isoproterenol. Heart rate variability and ambient arrhythmia activity were assessed with telemetric ECG monitors. Quantitative histological characterization was performed on serial sections of excised hearts. MyBP-C
t/t
and MyBP-C
t/+
mice have normal ECG intervals and sinus node, atrial, and ventricular conduction and refractoriness. Ventricular tachycardia was reproducibly inducible in 14 of 22 MyBP-C
t/t
mice (64%) during programmed stimulation, compared with 2 of 10 MyBP-C
t/+
mice (20%) and 0 of 17 wild-type controls (
P
<0.001). Ventricular ectopy was present only in MyBP-C
t/t
mice during ambulatory ECG recordings. There were no differences in heart rate variability parameters. Interstitial fibrosis correlated with genotype but did not predict arrhythmia susceptibility within the MyBP-C
t/t
group.

Conclusions

MyBP-C
t/t
mice, despite prominent histopathology and ventricular dysfunction, exhibit normal conduction and refractoriness, yet are vulnerable to ventricular arrhythmias. Somatic influences between genetically identical mutant mice most likely account for variability in arrhythmia susceptibility. A sarcomeric protein gene mutation leads to a dilated cardiomyopathy and ventricular arrhythmia vulnerability phenotype.
Adenovirus-Mediated Heme Oxygenase-1 Gene Delivery Inhibits Injury-Induced Vascular Neointima Formation
Authors: Tulis David A. , Durante William , Liu XiaoMing , Evans Alida J. , Peyton Kelly J. , Schafer Andrew I.
Published: September 2007

BackgroundRecent studies have demonstrated that systemic pharmacological induction of heme oxygenase-1 (HO-1), the inducible isoform of the initial and rate-limiting enzyme for heme catabolism, attenuates neointima formation after experimental vascular injury. We have now investigated the ability of localized adenovirus-mediated HO-1 (Ad-HO-1) gene delivery to modify arterial remodeling after balloon angioplasty.

Methods and ResultsTwo weeks after balloon angioplasty in the rat carotid artery, elevated HO-1 protein was observed in the Ad-HO-1 arteries compared with those exposed to empty adenovirus (Ad-E) or to PBS. The arteries exposed to Ad-HO-1 exhibited significantly reduced neointimal area, medial wall area, neointimal area/medial wall area ratio, and neointimal thickness compared with arteries exposed to Ad-E. The Ad-E vessels showed subtle reductions in each morphometric parameter compared with PBS vessels. In a separate group of animals, concomitant treatment of Ad-HO-1 with the HO-1 inhibitor tin protoporphyrin completely restored each morphometric parameter to control levels. Arteries exposed to Ad-HO-1 demonstrated significantly increased TUNEL labeling of apoptotic nuclei and significantly decreased PCNA labeling of DNA synthesis in the medial wall 48 hours after injury.

ConclusionsThese results indicate that HO-1 represents an important in vivo vasoprotective mediator that is capable of attenuating the pathophysiological remodeling response to endovascular injury and suggest that HO-1 may be a novel target for the treatment of vascular disease.