bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell Therapy Attenuates Deleterious Ventricular Remodeling and Improves Cardiac Performance After Myocardial Infarction
Authors: Jain Mohit , DerSimonian Harout , Brenner Daniel A. , Ngoy Soeun , Teller Paige , Edge Albert S. B. , Zawadzka Agatha , Wetzel Kristie , Sawyer Douglas B. , Colucci Wilson S. , Apstein Carl S. , Liao Ronglih
Published: June 2012

Background
—Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. We examined whether supplementing infarcted myocardium with skeletal myoblasts would (1) result in viable myoblast implants, (2) attenuate deleterious remodeling, and (3) enhance in vivo and ex vivo contractile performance.

Methods and Results
—Experimental MI was induced by 1-hour coronary ligation followed by reperfusion in adult male Lewis rats. One week after MI, 10
6
myoblasts were injected directly into the infarct region. Three groups of animals were studied at 3 and 6 weeks after cell therapy: noninfarcted control (control), MI plus sham injection (MI), and MI plus cell injection (MI+cell). In vivo cardiac function was assessed by maximum exercise capacity testing and ex vivo function was determined by pressure-volume curves obtained from isolated, red cell–perfused, balloon–in–left ventricle (LV) hearts. MI and MI+cell hearts had indistinguishable infarct sizes of ≈30% of the LV. At 3 and 6 weeks after cell therapy, 92% (13 of 14) of MI+cell hearts showed evidence of myoblast graft survival. MI+cell hearts exhibited attenuation of global ventricular dilation and reduced septum–to–free wall diameter compared with MI hearts not receiving cell therapy. Furthermore, cell therapy improved both post-MI in vivo exercise capacity and ex vivo LV systolic pressures.

Conclusions
—Implanted skeletal myoblasts form viable grafts in infarcted myocardium, resulting in enhanced post-MI exercise capacity and contractile function and attenuated ventricular dilation. These data illustrate that syngeneic myoblast implantation after MI improves both in vivo and ex vivo indexes of global ventricular dysfunction and deleterious remodeling and suggests that cellular implantation may be beneficial after MI.
State of Complementary and Alternative Medicine in Cardiovascular, Lung, and Blood Research
Authors: Lin Michael C. , Nahin Richard , Gershwin M. Eric , Longhurst John C. , Wu Kenneth K.
Published: June 2012

Abstract
—The National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine recently cosponsored a workshop on the use of complementary and alternative medicine (CAM) in cardiovascular, lung, and blood research. In view of the increasing use of CAM by the general public, it is imperative to promote credible research by the established biomedical community. The goal of this workshop was to enhance the exchange of information and ideas between alternative medicine practitioners and scientists in cardiovascular, lung, and blood research and to foster collaborative research among these researchers. The workshop focused on 5 areas of research, including a historical and cultural perspective of CAM, methodological issues in clinical trials, herbal medicine, chelation therapy, mind/body (meditation) therapy, and acupuncture. CAM has become widely used without rigorously proven efficacy and safety. To protect the public, it was recommended that the fundamental mechanistic research for these CAM approaches be vigorously pursued and that any large-scale clinical trial be carefully executed to avoid any waste of resources and any unnecessary risk. It was felt that standardization of botanical products and procedure-based CAM intervention, such as acupuncture and meditation, is essential for meaningful basic and clinical research. Although botanical products properly consumed are perceived as generally safe, potential herb-drug interactions are a major safety concern. Clearly, many challenges need to be addressed by the scientific community before the public can be assured of the proper use of CAM.
Impact of Peri-Stent Remodeling on Restenosis
Authors: Nakamura Mamoo , Yock Paul G. , Bonneau Heidi N. , Kitamura Katsuhiro , Aizawa Tadanori , Tamai Hideo , Fitzgerald Peter J. , Honda Yasuhiro
Published: June 2012

Background
—Vessel remodeling is an important mechanism of late lumen loss after nonstent coronary interventions. However, its impact on in-stent restenosis has not been systematically investigated.

Methods and Results
—Serial volumetric intravascular ultrasound analyses (poststent and follow-up) were performed in 55 lesions treated with a balloon-expandable stent (ACS MultiLink) using standard stent deployment techniques. The vessel volume (VV), lumen volume (LV), and volume bordered by the stent (SV) were measured using Simpson’s method. The volume of plaque and neointima outside the stent (peri-stent volume, PSV) and volume of neointima within the stent (intrastent volume) were also measured. The change of each parameter during the follow-up period (follow-up minus poststent) was calculated and then divided by SV to normalize these values (designated as percent change [%Δ]). As expected, %ΔPSV directly correlated with %ΔVV (
P
<0.0001,
r
=0.935), with no significant ΔSV. A highly significant inverse correlation was seen between %ΔPSV and the percent change of intrastent volume (
P
<0.0001,
r
=0.517). Consequently, %ΔLV significantly correlated with peri-stent remodeling, as measured by %ΔVV (
P
<0.0001,
r
=0.602).

Conclusion
—Positive remodeling of the vessel exterior to a coronary stent occurs to a variable degree after stent implantation. There is a distinct trade-off between positive remodeling and in-stent hyperplasia: in segments in which the degree of peri-stent remodeling is less, intrastent neointimal proliferation is greater and accompanied by more significant late lumen loss.
Metabolic Abnormalities Characteristic of Dysmetabolic Syndrome Predict the Development of Transplant Coronary Artery Disease
Authors: Valantine Hannah , Rickenbacker Peter , Kemna Mariska , Hunt Sharon , Chen Y.-D. Ida , Reaven Gerald , Stinson Edward B.
Published: June 2012

Background
—This study examines the hypothesis that metabolic abnormalities of dysmetabolic syndrome are risk factors for transplant coronary artery disease (TxCAD).

Methods and Results
—Sixty-six patients without overt diabetes, 2 to 4 years after surgery, underwent intracoronary ultrasound (ICUS), measurement of plasma glucose and insulin after oral glucose (75 g), and fasting lipid and lipoproteins. TxCAD incidence by angiography or autopsy was prospectively determined during subsequent follow-up (8 years). Coronary artery intimal thickness (IT) and subsequent outcomes were compared in patients stratified as having “high” versus “low” plasma glucose (>8.9 mmol/L) and insulin (>760 pmol/L) 2 hours after glucose challenge; and “abnormal” versus “normal” fasting lipid and lipoprotein concentrations as defined by the National Cholesterol Education Program. Patients with high glucose or insulin concentrations had greater IT: 0.38±0.05 versus 0.22±0.02 mm,
P
≤0.05, and 0.39±0.05 versus 0.20±0.02 mm,
P
≤0.01, respectively. Freedom from TxCAD was 56±11% versus 81±6% (
P
<0.01) in patients with high versus low glucose and 57±10% versus 82±7% (
P
<0.05) in patients with high versus low insulin. Actuarial survival was 60±12% versus 92±5% (
P
<0.005) in patients with high versus low glucose and 72±9% versus 88±6% (
P
<0.05) in patients with high versus low insulin. Triglycerides and VLDL were higher and HDL was lower in patients with IT >0.3 mm than with IT ≤0.3 mm. TxCAD incidence was higher in patients with high plasma TG and VLDL and low HDL.

Conclusions
—These data suggest that insulin resistance plays a role in TxCAD.
Atrial Reentrant Tachycardia After Surgery for Congenital Heart Disease
Authors: Paul Thomas , Windhagen-Mahnert Britta , Kriebel Thomas , Bertram Harald , Kaulitz Renate , Korte Thomas , Niehaus Michael , Tebbenjohanns Jürgen
Published: June 2012

Background
—The purpose of the present study was to determine the role of a novel, noncontact mapping system for assessing a variety of atrial reentrant tachycardias (ART) in patients after the surgical correction of congenital heart disease.

Methods and Results
—In 14 patients, an electrophysiological study using the Ensite 3000 system was performed to assess ARTs resistant to medical treatment. Sixteen different forms of ART were inducible in the 14 patients studied. The reentrant circuit of all ARTs could be characterized and localized with respect to anatomic landmarks such as atriotomy scars, intraatrial patches/baffles, and cardiac structures. In 15 of the 16 ARTs (in 13 of the 14 patients), a target area of the reentrant circuit for radiofrequency current application (ie, an area of conduction between 2 anatomical obstacles such as surgical barriers and cardiac structures of electrical isolation) could be localized within the systemic venous atrium. Nine patients exhibited macroreentry, and 4 showed microreentry. In 12 patients, ART could be terminated by creating linear radiofrequency current lesions (75°C, 180 to 390 s). Completeness of linear lesions after radiofrequency current delivery was proven by analyzing color-coded isopotential maps of atrial activation while applying atrial pacing techniques. The mean duration of the procedures was 286 minutes (range, 130 to 435 minutes); fluoroscopy time ranged from 7 to 33.8 minutes (mean, 17.4 minutes).

Conclusions
—In patients with ART after the surgical correction of congenital heart disease, the use of the noncontact mapping system allows for characterization of the tachycardia and guidance for effective radiofrequency current delivery.
Acute Effects of Continuous Positive Airway Pressure on Cardiac Sympathetic Tone in Congestive Heart Failure
Authors: Kaye David M. , Mansfield Darren , Aggarwal Ann , Naughton Matthew T. , Esler Murray D.
Published: June 2012

Background
—Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and β-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood.

Methods and Results
—In the present study, we examined the effect of short-term CPAP (10 cm H
2
O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8±0.3 to 4.4±0.2 L/min;
P
<0.05) and a significant reduction in cardiac norepinephrine spillover (370±58 to 299±55 pmol/min;
P
<0.05), although total systemic norepinephrine spillover was unchanged.

Conclusion
—The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.
Paradoxical Increase in Microvascular Resistance During Tachycardia Downstream From a Severe Stenosis in Patients With Coronary Artery Disease
Authors: Sambuceti Gianmario , Marzilli Mario , Fedele Silvio , Marini Cecilia , L’Abbate Antonio
Published: June 2012

Background
—The pathophysiology of microvascular response to a severe coronary stenosis has not been conclusively identified. The aim of this study was to characterize the human vasomotor response to pacing-induced ischemia of both the stenotic arterial segment and the distal microcirculation.

Methods and Results
—Sixteen patients with stable angina and single-vessel disease were studied. Blood flow velocity and transstenotic pressure gradient were monitored at baseline, after intracoronary adenosine (2 mg), and during ischemia induced by atrial pacing with and without adenosine. At the end of this protocol, the study was repeated after intracoronary phentolamine in 7 patients and after angioplasty in 9. Stenosis resistance was calculated as the ratio between mean pressure gradient and mean flow, and microvascular resistance as the ratio between mean distal pressure and mean flow; values were expressed as percent of baseline. Adenosine decreased (
P
<0.05) baseline microvascular resistance to 52±17%, but not stenosis resistance. Pacing increased both stenosis and microvascular resistances (244±96% and 164±60% of baseline, respectively,
P
<0.05). Addition of adenosine to pacing decreased both stenosis (143±96% of baseline,
P
<0.05 versus ischemia) and microvascular (51±17% of baseline,
P
<0.05 versus baseline and ischemia) resistances. Phentolamine did not affect coronary resistance at any step of the protocol. Angioplasty and stenting restored a progressive decline in microvascular resistance during pacing (51±19% of baseline,
P
<0.05 versus baseline).

Conclusions
—In patients with coronary artery disease, tachycardia-induced ischemia was associated with elevated resistance of both the stenotic segment and the microvasculature. Revascularization prevents this paradoxical behavior.
l
-Arginine and
S
-Nitrosoglutathione Reduce Embolization in Humans
Authors: Kaposzta Zoltan , Baskerville Paul A. , Madge David , Fraser Simon , Martin John F. , Markus Hugh S.
Published: June 2012

Background
—
l
-Arginine reduces platelet aggregation and adhesion in ex vivo studies, but there is no evidence as yet that it has a therapeutic effect on clinical end points. Doppler ultrasound can detect cerebral emboli noninvasively. Such embolic signals are common after carotid endarterectomy, and their frequency predicts risk of stroke recurrence. We used this situation to determine the antiplatelet efficacy of
l
-arginine and
S
-nitrosoglutathione (GSNO), a physiological nitric oxide donor with possible platelet specificity.

Methods and Results
—Patients undergoing carotid endarterectomy were randomized in a double-blind manner between
l
-arginine (n=14), GSNO (n=14), or placebo (n=14) administered intravenously for 90 minutes, starting 30 minutes after skin closure. All patients were pretreated with aspirin and given heparin during surgery. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 4 hours after surgery, beginning 30 minutes after skin closure, and also at 6 and 24 hours. There were highly significant reductions in the number of Doppler embolic signals in the
l
-arginine and GSNO groups; first 4 hours, median (range) number of embolic signals, placebo 44.7 (6 to 778),
l
-arginine 9.5 (0 to 225), and GSNO 0.8 (0 to 8), both
P
<0.001 versus control values. The reduction in the signals persisted at the 24-hour recording.

Conclusions
—Intravenous
l
-arginine and GSNO attenuate Doppler embolic signals in humans. Modulation of the NO system with these agents may have applications in the treatment of thromboembolic disease. This study demonstrates the potential application of ultrasonic embolic signal detection to examine the efficacy of new antiplatelet agents in relatively small numbers of patients.
Low-Energy Laser Irradiation Reduces Formation of Scar Tissue After Myocardial Infarction in Rats and Dogs
Authors: Oron Uri , Yaakobi Tali , Oron Amir , Mordechovitz Daniel , Shofti Rona , Hayam Gal , Dror Uzi , Gepstein Lior , Wolf Tamir , Haudenschild Christian , Haim Shlomo Ben
Published: June 2012

Background
—Low-energy laser irradiation (LELI) has been found to attenuate various biological processes in tissue culture and experimental animal models. The aim of the present study was to investigate the effect of LELI on the formation of scar tissue in experimentally induced chronic infarct in rats and dogs.

Methods and Results
—Myocardial infarction (MI) was induced in 50 dogs and 26 rats by ligation of the left anterior descending coronary artery. After induction of MI, the laser-irradiated (LI) group received laser irradiation (infrared laser, 803-nm wavelength) epicardially. Control MI-induced non–laser irradiated (NLI) dogs were sham-operated, and laser was not applied. All dogs were euthanized at 5 to 6 weeks after MI. Infarct size was determined by TTC staining and histology. The laser treatment (
P
<0.05) lowered mortality significantly, from 30% to 6.5%, after induction of MI. The infarct size in the LI dogs was reduced significantly (
P
<0.0001) (52%) compared with NLI dogs. Histological observation of the infarct revealed a typical scar tissue in NLI dogs and cellularity in most of the LI dogs. Only 14±3% of the mitochondria in the cardiomyocytes in the ischemic zone (4 hours after MI) of LI MI-induced rats were severely damaged, compared with 36±1% in NLI rats. Accordingly, ATP content in that zone was 7.6-fold (significantly) higher in LI than in NLI rats.

Conclusions
—Our observations indicate that epicardial LELI of rat and dog hearts after chronic MI caused a marked reduction in infarct size, probably due to a cardioprotective effect of the LELI.
β
3
-Integrin–Deficient Mice but Not P-Selectin–Deficient Mice Develop Intimal Hyperplasia After Vascular Injury
Authors: Smyth Susan S. , Reis Ernane D. , Zhang Wen , Fallon John T. , Gordon Ronald E. , Coller Barry S.
Published: June 2012

Background
—Intimal hyperplasia contributes to restenosis after percutaneous vascular interventions. Both β
3
-integrins, α
V
β
3
and α
IIb
β
3
(glycoprotein IIb/IIIa), and leukocytes have been implicated in neointimal formation, based in part on the results obtained using antagonists to 1 or both receptors in animal models.

Methods and Results
—The responses in wild-type mice, β
3
-integrin–deficient mice, and P-selectin–deficient mice were studied in a model of transluminal endothelial injury of the femoral artery. At 4 weeks, β
3
-integrin–deficient mice were not protected from developing intimal hyperplasia, whereas P-selectin–deficient mice were protected. Within 1 hour of injury, several layers of platelets deposited on the arteries of wild-type mice and a single layer of platelets deposited on the vessels of β
3
-integrin–deficient mice; in both cases, leukocytes were recruited to the platelet layer. In P-selectin–deficient mice, the platelet layer was less compact and extended further into the lumen but did not recruit leukocytes.

Conclusions
—In a model of transluminal arterial injury, absence of early leukocyte recruitment and not deficiency of β
3
-integrins correlated with a reduction in neointimal formation. Blockade of P-selectins may be an effective therapeutic strategy to decrease restenosis after percutaneous vascular interventions.
Percutaneous In Situ Coronary Venous Arterialization
Authors: Oesterle Stephen N. , Reifart Nicolaus , Hauptmann Eugen , Hayase Motoya , Yeung Alan C.
Published: June 2012

Abstract
—Diffuse coronary artery disease is frequently untreatable by coronary artery bypass or angioplasty. Many such “no-option” patients have been subjects for trials of angiogenesis using growth factor manipulation or laser injury. We think these novel revascularization strategies are limited by insufficient inflow to putative areas of new microvasculature and thus seek a more mechanical solution. We report the use of a catheter-based system for arterializing the adjacent anterior cardiac vein in a patient with chronic total occlusion of the left anterior descending coronary artery. A composite catheter system (phased-array ultrasound imaging system mounted on a catheter with extendable nitinol needle) was used to deliver an exchange-length intracoronary guidewire from the proximal left anterior descending coronary artery into the parallel anterior interventricular vein. Using standard angioplasty techniques, a fistula was then constructed from the proximal artery to the coronary vein using a self-expanding connector. The proximal vein was blocked with a novel self-expanding “blocker,” thus precluding “steal” through the coronary sinus and forcing retroperfusion of the anterior wall. The procedure was completed without complication, and a follow-up angiogram at 3 months confirmed continued patency of the arteriovenous connection. This patient, who had severe angina before the procedure, has been asymptomatic for 12 months. Percutaneous in situ venous arterialization may be an effective therapy for diffuse, “untreatable” coronary disease by supplying a robust inflow of arterialized blood via retroperfusion to severely ischemic myocardium.
Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E–Deficient Mice
Authors: Scalia Rosario , Gooszen Michael E. , Jones Steven P. , Hoffmeyer Michaela , Rimmer David M. , Trocha Steven D. , Huang Paul L. , Smith Melanie B. , Lefer Allan M. , Lefer David J.
Published: June 2012

Background
—Simvastatin attenuates ischemia and reperfusion in normocholesterolemic animals by stabilizing endothelial nitric oxide synthase activity and inhibiting neutrophil-mediated injury. Because endothelial dysfunction is a detrimental effect of hypercholesterolemia, we examined whether short-term treatment with simvastatin could inhibit leukocyte-endothelium interaction and attenuate myocardial ischemia-reperfusion injury in apoE-deficient (apoE
–/–
) mice fed a high-cholesterol diet.

Methods and Results
—We studied leukocyte-endothelium interactions in apoE
–/–
mice fed a normal or a high-cholesterol diet after short-term (ie, 18 hours) simvastatin treatment. We also studied simvastatin treatment in myocardial ischemia-reperfusion injury by subjecting apoE
–/–
mice to 30 minutes of ischemia and 24 hours of reperfusion. ApoE
–/–
mice fed a high-cholesterol diet exhibited higher blood cholesterol levels, which were not affected by short-term simvastatin treatment. However, the increased leukocyte rolling and adherence that occurred in cholesterol-fed apoE
–/–
mice (
P
<0.001 versus control diet) were significantly attenuated by simvastatin treatment (
P
<0.01 versus vehicle). Cholesterol-fed apoE
–/–
mice subjected to myocardial ischemia-reperfusion also experienced increased myocardial necrosis (
P
<0.01 versus control diet), which was significantly attenuated by simvastatin (
P
<0.01 versus vehicle). Simvastatin therapy also significantly increased vascular nitric oxide production in apoE
–/–
mice.

Conclusions
—Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.
Acyl-CoA:Cholesterol Acyltransferase Inhibition Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Kusunoki Jun , Hansoty Dipal K. , Aragane Katsumi , Fallon John T. , Badimon Juan J. , Fisher Edward A.
Published: June 2012

Background
—Acyl-CoA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters. The form of ACAT in macrophages, ACAT1, contributes to foam cell formation in the arterial wall and the development of atherosclerosis. Recent studies in a mouse model of atherosclerosis (the apolipoprotein E [apoE]–deficient mouse), however, have suggested that complete deficiency of ACAT1 activity is not antiatherogenic, in part because of toxicity resulting from adverse effects on tissue cholesterol homeostasis. We have tested whether partial inhibition of ACAT1 and ACAT2 (expressed in liver and intestine) activities reduces atherosclerosis development in apoE-deficient mice and avoids toxicity.

Methods and Results
—ApoE-deficient mice were maintained for 17 weeks on a Western-type diet without (control) or with the ACAT inhibitor F-1394 (effective against ACAT1 and ACAT2) at doses of either 300 (low) or 900 (high) mg/kg. Intimal lesion area at the aortic sinus in controls was 0.69±0.06 mm
2
. F-1394 treatment significantly decreased lesional area by 39% (low) or 45% (high). F-1394 treatment also reduced lesional immunostaining for macrophages by 61% (low) or 83% (high).
En face
analysis showed that surface lipid staining in control aortas was 20.0±2.8%; F-1394 treatment reduced this by 46% (low) or 62% (high). There were no obvious signs of systemic or vessel wall toxicity associated with F-1394 treatment.

Conclusions
—Partial ACAT inhibition by F-1394 had antiatherogenic effects in apoE-deficient mice that were achieved without obvious toxicity. Partial ACAT inhibition may have therapeutic potential in the clinical treatment of atherosclerosis.
Left-to-Right Gradient of Atrial Frequencies During Acute Atrial Fibrillation in the Isolated Sheep Heart
Authors: Mansour Moussa , Mandapati Ravi , Berenfeld Omer , Chen Jay , Samie Faramarz H. , Jalife José
Published: June 2012

Background
—Recent studies demonstrated spatiotemporal organization in atrial fibrillation (AF). We hypothesized that waves emanating from sources in the left atrium (LA) undergo fragmentation, resulting in left-to-right frequency gradient. Our objective was to characterize impulse propagation across Bachmann’s bundle (BB) and the inferoposterior pathway (IPP) during AF.

Methods and Results
—In 13 Langendorff-perfused sheep hearts, AF was induced in the presence of acetylcholine (ACh). Fast Fourier transform of optical and bipolar electrode recordings was performed. Frequency-dependent changes in the left-to-right dominant frequency (DF) gradient were studied by perfusing D600 (2 μmol/L) and by increasing ACh concentration from 0.2 to 0.5 μmol/L. BB and IPP were subsequently ablated. At baseline, a left-to-right decrease in DFs occurred along BB and IPP, resulting in an LA–right atrium (RA) frequency gradient of 5.7±1.4 Hz. Left-to-right impulse propagation was present in 81±5% and 80±10% of cases along BB and IPP, respectively. D600 decreased the highest LA frequency from 19.7±4.4 to 16.2±3.9 Hz (
P
<0.01) and raised RA DF from 8.6±2.0 to 10.7±1.8 Hz (
P
<0.05). An increase in ACh concentration increased the LA-RA frequency gradient from 4.9±1.8 to 8.9±1.8 Hz (
P
<0.05). Ablation of BB and IPP decreased RA DF from 10.9±1.2 to 9.0±1.5 Hz (
P
<0.01) without affecting LA DF (16.8±1.5 versus 16.9±1.8 Hz,
P
=NS).

Conclusions
—Left-to-right impulse propagation and frequency-dependent changes in the LA-RA frequency gradient during AF strongly support the hypothesis that this arrhythmia is the result of high-frequency periodic sources in the LA, with fibrillatory conduction away from such sources.
Assessment of Global Atrial Fibrillation Organization to Optimize Timing of Atrial Defibrillation
Authors: Everett Thomas H. , Moorman J. Randall , Kok Lai-Chow , Akar Joseph G. , Haines David E.
Published: June 2012

Background
—We hypothesized that frequency domain analysis of a wide bipolar interatrial electrogram describes the global organization of atrial fibrillation (AF) and should vary over time. By timing shocks to periods of high organization of AF, cardioversion efficacy should improve.

Methods and Results
—A total of 15 dogs (weight, 28.2±3.4 kg) were rapidly paced for 48 to 72 hours to induce AF. Coil electrodes with a surface area of 1.80 cm
2
were then placed in the left and right atria to form a wide bipole. Wide bipolar electrograms were digitally filtered, and a fast Fourier transform was performed over a sliding 2-s window every 0.5 s. The organization index (OI) was calculated as the ratio of the area of the dominant peak and its harmonics to the total area of the magnitude spectrum. The atrial defibrillation threshold (ADFT
50
) was determined using a 3-ms/3-ms biphasic shock and an up-down-up protocol. Additional shocks with higher and lower energies were delivered in a random sequence to develop a distribution curve. The OI varied over time, with a mean of 0.42±0.03, a maximum of 0.65±0.07, and a minimum of 0.20±0.06. The OI changed rapidly, with durations of high organization (OI>0.5) ranging from 1 to 5 s. The ADFT
50
for QRS complex–synchronized shocks was 183±56 V, versus 142±49 V for shocks synchronized to an OI>0.5 (
P
<0.001). The distribution curve shifted leftward when shocks were synchronized to an OI>0.5.

Conclusions
—AF signals show a high degree of variability. Shock efficacy is increased when shocks are delivered during periods of high AF organization as determined by the OI method.
Atypical Right Atrial Flutter Patterns
Authors: Yang Yanfei , Cheng Jie , Bochoeyer Andy , Hamdan Mohamed H. , Kowal Robert C. , Page Richard , Lee Randall J. , Steiner Paul R. , Saxon Leslie A. , Lesh Michael D. , Modin Gunnard W. , Scheinman Melvin M.
Published: June 2012

Background
—The purpose of our study was to define the incidence and mechanisms of atypical right atrial flutter.

Methods and Results
—A total of 28 (8%) of 372 consecutive patients with atrial flutter (AFL) had 36 episodes of sustained atypical right AFL. Among 24 (67%) of 36 episodes of lower loop reentry (LLR), 13 (54%) of 24 episodes had early breakthrough at the lower lateral tricuspid annulus, whereas 11 (46%) of 24 episodes had early breakthrough at the high lateral tricuspid annulus, and 9 (38%) of 24 episodes showed multiple annular breaks. Bidirectional isthmus block resulted in elimination of LLR. A pattern of posterior breakthrough from the eustachian ridge to the septum was observed in 4 (14%) of 28 patients. Upper loop reentry was observed in 8 (22%) of 36 episodes and was defined as showing a clockwise orientation with early annular break and wave-front collision over the isthmus. Two patients had atypical right AFL around low voltage areas (“scars”) in the posterolateral right atrium.

Conclusions
—Atypical right AFL is most commonly associated with an isthmus-dependent mechanism (ie, LLR or subeustachian isthmus breaks). Non–isthmus-dependent circuits include upper loop reentry or scar-related circuits.
Superiority of Clopidogrel Versus Aspirin in Patients With Prior Cardiac Surgery
Authors: Bhatt Deepak L. , Chew Derek P. , Hirsch Alan T. , Ringleb Peter A. , Hacke Werner , Topol Eric J.
Published: June 2012

Background
—After coronary artery bypass surgery, patients have a high cumulative rate of graft closure and recurrent ischemic events. We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin, the accepted standard, in these patients.

Methods and Results
—The event rates for all-cause mortality, vascular death, myocardial infarction, stroke, and rehospitalization were determined for the 1480 patients with a history of cardiac surgery randomized to either clopidogrel or aspirin in a trial of 19 185 patients. The event rate per year of vascular death, myocardial infarction, stroke, or rehospitalization was 22.3% in the 705 patients randomized to aspirin and 15.9% in the 775 patients randomized to clopidogrel (
P
=0.001). A risk reduction was also seen in each of the individual end points examined, including a 42.8% relative risk reduction in vascular death in patients on clopidogrel versus aspirin (
P
=0.030). In a multivariate model incorporating baseline clinical characteristics, clopidogrel therapy was independently associated with a decrease in vascular death, myocardial infarction, stroke, or rehospitalization in patients with a history of cardiac surgery, with a 31.2% relative risk reduction (95% CI, 15.8 to 43.8;
P
=0.0003). Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) population, multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit (
P
=0.015).

Conclusion
—Compared with aspirin, clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery, along with a decreased risk of bleeding.
Estradiol Accelerates Reendothelialization in Mouse Carotid Artery Through Estrogen Receptor-α but Not Estrogen Receptor-β
Authors: Brouchet L. , Krust A. , Dupont S. , Chambon P. , Bayard F. , Arnal J. F.
Published: June 2012

Background
—The atheroprotective effect of 17β-estradiol (E
2
) has been suggested in women and clearly demonstrated in animals through both an effect on lipid metabolism and a direct effect on the cells of the arterial wall. It has been shown, for example, that E
2
promotes endothelium-dependent relaxation and accelerates reendothelialization in rats. Similar studies have been undertaken in mice to appreciate the molecular mechanism of this process.

Methods and Results
—We report here a model of electric carotid injury adapted from that described by Carmeliet et al (1997) that allows us to precisely evaluate the reendothelialization process. We demonstrate that E
2
accelerates endothelial regeneration in castrated female wild-type mice. In ovariectomized transgenic mice in which either the estrogen receptor (ER)-α or ERβ gene has been disrupted, E
2
accelerated reendothelialization in female ERβ knockout mice, whereas this effect was abolished in female ERα knockout mice.

Conclusions
—This study demonstrates that ERα but not ERβ mediates the beneficial effect of E
2
on reendothelialization and potentially the prevention of atherosclerosis.
Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats
Authors: Wassmann Sven , Bäumer Anselm T. , Strehlow Kerstin , van Eickels Martin , Grohé Christian , Ahlbory Katja , Rösen Renate , Böhm Michael , Nickenig Georg
Published: June 2012

Background
—Postmenopausal estrogen deficiency is associated with an increased cardiovascular risk, hypertension, and oxidative stress. Angiotensin type 1 (AT
1
) receptor regulation is involved in the pathogenesis of atherosclerosis. To characterize vascular function, oxidative stress, and AT
1
receptor regulation during estrogen deficiency, ovariectomized spontaneously hypertensive rats (SHR) were investigated in comparison with sham-operated animals and with ovariectomized rats receiving estrogen replacement therapy with 17β-estradiol.

Methods and Results
—Arterial blood pressure was similar in all 3 groups investigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Estrogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vascular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. Estrogen substitution normalized the production of free radicals in the vessel wall. Vascular AT
1
receptor expression was significantly upregulated by estrogen deficiency, as shown by quantitative reverse transcription–polymerase chain reaction, whereas endothelial NO synthase mRNA expression and NO release were unchanged. Five-week treatment of the animals with the AT
1
receptor antagonist irbesartan prevented endothelial dysfunction in ovariectomized rats and normalized the vascular production of free radicals.

Conclusions
—In SHR, estrogen deficiency leads to increased vascular free radical production and enhanced angiotensin II–induced vasoconstriction via increased vascular AT
1
receptor expression, resulting in endothelial dysfunction. Estrogen replacement therapy and AT
1
receptor antagonism prevent these pathological changes. Therefore, estrogen deficiency–induced AT
1
receptor overexpression and oxidative stress may play an important role in cardiovascular diseases associated with menopause.
Cardiac Memory in Canine Atrium
Authors: Herweg Bengt , Chang Fang , Chandra Parag , Danilo Peter , Rosen Michael R.
Published: June 2012

Background
—Memory is a diverse biological phenomenon whose importance in the ventricle has been demonstrated. We hypothesized its occurrence in the atrium, contributing to the modulation of cardiac rhythm.

Methods and Results
—We analyzed P and Ta waves in conscious chronically instrumented dogs with complete heart block. Animals were atrioventricularly sequentially paced at 5% greater than the sinus rate from the lateral right atrium (RA) during control, followed by 2 periods of 1-hour test pacing at 50% greater than the sinus rate, or by equivalent test pacing from the left atrial appendage (LAA) at 5% or 50% greater than the sinus rate. Recovery RA pacing periods of 20- and 30-minute duration, respectively, succeeded each test pacing period. RA test pacing at either rate did not affect the variables measured, but changing the pacing site from RA to LAA altered the P and Ta waves. Displacement of the spatial atrial gradient vector occurred during recovery from LAA pacing, was more marked at rapid pacing rates, and manifested accumulation and resolution consistent with cardiac memory. Concurrently, the right effective refractory period decreased.

Conclusions
—Memory is demonstrable in canine atrium, showing rapid onset, accumulation during successive pacing periods, and resolution on cessation of pacing. Given its association with a reduced effective refractory period, it may contribute to the substrate for atrial arrhythmias.
Cocaine Use and the Likelihood of Nonfatal Myocardial Infarction and Stroke
Authors: Qureshi Adnan I. , Suri M. Fareed K. , Guterman Lee R. , Hopkins L. Nelson
Published: June 2012

Background
—Numerous case series have implicated cocaine use as a cause of both myocardial infarction (MI) and stroke on the basis of the temporal relationship between drug use and event onset. Increasing cocaine use in the US population, especially in younger individuals, mandates a more extensive investigation of this relationship.

Methods and Results
—We determined the association of cocaine use with self-reported physician diagnosis of MI or stroke in a nationally representative sample of 10 085 US adults aged 18 to 45 years who participated in the Third National Health and Nutrition Examination Survey. A total of 46 nonfatal MIs and 33 nonfatal strokes were reported. After adjusting for differences in age, sex, race/ethnicity, education, hypertension, diabetes mellitus, cholesterol level, body mass index, and cigarette smoking, persons who reported frequent lifetime cocaine use had a significantly higher likelihood of nonfatal MI than nonusers (odds ratio, 6.9; 95% confidence interval, 1.3 to 58) but not stroke. In this age group, the population-attributable risk percent of frequent cocaine for nonfatal MI was estimated as 25%.

Conclusion
—Regular cocaine use was associated with an increased likelihood of MI in younger patients. Approximately 1 of every 4 nonfatal MIs in persons aged 18 to 45 years was attributable to frequent cocaine use in this survey. Behavior modification by public awareness and education may reduce the cardiovascular morbidity associated with cocaine use.
Immediate and Late Clinical Outcomes of Carotid Artery Stenting in Patients With Symptomatic and Asymptomatic Carotid Artery Stenosis
Authors: Roubin Gary S. , New Gishel , Iyer Sriram S. , Vitek Jiri J. , Al-Mubarak Nadim , Liu Ming W. , Yadav Jay , Gomez Camilo , Kuntz Richard E.
Published: June 2012

Background
—Carotid stenting is a less invasive percutaneous procedure than carotid endarterectomy for the treatment of carotid stenosis. Reports suggest that it can be performed with periprocedural complication rates similar to those of carotid endarterectomy. The purpose of this study was to determine short- and long-term outcomes in the largest prospective cohort of carotid stenting patients.

Methods and Results
—This study followed 528 consecutive patients (604 hemispheres/arteries) undergoing carotid stenting. There was a 0.6% (n=3) fatal stroke rate and 1% (n=5) nonstroke death rate at 30 days. The major stroke rate was 1% (n=6), and the minor stroke rate was 4.8% (n=29). The overall 30-day stroke and death rate was 7.4% (n=43). Over the 5-year study period, the 30-day minor stroke rate improved from 7.1% (n=7) for the first year to 3.1% (n=5) for the fifth year (
P
<0.05 for trend). The best predictor of 30-day stroke and death was age ≥80 years. After the 30-day period, the incidence of fatal and nonfatal stroke was 3.2% (n=31). On Kaplan-Meier analysis, the 3-year freedom from ipsilateral or fatal stroke was 92±1%.

Conclusions
—Experience from a single group of operators demonstrates that carotid stenting can be performed with an acceptable 30-day complication rate. Late follow-up also demonstrates a low rate of fatal and nonfatal stroke. These results suggest that carotid stenting may be comparable to carotid endarterectomy, and it underscores the clinical equipoise and premise for the National Institute of Health–supported, randomized Carotid Revascularization Endarterectomy Versus Stent Trial comparing carotid stenting with carotid endarterectomy.
Prognostic Significance of Thrombocytopenia During Hirudin and Heparin Therapy in Acute Coronary Syndrome Without ST Elevation
Authors: Eikelboom John W. , Anand Sonia S. , Mehta Shamir R. , Weitz Jeffrey I. , Yi Cheelong , Yusuf Salim
Published: June 2012

Background
—The development of thrombocytopenia in acute coronary syndromes (ACS) appears to be associated with adverse clinical outcomes. Unfractionated heparin is a recognized cause of thrombocytopenia, but the incidence, predictors, and prognostic significance of thrombocytopenia during hirudin therapy in ACS have not been reported.

Methods and Results
—Patients with ACS without ST elevation were randomized in a double-blind manner to receive a 72-hour intravenous infusion of unfractionated heparin or hirudin. Platelet counts were measured at baseline and within 24 hours of completion of study drug. The overall incidence of thrombocytopenia (<100×10
9
/L) was 1% and was similar in unfractionated heparin– and hirudin-treated patients (
P
=0.42). Thrombocytopenia during study drug infusion was an independent predictor of 7-day outcomes, including death (OR, 6.7; 95% CI, 1.9 to 25); the composite of death, myocardial infarction, and recurrent ischemia (OR, 2.0; 95% CI, 1.0 to 1.5); revascularization (OR, 4.0; 95% CI, 2.2 to 7.1); and major bleeding (OR, 8.3; 95% CI, 3.4 to 17.7). Among patients who developed thrombocytopenia, hirudin (OR, 5.4; 95% CI, 2.6 to 11.3) but not unfractionated heparin (OR, 2.0; 95% CI, 0.3 to 14.4) therapy was associated with a significantly increased risk of major bleeding.

Conclusions
—Early-onset thrombocytopenia in patients with ACS without ST elevation is strongly associated with adverse clinical outcomes, including death, ischemic events, and bleeding. The excess of major bleeding in hirudin-treated patients who develop thrombocytopenia suggests that thrombocytopenia may contribute to the increased risk of bleeding observed with hirudin.
Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart Failure
Authors: Haq Syed , Choukroun Gabriel , Lim Hae , Tymitz Kevin M. , del Monte Federica , Gwathmey Judith , Grazette Luanda , Michael Ashour , Hajjar Roger , Force Thomas , Molkentin Jeffery D.
Published: June 2012

Background
—Left ventricular failure is commonly preceded by a period of hypertrophy. Intriguingly, many of the signaling pathways that have been implicated in the regulation of hypertrophy, including the 3 mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, stress-activated protein kinase, and p38), protein phosphatase, calcineurin, and the protein kinase Akt and its target glycogen synthase kinase-3 (GSK-3), also regulate the apoptotic response.

Methods and Results
—To understand the mechanisms that might regulate the progression of heart failure, we analyzed the activity of these signaling pathways in the hearts of patients with advanced heart failure, patients with compensated cardiac hypertrophy, and normal subjects. In patients with hypertrophy, neither the MAPK nor the Akt/GSK-3 pathways were activated, and the dominant signaling pathway was calcineurin. In failing hearts, calcineurin activity was increased but less so than in the hypertrophied hearts, and all 3 MAPKs and Akt were activated (and, accordingly, GSK-3β was inhibited), irrespective of whether the underlying diagnosis was ischemic or idiopathic cardiomyopathy.

Conclusions
—In the failing heart, there is a clear prohypertrophic activity profile, likely occurring in response to increased systolic wall stress and neurohormonal mediators. However, with the activation of these hypertrophic pathways, potent proapoptotic and antiapoptotic signals may also be generated. Therapies directed at altering the balance of activity of these signaling pathways could potentially alter the progression of heart failure.
Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation
Authors: Brundel Bianca J. J. M. , Van Gelder Isabelle C. , Henning Robert H. , Tieleman Robert G. , Tuinenburg Anton E. , Wietses Mirian , Grandjean Jan G. , Van Gilst Wiek H. , Crijns Harry J. G. M.
Published: June 2012

Background
—Sustained shortening of the atrial effective refractory period (AERP), probably due to reduction in the L-type calcium current, is a major factor in the initiation and maintenance of atrial fibrillation (AF). We investigated underlying molecular changes by studying the relation between gene expression of the L-type calcium channel and potassium channels and AERP in patients with AF.

Methods and Results
—mRNA and protein expression were determined in the left and right atrial appendages of patients with paroxysmal (n=13) or persistent (n=16) AF and of 13 controls in sinus rhythm using reverse transcription polymerase chain reaction and slot-blot, respectively. The mRNA content of almost all investigated ion channel genes was reduced in persistent but not in paroxysmal AF. Protein levels for the L-type Ca
2+
channel and 5 potassium channels (Kv4.3, Kv1.5, HERG, minK, and Kir3.1) were significantly reduced in both persistent and paroxysmal AF. Furthermore, AERPs were determined intraoperatively at 5 basic cycle lengths between 250 and 600 ms. Patients with persistent and paroxysmal AF displayed significant shorter AERPs. Protein levels of all ion channels investigated correlated positively with the AERP and with the rate adaptation of AERP. Patients with reduced ion channel protein expression had a shorter AERP duration and poorer rate adaptation.

Conclusions
—AF is predominantly accompanied by decreased protein contents of the L-type Ca
2+
channel and several potassium channels. Reductions in L-type Ca
2+
channel correlated with AERP and rate adaptation, and they represent a probable explanation for the electrophysiological changes during AF.
Estrogen Prevents Oxidative Stress–Induced Endothelial Cell Apoptosis in Rats
Authors: Sudoh Noriko , Toba Kenji , Akishita Masahiro , Ako Junya , Hashimoto Masayoshi , Iijima Katsuya , Kim Seungbum , Liang Yi-Qiang , Ohike Yumiko , Watanabe Tokumitsu , Yamazaki Ieharu , Yoshizumi Masao , Eto Masato , Ouchi Yasuyoshi
Published: June 2012

Background
—Estrogen replacement attenuates the increased risk of cardiovascular disease in postmenopausal women. Recent studies using an in vitro culture system have shown that estrogen inhibits endothelial cell (EC) apoptosis. The in vivo relevance of this finding, however, is not defined. To do so, we have developed a rat vascular injury model in which EC apoptosis induced by hydrogen peroxide plays a role.

Methods and Results
—Intracarotid arterial administration of 0.01 mmol/L hydrogen peroxide for 5 minutes evoked EC apoptosis after 6 to 24 hours, determined by nuclear staining with Hoechst 33342, terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling, and electron microscopy. Apoptosis was associated with EC loss and was followed by EC regeneration at 72 hours and neointima formation at 1 to 2 weeks. Estradiol replacement in ovariectomized female Wistar rats decreased the rate of apoptotic ECs by ≈50%, assayed by nuclear morphology of en face specimens, resulting in increased remaining ECs and decreased neointima formation. Progesterone did not influence the effects of estradiol on EC apoptosis.

Conclusions
—These results provide new insight into the cardioprotective action of estrogen as well as a paradigm of the response-to-injury hypothesis.