bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement in Coronary Flow Reserve Determined by Positron Emission Tomography After 6 Months of Cholesterol-Lowering Therapy in Patients With Early Stages of Coronary Atherosclerosis
Authors: Baller Detlev , Notohamiprodjo Gunawan , Gleichmann Ulrich , Holzinger Jens , Weise Reiner , Lehmann Joachim
Published: June 2012

Background
—Early stages of coronary atherosclerosis are characterized by a mainly functional impairment of coronary vasodilator capacity under the impact of such risk factors as hypercholesterolemia. The goal of this study was to determine whether 6-month cholesterol-lowering therapy improves coronary flow reserve in patients with angina, reduced flow reserve despite minimally diseased coronary vessels or even normal angiogram, and mild to moderately elevated LDL levels on average.

Methods and Results
—We noninvasively investigated 23 consecutive patients (18 men, 5 women; mean age, 56±7.6 years) with a mean LDL level of 165±34 mg/dL at baseline by PET for myocardial blood flow measurement with [
13
N]ammonia at rest and under dipyridamole stress (0.56 mg/kg) before and after lipid-lowering therapy with simvastatin for 6 months. Between baseline and the 6-month follow-up, total cholesterol concentration fell from 241±44 to 168±34 mg/dL, and the LDL level decreased from 165±34 to 95±26 mg/dL (
P
<0.001). Overall, coronary flow reserve increased from 2.2±0.6 to 2.64±0.6 (
P
<0.01). Maximal coronary flow increased significantly from 182±36 to 238±58 mL/min×100 g (
P
<0.001) at follow-up. Minimum coronary resistance declined significantly from 0.51±0.12 to 0.40±0.14 mm Hg · mL
−1
· min×100 g (
P
<0.001). Concomitantly, a regression of anginal symptoms was observed in most patients.

Conclusions
—Our results suggest that cholesterol-lowering therapy with simvastatin may improve overall coronary vasodilator capacity assessed noninvasively by PET in patients with mild to moderate hypercholesterolemia. Consequently, intensive lipid-lowering therapy is considered a vasoprotective treatment for selected patients in very early stages of coronary atherosclerosis with the potential of preventing further disease progression.
Distinct Patterns of Transforming Growth Factor-β Isoform and Receptor Expression in Human Atherosclerotic Lesions
Authors: Bobik Alex , Agrotis Alex , Kanellakis Peter , Dilley Rodney , Krushinsky Anatoly , Smirnov Vladimir , Tararak Eduard , Condron Melanie , Kostolias Gina
Published: June 2012

Background
—Some animal studies suggest that transforming growth factor-β (TGF-β) protects vessels from atherosclerosis by preventing intima formation, but others indicate a role in vessel proteoglycan accumulation and lipoprotein retention. To distinguish between these possibilities in humans, immunohistochemical studies were performed examining the coexpression of TGF-β isoforms and the TGF-β receptors ALK-5 and TβR-II in aorta during the various stages of atherosclerotic lesion development.

Methods and Results
—The spatial relationships between TGF-β
1
, TGF-β
3
, ALK-5, and TβR-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-β
1
, low concentrations of TβR-II, and barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-β isoforms. Smooth muscle cells (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to these high levels. These lesions also contained high, colocalized concentrations of ALK-5 and TβR-II. Despite fibrous plaques containing TGF-β
1
, its receptors were at detection limits. We found no evidence for truncated TβR-II expression in either normal intima or the various atherosclerotic lesions.

Conclusions
—TGF-β appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-β contributes primarily to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle proliferation, and activating proteolytic mechanisms in macrophages.
Angiotensin-Converting Enzyme–Independent Contraction to Angiotensin I in Human Resistance Arteries
Authors: Padmanabhan Neal , Jardine Alan G. , McGrath John C. , Connell John M. C.
Published: June 2012

Background
—In vitro studies of myocardial tissue suggest that angiotensin II (Ang II) may be generated by both ACE and chymase. A similar dual pathway may exist in the vasculature. We studied the effects of ACE and chymase inhibitors on the contractile response to angiotensin I (Ang I) in human resistance arteries to investigate ACE-independent generation of Ang II.

Methods and Results
—Subcutaneous resistance arteries (250 to 350 μm) were obtained from gluteal biopsies from volunteers and New Zealand White rabbits and mounted on a wire myograph. Contractile ability was tested with high-potassium depolarization and norepinephrine 10 μmol/L and endothelial integrity by relaxation to acetylcholine 3 μmol/L. Cumulative concentration-response curves were constructed for Ang I in the presence of enalaprilat 1 μmol/L, chymostatin 10 μmol/L, or both inhibitors together. In the rabbit, enalaprilat completely inhibited the Ang I response. In human vessels, enalaprilat or chymostatin alone had no effect, but the combination of enalaprilat and chymostatin almost completely inhibited the response to Ang I.

Conclusions
—A dual pathway for Ang II generation exists in human resistance arteries, mediated by ACE and a chymostatin-sensitive enzyme, probably chymase. We confirm that a marked species difference exists in the mechanism of Ang II generation between the human and the rabbit. More efficacious suppression of the renin-angiotensin system may require development of novel enzyme inhibitors or combinations of currently available drugs.
Troglitazone Inhibits Voltage-Dependent Calcium Currents in Guinea Pig Cardiac Myocytes
Authors: Nakajima Toshiaki , Iwasawa Kuniaki , Oonuma Hitoshi , Imuta Hiroyuki , Hazama Hisanori , Asano Michiko , Morita Toshihiro , Nakamura Fumitaka , Suzuki Jun-ichi , Suzuki Seiji , Kawakami Yasushi , Omata Masao , Okuda Yukichi
Published: June 2012

Background
—It has been suggested that intracellular Ca
2+
overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca
2+
currents were examined and compared with classic Ca
2+
antagonists (verapamil and nifedipine).

Methods and Results
—Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca
2+
currents consisted of both T-type (
I
Ca,T
) and L-type (
I
Ca,L
) Ca
2+
currents. Troglitazone effectively reduced the amplitude of
I
Ca,L
in a concentration-dependent manner. Troglitazone also suppressed
I
Ca,T
, but the effect of troglitazone on
I
Ca,T
was less potent than that on
I
Ca,L
. The current-voltage relationships for
I
Ca,L
and the reversal potential for
I
Ca,L
were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on
I
Ca,L
measured at a holding potential of −40 mV was 6.3 μmol/L, and 30 μmol/L troglitazone almost completely inhibited
I
Ca,L
. Troglitazone 10 μmol/L did not affect the time courses for inactivation of
I
Ca,L
and inhibited
I
Ca,L
mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced
I
Ca,L
.

Conclusions
—These results demonstrate that troglitazone inhibits voltage-dependent Ca
2+
currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca
2+
overload and subsequent myocardial changes.
Nitric Oxide Synthase Gene Therapy Rapidly Reduces Adhesion Molecule Expression and Inflammatory Cell Infiltration in Carotid Arteries of Cholesterol-Fed Rabbits
Authors: Qian HuSheng , Neplioueva Valentina , Shetty Geetha A. , Channon Keith M. , George Samuel E.
Published: June 2012

Background
—Hypercholesterolemia reduces nitric oxide bioavailability, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration.

Methods and Results
—Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.βGal (recombinant adenoviruses expressing neuronal NO synthase or β-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11–positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad.βGal or sham-treated arteries within 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-treated arteries had >3-fold fewer monocytes than Ad.βGal- or sham-treated arteries.

Conclusions
—NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.
Endomyocardial Nitric Oxide Synthase and Left Ventricular Preload Reserve in Dilated Cardiomyopathy
Authors: Heymes Christophe , Vanderheyden Marc , Bronzwaer Jean G. F. , Shah Ajay M. , Paulus Walter J.
Published: June 2012

Background
—Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. The functional significance of this modified NOS gene expression for left ventricular (LV) contractile performance was investigated in patients with dilated nonischemic cardiomyopathy.

Methods and Results
—In patients with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance were derived from LV microtip pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simultaneously procured LV endomyocardial biopsies (n=20). LV endomyocardial expression of NOS2 was linearly correlated with LV stroke volume (
P
=0.001;
r
=0.66), LV ejection fraction (
P
=0.007;
r
=0.58), and LV stroke work (
P
=0.003;
r
=0.62). In patients with elevated LV end-diastolic pressure (>16 mm Hg), a closer correlation was observed between endomyocardial expression of NOS2 and LV stroke volume (
P
=0.001;
r
=0.74), LV ejection fraction (
P
=0.0007;
r
=0.77), and LV stroke work (
r
=0.82;
P
=0.0002). LV endomyocardial expression of NOS3 was linearly correlated with LV stroke volume (
P
=0.01;
r
=0.53) and LV stroke work (
P
=0.01;
r
=0.52). To establish the role of nitric oxide (NO) as a mediator of the observed correlations, substance P (which causes endothelial release of NO) was infused intracoronarily (n=12). In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P increased LV stroke volume from 72±13 to 91±16 mL (
P
=0.06) and LV stroke work from 67±11 to 90±15 g · m (
P
=0.03) and shifted the LV end-diastolic pressure–volume relation to the right.

Conclusions
—In patients with dilated cardiomyopathy, an increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume relation and a concomitant increase in LV preload reserve.
Characterization of Different Subsets of Atrial Fibrillation in General Practice in France
Authors: Lévy Samuel , Maarek Martine , Coumel Philippe , Guize Louis , Lekieffre Jean , Medvedowsky Jean-Louis , Sebaoun Alain
Published: June 2012

Background
—The clinical presentation and causes of atrial fibrillation (AF) in the 1990s may differ from AF seen 2 to 3 decades ago. It was the objective of this prospective study to characterize various clinical presentations and underlying conditions of patients with AF observed in general practice in France.

Methods and Results
—The study population comprised 756 patients (19 to 95 years of age) with electrocardiographically documented AF subdivided into paroxysmal (<7 days), chronic (last episode >1 month) and recent onset AF(persistent >7 days and<1 month). Symptoms were present in 670 patients (88.6%). The relative prevalences of paroxysmal, chronic, and recent onset AF were 22.1%, 51.4%, and 26.4%, respectively. Cardiac disorders, present in 534 patients (70.6%), included hypertension (39.4%), coronary artery disease (16.6%), and myocardial diseases (15.3%) as the most common. Rheumatic valvular disease represented a common cause in women (25.0%) but not in men (8.0%). The paroxysmal group differed by a high percentage of palpitations (79.0%) and a low percentage of underlying heart disease (53.9%). With a mean follow-up of 8.6±3.7 months, 28 patients (3.7%) died, including 6 fatal cerebrovascular accidents. Among the 728 patients who survived, congestive heart failure occurred in 30 patients (4.1%), and embolic complications occurred in 13 patients (1.8%). In the paroxysmal AF group, 13 patients (8.0%) developed chronic AF and 51 (31.3%) had AF recurrences. At the time of follow-up, 53 patients (14.3%) from the chronic AF group and 108 patients (55.7%) from the recent onset AF group were in sinus rhythm.

Conclusions
—This large-scale study establishes the current demographic profile of out-of-hospital patients with AF and highlights some of the changes that have occurred in the past decades, including a particular shift in cardiac causes toward nonrheumatic AF. This study also demonstrates significant differences between various subsets of AF.
Increased Cardiomyocyte Apoptosis and Changes in Proapoptotic and Antiapoptotic Genes
bax
and
bcl
-2 During Left Ventricular Adaptations to Chronic Pressure Overload in the Rat
Authors: Condorelli Gianluigi , Morisco Carmine , Stassi Giorgio , Notte Antonella , Farina Felicia , Sgaramella Giuseppe , de Rienzo Assunta , Roncarati Roberta , Trimarco Bruno , Lembo Giuseppe
Published: June 2012

Background
—Left ventricular hypertrophy (LVH) represents both an adaptive response to increased cardiac work load and a precursor state of heart failure. Recent evidence linked cardiac myocyte death by apoptosis with LVH and heart failure. It remained unclear, however, whether apoptosis participated in the transition from LVH to left ventricular dysfunction (LVD).

Methods and Results
—Cardiac myocyte apoptotic events and changes in apoptosis-specific genes were studied in a rat model of chronic pressure overload induced by transverse aortic constriction. The changes in left ventricular geometry and function were assessed by echocardiography. Transverse aortic constriction rats progressively developed “concentric” LVH and subsequently, LVD. A similar distribution of LVH and LVD was found 18 weeks after surgery. At this time point, we determined the occurrence of myocyte apoptosis by DNA laddering, in situ DNA TUNEL labeling, and light and electron microscopy. The monitoring of proapoptotic and antiapoptotic genes was determined by Western blot and immunohistochemistry. Our data demonstrated that cardiomyocyte apoptotic events increased from virtually undetectable (in sham-operated controls, SH) to 0.8/10
3
and 1.5/10
3
positive nuclei in LVH and LVD, respectively. Fibrosis also increased in the subendocardial and midwall regions of LVH and LVD rats compared with SH. Expression of the proapoptotic gene
bax
increased, whereas that of antiapoptotic gene
bcl
-2 decreased in LVH and LVD compared with SH.

Conclusions
—These data suggest that in response to chronic pressure overload, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD. LVH and LVD were accompanied by a dramatic cardiomyocyte upregulation of the proapoptotic gene
bax
and reduced
bcl
-2/
bax
ratio, predisposing cardiomyocytes to apoptosis.
PPARα Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells
Authors: Marx Nikolaus , Sukhova Galina K. , Collins Tucker , Libby Peter , Plutzky Jorge
Published: June 2012

Background
—Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation. Peroxisome proliferator–activated receptor-α (PPARα), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPARα expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1).

Methods and Results
—Immunohistochemistry revealed that human carotid artery ECs express PPARα. Pretreatment of cultured human ECs with the PPARα activators fenofibrate or WY14643 inhibited TNF-α–induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPARγ activators. Both PPARα activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life. Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-κB. Finally, PPARα activators significantly reduced adhesion of U937 cells to cultured human ECs.

Conclusions
—Human ECs express PPARα, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARα.
Evidence for a Causal Role of the Renin-Angiotensin System in Nitrate Tolerance
Authors: Kurz Sabine , Hink Ulrich , Nickenig Georg , Borthayre Alain B. , Harrison David G. , Münzel Thomas
Published: June 2012

Background
—We have previously shown that nitroglycerin (NTG) therapy increases vascular expression of endothelin 1 (ET-1) and stimulates vascular superoxide (O
2
·−
) production via activation of NADH/NADPH oxidases. Both phenomena are stimulated by angiotensin II in vitro, and the renin-angiotensin system is activated during early nitrate therapy. We hypothesized that either angiotensin II or ET-1 may increase vascular O
2
·−
production during nitrate therapy.

Methods and Results
—In New Zealand White rabbits, 3 days of treatment with NTG patches increased plasma renin activity for the entire treatment period. After 24 hours of NTG treatment, angiotensin II type 1 (AT
1
) receptor expression and vascular ACE activity were significantly decreased. At this time, constrictions to angiotensin I and II were depressed, but there was no loss of NTG vasodilator potency. Within 3 days of continuous NTG treatment, relaxations to NTG were markedly blunted. This was associated with an increase in AT
1
receptor mRNA expression, a return of ACE activity back to baseline, and a marked increase in constrictions to angiotensin I and II despite continuously increased plasma renin activity. Tolerance was associated with a 2-fold increase in vascular O
2
·−
, as estimated by lucigenin-enhanced chemiluminescence. Concomitant treatment with the AT
1
receptor antagonist losartan (5 to 25 mg · kg
−1
· d
−1
) dose-dependently normalized vascular O
2
·−
and prevented tolerance to NTG and cross-tolerance to endogenous nitric oxide released by acetylcholine. The nonselective ET-1 receptor blocker bosentan (100 mg · kg
−1
· d
−1
) had similar but less pronounced effects.

Conclusions
—The positive effects of AT
1
and ET-1 receptor blockade on tolerance and O
2
·−
production imply a pathophysiological role for angiotensin II and to some extent for ET-1 in the development of nitrate tolerance.
Aggressive Cholesterol Lowering Delays Saphenous Vein Graft Atherosclerosis in Women, the Elderly, and Patients With Associated Risk Factors
Authors: Campeau Lucien , Hunninghake Donald B. , Knatterud Genell L. , White Carl W. , Domanski Michael , Forman Sandra A. , Forrester James S. , Geller Nancy L. , Gobel Fredarick L. , Herd J. Alan , Hoogwerf Byron J. , Rosenberg Yves
Published: June 2012

Background
—The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.
1
Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (
P
<0.001).

Methods and Results
—The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels ≥200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease ≥0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment.

Conclusions
—Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.
Five-Year Outcome in Patients With Isolated Proximal Left Anterior Descending Coronary Artery Stenosis Treated by Angioplasty or Left Internal Mammary Artery Grafting
Authors: Goy Jean-Jacques , Eeckhout Eric , Moret Christel , Burnand Bernard , Vogt Pierre , Stauffer Jean-Chrisophe , Hurni Michel , Stumpe Frank , Ruchat Patrick , von Segesser Ludwig , Urban Philip , Kappenberger Lukas
Published: June 2012

Background
—Percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery (CABG) improve the clinical status of patients with isolated proximal left anterior descending coronary artery stenosis. At 2 years, only additional revascularization was more frequently required after PTCA.

Methods and Results
—We monitored 134 patients randomized to PTCA (n=68) or CABG (n=66) for ≤5 years. End points were death, myocardial infarction, need for additional revascularization, clinical status, and medical treatment. At 5 years, 6 patients (9%) had died in the PTCA group versus 2 (3%) in the CABG group (
P
=0.12). One patient in each group died of a cardiac cause. Myocardial infarction was more frequent after PTCA (15% versus 4%;
P
=0.0001), but Q-wave infarction was not (6% in the PTCA group versus 3% in the CABG group;
P
=0.8). Additional revascularization was required in 38% of patients in the PTCA group versus 9% in the CABG group (
P
=0.0001). Functional status was comparable, with 6% of patients after PTCA and 3% after CABG in functional class III or IV. Finally, after PTCA or CABG, 62% and 91% of patients, respectively, were free of events (
P
=0.0001).

Conclusions
—The 5-year prognosis of patients with isolated proximal left anterior descending coronary artery stenosis is good. Both PTCA and CABG improve clinical status, but revascularization was needed more frequently after PTCA. There is an excess incidence of non–Q-wave myocardial infarction in the PTCA group that does not affect the vital or symptomatic outcome.
Late Results of Percutaneous Mitral Commissurotomy in a Series of 1024 Patients
Authors: Iung Bernard , Garbarz Eric , Michaud Pierre , Helou Steeven , Farah Bruno , Berdah Patricia , Michel Pierre-Louis , Cormier Bertrand , Vahanian Alec
Published: June 2012

Background
—The optimal use of percutaneous mitral commissurotomy (PMC) in a wide range of patients requires accurate evaluation of late results and identification of their predictors.

Methods and Results
—Late results of PMC were assessed in 1024 patients whose mean age was 49±14 years. Echocardiography showed that 141 patients (14%) had pliable valves and mild subvalvular disease, 569 (55%) had extensive subvalvular disease, and 314 (31%) had calcified valves. A single balloon was used in 26 patients, a double balloon in 390, and the Inoue Balloon in 608. Good immediate results were defined as valve area ≥1.5 cm
2
without regurgitation >2/4 (Sellers’ grade) and were obtained in 912 patients. Median duration of follow-up was 49 months. The 10-year actuarial rate of good functional results (survival with no cardiovascular death and no need for surgery or repeat dilatation and in New York Heart Association [NYHA] class I or II) was 56±4% in the entire population. Follow-up echocardiography was available in 90% of the patients who experienced poor functional results after good immediate results and showed restenosis in 97% of these. In multivariate analysis, the predictors of poor functional results were old age (
P
=0.0008), unfavorable valve anatomy (
P
=0.003), high NYHA class (
P
<0.0001), atrial fibrillation (
P
<0.0001), low valve area after PMC (
P
=0.001), high gradient after PMC (
P
<0.0001), and grade 2 mitral regurgitation after PMC (
P
=0.04).

Conclusions
—PMC can be performed with good late results in a variety of patient subsets. Prediction of late events is multifactorial. Knowledge of these predictors can improve patient selection and follow-up.
Urokinase Receptor (uPAR, CD87) Is a Platelet Receptor Important for Kinetics and TNF-Induced Endothelial Adhesion in Mice
Authors: Piguet Pierre Francois , Vesin Christian , Donati Yves , Tacchini-Cottier Fabienne , Belin Dominique , Barazzone Constance
Published: June 2012

Background
—Urokinase plasminogen activator receptor (uPAR, CD87) is a widely distributed 55-kD, glycoprotein I–anchored surface receptor. On binding of its ligand uPA, it is known to increase leukocyte adhesion and traffic. Using genetically deficient mice, we explored the role of uPAR in platelet kinetics and TNF-induced platelet consumption.

Methods and Results
—Anti-uPAR antibody stained platelets from normal (+/+) but not from uPAR
−/−
mice, as seen by fluorescence-activated cell sorter analysis.
51
Cr-labeled platelets from uPAR
−/−
donors survived longer than those from +/+ donors when injected into a +/+ recipient. Intratracheal TNF injection induced thrombocytopenia and a platelet pulmonary localization, pronounced in +/+ but absent in uPAR
−/−
mice. Aprotinin, a plasmin inhibitor, decreased TNF-induced thrombocytopenia. TNF injection markedly reduced the survival and increased the pulmonary localization of
51
Cr-labeled platelets from +/+ but not from uPAR
−/−
donors, indicating that it is the platelet uPAR that is critical for their response to TNF. As seen by electron microscopy, TNF injection increased the number of platelets and polymorphonuclear neutrophils (PMNs) in the alveolar capillaries of +/+ mice, whereas in uPAR
−/−
mice, platelet trapping was insignificant and PMN trapping was slightly reduced. Platelets within alveolar capillaries of TNF-injected mice were activated, as judged from their shape, and this was evident in +/+ but not in uPAR
−/−
mice.

Conclusions
—These results demonstrate for the first time the critical role of platelet uPAR for kinetics as well as for activation and endothelium adhesion associated with inflammation.
Vascular Effects of Estrogen and Cholesterol-Lowering Therapies in Hypercholesterolemic Postmenopausal Women
Authors: Koh Kwang Kon , Cardillo Carmine , Bui Minh N. , Hathaway Londa , Csako Gyorgy , Waclawiw Myron A. , Panza Julio A. , Cannon Richard O.
Published: June 2012

Background
—Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic postmenopausal women.

Methods and Results
—We randomly assigned 28 women to conjugated equine estrogen (CE) 0.625 mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined with CE reduced LDL cholesterol to a greater extent than CE alone (both
P
<0.05). CE alone and combined with simvastatin raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all
P
<0.05). Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all
P
<0.001 versus baseline values) on CE (4.0±2.6% to 10.2±3.9%), simvastatin (4.3±2.4% to 10.0±3.9%), and CE combined with simvastatin (4.6±2.0% to 9.8±2.6%), but similarly among therapies (
P
=0.507 by ANOVA). None of the therapies improved the dilator response to nitroglycerin (all
P
≥0.184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell adhesion molecule E-selectin (all
P
<0.05 versus simvastatin).

Conclusions
—Although estrogen and statin therapies have differing effects on lipoprotein levels, specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they are already on cholesterol-lowering therapy.
Role of Extracellular Signal-Regulated Kinases in Angiotensin II–Stimulated Contraction of Smooth Muscle Cells From Human Resistance Arteries
Authors: Touyz Rhian M. , He Gang , Deng Li-Yuan , Schiffrin Ernesto L.
Published: June 2012

Background
—We assessed the role of extracellular signal–regulated kinases (ERKs) in Ang II–stimulated contraction and associated signaling pathways in vascular smooth muscle cells (VSMCs) from human small arteries.

Methods and Results
—VSMCs derived from resistance arteries (<300 μm in diameter) from subcutaneous gluteal biopsies of healthy subjects (n=8) were used to assess Ang II–stimulated [Ca
2+
]
i
, pH
i
, and contractile responses. [Ca
2+
]
i
and pH
i
were measured with fura 2-
AM
and BCECF-AM, respectively, and contraction was measured photomicroscopically in cells grown on Matrigel matrix. To determine whether tyrosine kinases and ERKs influence Ang II–stimulated responses, cells were pretreated with 10
−5
mol/L tyrphostin A-23 (tyrosine kinase inhibitor) and PD98059 (MEK inhibitor). Ang II–stimulated MEK activity was determined by tyrosine phosphorylation of ERKs. The angiotensin receptor subtypes (AT
1
and AT
2
) were assessed with [Sar
1
,Ile
8
]Ang II (a nonselective subtype antagonist), losartan (a selective AT
1
antagonist), and PD123319 (a selective AT
2
antagonist). Ang II dose-dependently increased [Ca
2+
]
i
(pD
2
=8.4±0.36, E
max
=541±55 nmol/L), pH
i
(pD
2
=9.4±0.29, E
max
=7.19±0.01), and contraction (pD
2
=9.2±0.21, E
max
=36±2.2%). Ang II induced rapid tyrosine phosphorylation of ERKs, which was inhibited by PD98059. Tyrphostin A-23 and PD98059 attenuated (
P
<0.05) Ang II–stimulated second messengers, and PD98059 reduced Ang II–induced contraction by >50%. [Sar
1
,Ile
8
]Ang II and losartan, but not PD123319, blocked Ang II–stimulated responses.

Conclusions
—These data demonstrate that in VSMCs from human peripheral resistance arteries, functional Ang II receptors of the AT
1
subtype are coupled to signaling cascades involving Ca
2+
and pH
i
pathways that are partially dependent on tyrosine kinases and ERKs. ERKs, the signaling cascades characteristically associated with cell growth, may play an important role in Ang II–stimulated contraction of human VSMCs.
Impact of Preoperative Symptoms on Survival After Surgical Correction of Organic Mitral Regurgitation
Authors: Tribouilloy Christophe M. , Enriquez-Sarano Maurice , Schaff Hartzell V. , Orszulak Thomas A. , Bailey Kent R. , Tajik A. Jamil , Frye Robert L.
Published: June 2012

Background
—Surgical correction of mitral regurgitation in patients with no or mild symptoms remains controversial, particularly because the impact of preoperative symptoms on postoperative outcome is unknown.

Methods and Results
—The long-term outcome of 478 patients with organic mitral regurgitation (199 in NYHA functional class I/II and 279 in class III/IV before surgery) operated on between 1984 and 1991 was analyzed. In patients in NYHA class I/II before surgery compared with those in class III/IV, postoperative long-term survival was higher (at 10 years, 76±5% versus 48±4%,
P
<0.0001), with lower operative mortality (0.5% versus 5.4%,
P
=0.003) and better late survival (
P
<0.0001). Comparison of observed and expected survival showed identical curves in patients in class I/II before surgery (
P
=0.18), whereas excess mortality was observed in patients in class III/IV before surgery (
P
<0.0001). Excess mortality associated with severe symptoms was also confirmed in all subgroups (all
P
<0.003) and in multivariate analysis (
P
=0.0036; adjusted hazard ratio [95% CI], 1.81 [1.21 to 2.70]).

Conclusions
—In patients with organic mitral regurgitation, preoperative functional class III/IV symptoms are associated with excess short- and long-term postoperative mortality independently of all baseline characteristics. These data should lead to consideration of surgical correction of severe organic mitral regurgitation when no or minimal symptoms are present in patients at low operative risk, especially if repair is feasible.
Use of an Extended Monitoring Strategy in Patients With Problematic Syncope
Authors: Krahn Andrew D. , Klein George J. , Yee Raymond , Takle-Newhouse Teri , Norris Caro
Published: June 2012

Background
—The conventional investigation of patients who present with syncope involves short-term ECG monitoring or provocative testing with head-up tilt and electrophysiological testing. A symptom-rhythm correlation is often difficult to obtain during spontaneous syncope because of its sporadic, infrequent, and unpredictable nature.

Methods and Results
—We used a prolonged monitoring strategy to determine the cause of syncope in 85 patients (age, 59±18 years; 44 men) with recurrent undiagnosed syncope with an implantable loop recorder capable of cardiac monitoring for up to 18 months. During a mean of 10.5±4.0 months of follow-up, symptoms recurred in 58 patients (68%) 71±79 days (2.3±2.6 months) after implantable loop recorder insertion. An arrhythmia was detected in 42% of patients who recorded a rhythm during recurrent symptoms, with bradycardia present in 18 and tachycardia in 3. Five of the 18 bradycardic patients and 2 additional sinus rhythm patients received a clinical diagnosis of neurally mediated syncope. Patients who experienced presyncope were much less likely to record an arrhythmia during symptoms compared with recurrence of syncope (24% versus 70%,
P
=0.0005). There were no adverse events associated with recurrent symptoms, and there were no sudden deaths. Inability to freeze after an event occurred in 8 patients, and pocket infection occurred in 3.

Conclusions
—The strategy of prolonged monitoring is effective and safe in patients with problematic syncope.
Delayed Treatment of Traumatic Rupture of the Thoracic Aorta With Endoluminal Covered Stent
Authors: Rousseau H. , Soula P. , Perreault P. , Bui B. , d’Othée B. Janne , Massabuau P. , Meites G. , Concina P. , Mazerolles M. , Joffre F. , Otal P.
Published: June 2012

Background
—Stent grafting is emerging as a new treatment for several pathological conditions involving the thoracic aorta. We studied the feasibility and safety of this technique for delayed treatment of ruptures of the aortic isthmus.

Methods and Results
—Nine patients (14 to 76 years old; mean, 37 years; male/female ratio, 8/1) underwent stent grafting of the aortic isthmus in subacute (n=5) or chronic (n=4) aortic traumatic rupture after a motor accident. In subacute ruptures, this treatment was delayed (1 to 8 months; mean, 5.4 months) because of the severity of other associated injuries. Stent grafting was technically successful (defined as complete exclusion of the pseudoaneurysmal sac) in all patients. Short-term fever and biological inflammatory syndrome occurred in 3 patients. Two major complications occurred: in 1 patient, an early occlusion of the left subclavian artery was treated by placement of 2 Palmaz stents. In another patient, an atelectasis related to an increase of preexisting compression of the left main bronchus by the pseudoaneurysmal sac was successfully treated by temporary placement of an endobronchial silicone stent. Mean follow-up was 11.6 months (range, 3 to 21 months). Thrombosis of the pseudoaneurysmal sac was found in all patients.

Conclusions
—In the absence of available extended follow-up about the safety and effectiveness of endovascular grafting, this approach seems to be a viable therapeutic option for traumatic rupture of the aortic isthmus, but appropriately controlled prospective studies are needed before we can recommend its widespread use.
Association of Body Fat Distribution and Cardiovascular Risk Factors in Children and Adolescents
Authors: Daniels Stephen R. , Morrison John A. , Sprecher Dennis L. , Khoury Philip , Kimball Thomas R.
Published: June 2012

Background
—Obesity is associated with increased risk of cardiovascular disease in adults and less favorable cardiovascular risk factor status in children and adolescents. In adults, fat distribution has been shown to be related to lipid and lipoprotein concentrations, blood pressure levels, and left ventricular mass. These relationships have not been extensively studied in young subjects.

Methods and Results
—This was a cross-sectional study of 127 children and adolescents 9 to 17 years of age. Dual-energy x-ray absorptiometry was used to measure total and regional fat mass. The dependent variables were fasting lipid and lipoprotein concentrations, systolic and diastolic blood pressures, and left ventricular mass. There were significant (
P
<0.05) univariate correlations between fat distribution and log triglycerides (
r
=0.27), log HDL cholesterol (
r
=−0.23), systolic blood pressure (
r
=0.26), and left ventricular mass (
r
=0.37). Multiple regression analysis showed that the significant independent correlates for triglycerides and HDL cholesterol were age and fat distribution; for systolic blood pressure, height and fat distribution; and for left ventricular mass, height, race, sex, and fat distribution.

Conclusions
—These results demonstrate that fat distribution is a more important independent correlate of cardiovascular risk factors than percent body fat in children and adolescents. Greater deposition of central fat (an android fat pattern) is associated with less favorable plasma lipid and lipoprotein concentrations, blood pressure, and left ventricular mass.
Cardiac Myocytes Produce Interleukin-6 in Culture and in Viable Border Zone of Reperfused Infarctions
Authors: Gwechenberger Marianne , Mendoza Leonardo H. , Youker Keith A. , Frangogiannis Nikolaos G. , Smith C. Wayne , Michael Lloyd H. , Entman Mark L.
Published: June 2012

Background
—Previous work from our laboratory demonstrated that interleukin (IL)-6 plays a potentially critical role in postreperfusion myocardial injury and is the major cytokine responsible for induction of intracellular adhesion molecule (ICAM)-1 on cardiac myocytes during reperfusion. Myocyte ICAM-1 induction is necessary for neutrophil-associated myocyte injury. We have previously demonstrated the induction of IL-6 in the ischemic myocardium, and the current study addresses the cells of origin of IL-6.

Methods and Results
—In the present study, we combined Northern blot analysis and in situ hybridization to demonstrate IL-6 gene expression in cardiac myocytes. Isolated ventricular myocytes were stimulated with tumor necrosis factor-α, IL-1β, lipopolysaccharide, preischemic lymph, and postischemic lymph. Unstimulated myocytes showed no significant IL-6 mRNA expression. Myocytes stimulated with preischemic lymph showed minimal or no IL-6 mRNA expression, whereas myocytes stimulated with tumor necrosis factor-α, IL-1β, lipopolysaccharide, or postischemic lymph showed a strong IL-6 mRNA induction. Northern blot with ICAM-1 probe revealed ICAM-1 expression under every condition that demonstrated IL-6 induction. We then investigated the expression of IL-6 mRNA in our canine model of ischemia and reperfusion. Cardiac myocytes in the viable border zone of a myocardial infarction exhibited reperfusion-dependent expression of IL-6 mRNA within 1 hour after reperfusion. Mononuclear cells infiltrate the border zone and express IL-6 mRNA.

Conclusions
—Isolated cardiac myocytes produce IL-6 mRNA in response to several cytokines as well as postischemic cardiac lymph. In addition to its production by inflammatory cells, we demonstrate that IL-6 mRNA is induced in myocytes in the viable border zone of a myocardial infarct. The potential roles of IL-6 in cardiac myocytes in an infarct border are discussed.
Inhibition of P-Glycoprotein–Mediated Drug Transport
Authors: Fromm Martin F. , Kim Richard B. , Stein C. Michael , Wilkinson Grant R. , Roden Dan M.
Published: June 2012

Background
—Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein–mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction.

Methods and Results
—First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 μmol/L quinidine inhibited P-glycoprotein–mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in
mdr1a
(−/−) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data showed that quinidine itself is a P-glycoprotein substrate, quinidine doses were reduced in
mdr1a
(−/−) mice to produce plasma concentrations similar to those in wild-type control animals. Quinidine increased plasma digoxin concentrations by 73.0% (
P
=0.05) in wild-type animals, compared with 19.5% (
P
=NS) in
mdr1a
(−/−) mice. Moreover, quinidine increased digoxin brain concentrations by 73.2% (
P
=0.05) in wild-type animals; by contrast, quinidine did not increase digoxin brain concentrations in
mdr1a
(−/−) mice but rather decreased them (−30.7%,
P
<0.01).

Conclusions
—Quinidine and digoxin are both substrates for P-glycoprotein, and quinidine is a potent inhibitor of digoxin transport in vitro. The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein–mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.
Usefulness of Fractional Flow Reserve to Predict Clinical Outcome After Balloon Angioplasty
Authors: Bech G. Jan Willem , Pijls Nico H. J. , De Bruyne Bernard , Peels Kathinka H. , Michels H. Rolf , Bonnier Hans J. R. M. , Koolen Jacques J.
Published: June 2012

Background
—After regular coronary balloon angioplasty, it would be helpful to identify those patients who have a low cardiac event rate. Coronary angiography alone is not sensitive enough for that purpose, but it has been suggested that the combination of optimal angiographic and optimal functional results indicates a low restenosis chance. Pressure-derived myocardial fractional flow reserve (FFR) is an index of the functional severity of the residual epicardial lesion and could be useful for that purpose.

Methods and Results
—In 60 consecutive patients with single-vessel disease, balloon angioplasty was performed by use of a pressure instead of a regular guide wire. Both quantitative coronary angiography (QCA) and measurement of FFR were performed 15 minutes after the procedure. A successful angioplasty result, defined as a residual diameter stenosis (DS) <50%, was achieved in 58 patients. In these patients, DS and FFR, measured 15 minutes after PTCA, were analyzed in relation to clinical outcome. In those 26 patients with both optimal angiographic (residual DS by QCA ≤35%) and optimal functional (FFR ≥0.90) results, event-free survival rates at 6, 12, and 24 months were 92±5%, 92±5%, and 88±6%, respectively, versus 72±8%, 69±8%, and 59±9%, respectively, in the remaining 32 patients in whom the angiographic or functional result or both were suboptimal (
P
=0.047,
P
=0.028, and
P
=0.014, respectively).

Conclusions
—In patients with a residual DS ≤35% and FFR ≥0.90, clinical outcome up to 2 years is excellent. Therefore, there is a complementary value of coronary angiography and coronary pressure measurement in the evaluation of PTCA result.
Endothelial Function in Marfan Syndrome
Authors: Wilson Dirk G. , Bellamy Michael F. , Ramsey Mark W. , Goodfellow Jonathan , Brownlee Moira , Davies Sally , Wilson John F. , Lewis Malcolm J. , Stuart A. Graham
Published: June 2012

Background
—The cardiovascular complications of Marfan syndrome arise due to alterations in the structural and functional properties of fibrillin, a constituent of vascular connective tissues. Fibrillin-containing microfibrils are closely associated with arterial endothelial cells, indicating a possible functional role for fibrillin in the endothelium. Plasma concentrations of endothelial cell products are elevated in Marfan subjects, which indirectly indicates endothelial dysfunction. This study directly assessed flow- and agonist-mediated endothelium-dependent brachial artery reactivity in Marfan subjects.

Methods and Results
—In 20 Marfan and 20 control subjects, brachial artery diameter, blood flow, and blood pressure were measured by ultrasonic wall tracking, Doppler ultrasound, and photoplethysmography, respectively. Measurements were taken during hand hyperemia (a stimulus for endothelium-derived nitric oxide [NO] release in the upstream brachial artery) and after sublingual administration of the endothelium-independent vasodilator nitroglycerin. In 9 Marfan and 6 control subjects, the above parameters were also assessed during intra-arterial infusions of acetylcholine and bradykinin (agonists that stimulate NO production) and
N
G
-monomethyl-
l
-arginine (L-NMMA, an inhibitor of NO production). Flow-mediated responses differed markedly between Marfan and control subjects (−1.6±3.5% versus 6.50±4.1%, respectively;
P
<0.0001), whereas nitroglycerin produced similar vasodilation (14.2±5.7% versus 15.2±7.8%;
P
=NS). Agonist-induced vasodilation to incremental intra-arterial infusions of acetylcholine and bradykinin were not significantly different between Marfan and control subjects, and intra-arterial L-NMMA produced similar reductions in brachial artery diameter in both groups.

Conclusions
—These data demonstrate impaired flow-mediated but preserved agonist-mediated endothelium-dependent vasodilation in Marfan subjects and suggest preservation of basal NO release. Selective loss of flow-mediated dilation suggests a role for fibrillin in endothelial cell mechanotransduction.