bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Oral Anticoagulant Therapy in Patients With Unstable Angina or Suspected Non–Q-Wave Myocardial Infarction
Authors: Anand Sonia S. , Yusuf Salim , Pogue Janice , Weitz Jeffrey I. , Flather Marcus
Published: June 2012

Background
—Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies.

Methods and Results
—In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5±0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1.66; 95% CI, 0.62 to 4.44;
P
=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75;
P
=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5;
P
=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3±0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5.1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15;
P
=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05;
P
=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96;
P
=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36;
P
=0.004).

Conclusions
—Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.
Prognostic Value of Myocardial Viability in Medically Treated Patients With Global Left Ventricular Dysfunction Early After an Acute Uncomplicated Myocardial Infarction
Authors: Picano Eugenio , Sicari Rosa , Landi Patrizia , Cortigiani Lauro , Bigi Riccardo , Coletta Claudio , Galati Alfonso , Heyman Joanna , Mattioli Roberto , Previtali Mario , Mathias Wilson , Dodi Claudio , Minardi Giovanni , Lowenstein Jorge , Seveso Giovanni , Pingitore Alessandro , Salustri Alessandro , Raciti Mauro
Published: June 2012

Background
—Residual viable myocardium identified by dobutamine stress after myocardial infarction may act as an unstable substrate for further events such as subsequent angina and reinfarction. However, in patients with severe global left ventricular dysfunction, viability might be protective rather than detrimental. The aim of this study was to assess the impact on survival of echocardiographically detected viability in medically treated patients with global left ventricular dysfunction evaluated after acute uncomplicated myocardial infarction.

Methods and Results
—The data bank of the large-scale, prospective, multicenter, observational Echo Dobutamine International Cooperative (EDIC) study was interrogated to select 314 medically treated patients (271 men; age, 58±9 years) who underwent low-dose (≤10 μg · kg
−1
· min
−1
) dobutamine for the detection of myocardial viability and high-dose dobutamine for the detection of myocardial ischemia (≤40 μg · kg
−1
· min
−1
with atropine ≤1 mg) performed 12±6 days after an acute uncomplicated myocardial infarction and showing a moderate to severe resting left ventricular dysfunction (wall motion score index [WMSI] >1.6). Patients were followed up for 9±7 months. Low-dose dobutamine stress echocardiography identified myocardial viability in 130 patients (52%). Dobutamine-atropine stress echocardiography was positive for ischemia in 148 patients (47%) and negative in 166 patients (53%). During the follow-up, there were 12 cardiac deaths (3.8% of the total population). With the use of Cox proportional hazards model, delta low-dose WMSI (the variation between rest WMSI and low-dose WMSI) was shown to exert a protective effect by reducing cardiac death by 0.8 for each decrease in WMSI at low-dose dobutamine (coefficient, −0.2; hazard ratio, 0.8;
P
<0.03); WMSI at peak stress was the best predictor of cardiac death in this set of patients (hazard ratio, 14.9;
P
<0.0018).

Conclusions
—In medically treated patients with severe global left ventricular dysfunction early after acute uncomplicated myocardial infarction, the presence of myocardial viability identified as inotropic reserve after low-dose dobutamine is associated with a higher probability of survival. The higher the number of segments showing improvement of function, the better the impact is of myocardial viability on survival. The presence of inducible ischemia in this set of patients is the best predictor of cardiac death.
Antibodies to Endothelial Cells in Borderline Hypertension
Authors: Frostegård Johan , Wu Ruihua , Gillis-Haegerstrand Caroline , Lemne Carola , de Faire Ulf
Published: June 2012

Background
—Antibodies to endothelial cells (aECs) and to cardiolipin (aCLs) are implicated in autoimmune diseases like systemic lupus erythematosus vasculitis. β
2
-Glycoprotein 1 (β2GP1) is a cofactor for aCLs. The present study investigated the possible role of aECs, aCLs, and aβ2GP1 in borderline hypertension.

Methods and Results
—Seventy-three men with borderline hypertension (BHT) and 73 age-matched normotensive (NT) men (diastolic blood pressure, 85 to 94 and <80 mm Hg, respectively) were recruited from a population screening program. Antibody levels were determined by ELISA. Presence of carotid atherosclerosis was determined by B-mode ultrasonography, and 29 individuals had atherosclerotic plaques. BHT men had significantly higher aEC and aβ2GP1 levels of IgG class than NT control subjects (
P
=0.029 and
P
=0.0001, respectively). aEC levels of IgM class were higher in BHT (
P
=0.012), but not aβ2GP1 levels. There was no correlation between aCL levels and BHT. Individuals with atherosclerotic plaques had significantly higher aEC levels of both IgG (
P
=0.042) and IgM subclasses (
P
=0.018) than those without plaques, but no difference was found in aCL and aβ2GP1 levels. Endothelin and aECs of IgM class were significantly associated.

Conclusions
—We demonstrate the first evidence of a significant elevation of aEC and aβ2GP1 levels in borderline hypertension. These findings provide a new link between hypertension and atherosclerosis and indicate that humoral immune reactions to the endothelium may play an important role in both conditions.
Cellular Basis of Biventricular Hypertrophy and Arrhythmogenesis in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsade de Pointes
Authors: Volders Paul G. A. , Sipido Karin R. , Vos Marc A. , Kulcsár Attila , Verduyn S. Cora , Wellens Hein J. J.
Published: June 2012

Background
—In the dog with chronic complete atrioventricular block (AVB), torsade de pointes arrhythmias (TdP) can be induced reproducibly by class III antiarrhythmic agents. In vivo studies reveal important electrophysiological alterations of the heart at 5 weeks of AVB, resulting in increased proarrhythmia. Autopsy studies indicate the presence of biventricular hypertrophy. In this study, the cellular basis of proarrhythmia and hypertrophy in chronic AVB was investigated.

Methods and Results
—From chronic-AVB dogs with increased heart weights and TdP, left midmyocardial and right ventricular myocytes were isolated by enzymatic dispersion. These myocytes were significantly larger than sinus rhythm (SR) controls. In chronic AVB, the action potential spike-and-dome configuration was preserved. However, the action potential duration (APD) at 95% and 50% of repolarization of the left midmyocardium was significantly larger in chronic AVB than in SR, with little change in the right ventricle, causing enhanced interventricular dispersion of repolarization at slow pacing rates. Treatment with the class III agent almokalant increased the APD to a much larger extent in chronic-AVB than in SR myocytes and resulted in a higher incidence of early afterdepolarizations (EADs). EADs had their takeoff potential between −35 and 0 mV. There was no evidence that spontaneous sarcoplasmic reticulum Ca
2+
release underlies these EADs.

Conclusions
—In the dog, chronic AVB leads to hypertrophy of both right and left ventricular myocytes. The repolarization abnormalities predisposing for class III–dependent TdP in vivo are the results of cellular electrophysiological remodeling.
Estradiol Therapy Combined With Progesterone and Endothelium-Dependent Vasodilation in Postmenopausal Women
Authors: Gerhard Marie , Walsh Brian W. , Tawakol Ahmed , Haley Elizabeth A. , Creager Shelly J. , Seely Ellen W. , Ganz Peter , Creager Mark A.
Published: June 2012

Background
—Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function.

Methods and Results
—Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1±1.0% change in brachial artery diameter compared with 4.7±0.6% during placebo therapy (
P
<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6±0.8% (
P
=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all
P
<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation.

Conclusions
—The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.
Plasma Lipoprotein(a) Is Not a Predictor for Restenosis After Elective High-Pressure Coronary Stenting
Authors: Ribichini Flavio , Steffenino Giuseppe , Dellavalle Antonio , Vado Antonello , Ferrero Valeria , Camilla Terenzio , Giubergia Silvia , Uslenghi Eugenio
Published: June 2012

Background
—Lipoprotein(a) is a risk factor for coronary artery disease. Although it has been implicated in restenosis after balloon angioplasty, its role in restenosis within coronary stents is unknown. The aim of the study was to assess the role of plasma lipoprotein(a) as a predictor for restenosis after elective coronary stenting.

Methods and Results
—Elective, high-pressure stenting of de novo lesions in native coronary arteries with Palmaz-Schatz stents was performed in 325 consecutive patients. Clinical, angiographic, and biochemical data were analyzed prospectively. Angiographic follow-up was performed at 6 months. Lipoprotein(a) levels were compared in patients with and without restenosis. Angiographic follow-up was obtained in 312 patients (96%); recurrence was observed in 67 patients (21.5%). No clinical or biochemical variable was associated with restenosis. Lipoprotein(a) level was 37.81±49.01 mg/dL (median, 22 mg/dL; range, 3 to 262 mg/dL) in restenotic patients and 36.95±40.65 mg/dL (median, 22 mg/dL; range, 0 to 244 mg/dL) in nonrestenotic patients (
P
=NS). The correlations between percent diameter stenosis, minimum luminal diameter, and late loss at follow-up angiography and basal lipoprotein(a) plasma level after logarithmic transformation were 0.006, 0.002, and 0.0017, respectively. Multiple stents were associated with a higher incidence of restenosis (
P
=0.006), but biochemical data in these patients were similar to those treated with single stents.

Conclusions
—The basal plasma level of lipoprotein(a) measured before the procedure is not a predictor for restenosis after elective high-pressure coronary stenting.
Comparison of Exercise Performance in Patients With Chronic Severe Heart Failure Versus Left Ventricular Assist Devices
Authors: Mancini Donna , Goldsmith Rochelle , Levin Howard , Beniaminovitz Ainat , Rose Eric , Catanese Katharine , Flannery Margaret , Oz Mehmet
Published: June 2012

Background
—Left ventricular assist devices (LVADs) are frequently used as a bridge to cardiac transplantation and may be useful as long-term therapy. The purpose of this study was to compare the exercise performance of LVAD patients with that of ambulatory heart failure patients.

Methods and Results
—Exercise testing with hemodynamic and respiratory gas measurements was performed in 65 congestive heart failure (CHF) patients (age 53±10 years) and 20 LVAD patients (age 49±8 years). Peak V̇
o
2
was significantly higher in the LVAD than the CHF patients (CHF, 12±3; LVAD, 15.9±3.8 mL · kg
−1
· min
−1
;
P
<0.001), as was the V̇
o
2
at the anaerobic threshold (CHF, 8.1±2.1; LVAD, 12.2±2.9 mL · kg
−1
· min
−1
;
P
<0.001). At rest, mean arterial blood pressure (CHF, 87±11; LVAD, 94±9 mm Hg) and cardiac output (CHF, 4±1; LVAD, 4.9±0.9 L/min) were increased, whereas mean pulmonary artery pressure (CHF, 28±11; LVAD, 18±4 mm Hg) and pulmonary artery wedge pressure (CHF, 16±10; LVAD 5±3 mm Hg) were reduced (all
P
<0.01). At peak exercise, heart rate (CHF,125±24; LVAD, 148±24 bpm), blood pressure (CHF, 87±14; LVAD,96±12 mm Hg), and cardiac output (CHF, 7.6±2.2; LVAD, 11.2±2.6 L/min) were higher (all
P
<0.01), whereas mean pulmonary artery pressure (CHF, 48±12; LVAD, 30±5 mm Hg) and mean pulmonary capillary wedge pressure (CHF, 31±11; LVAD, 14±6 mm Hg) were lower in the LVAD group (both
P
<0.001). In the LVAD patients, Fick cardiac output was higher than LVAD flow sensor value measurements (Fick, 11.6±2.5; LVAD, 8.1±1.2 L/min;
P
<0.001).

Conclusions
—Hemodynamic measurements at rest and during exercise are significantly improved in patients with devices compared with those in ambulatory heart failure patients awaiting cardiac transplantation. Similarly, the exercise capacity of device patients is better than that of transplant candidates and in the majority of patients is similar to that of patients with mild CHF.
Delivery of Colloidal Particles and Red Blood Cells to Tissue Through Microvessel Ruptures Created by Targeted Microbubble Destruction With Ultrasound
Authors: Price Richard J. , Skyba Danny M. , Kaul Sanjiv , Skalak Thomas C.
Published: June 2012

Background
—We have previously shown that the application of ultrasound to thin-shelled microbubbles flowing through small microvessels (<7 μm in diameter) produces vessel wall ruptures in vivo. Because many intravascular drug- and gene-delivery vehicles are limited by the endothelial barrier, we hypothesized that this phenomenon could be used to deliver drug-bearing vehicles to tissue.

Methods and Results
—An exteriorized rat spinotrapezius muscle preparation was used. Intravascular fluorescent red blood cells and polymer microspheres (PM) (205 and 503 nm in diameter) were delivered to the interstitium of rat skeletal muscle through microvessel ruptures created by insonifying microbubbles in vivo. On intravital microscopy, mean dispersion areas per rupture for red blood cells, 503-nm PM, and 205-nm PM were 14.5×10
3
μm
2
, 24.2×10
3
μm
2
, and 27.2×10
3
μm
2
, respectively. PM dispersion areas were significantly larger than the mean dispersion area for red blood cells (
P
<0.05).

Conclusions
—Microvessel ruptures caused by insonification of microbubbles in vivo may provide a minimally invasive means for delivering colloidal particles and engineered red blood cells across the endothelial lining of a targeted tissue region.
Effect of High- and Low-Molecular-Weight Heparins on Thrombin-Thrombomodulin Interaction and Protein C Activation
Authors: De Cristofaro Raimondo , De Candia Erica , Landolfi Raffaele
Published: June 2012

Background
—Thrombin-thrombomodulin (TM) interaction, which is critical for accelerating the protein C anticoagulant pathway, involves the heparin-like domain of TM. This study was aimed at investigating the possible effect of heparin on thrombin-TM binding and protein C activation.

Methods and Results
—The affinity of thrombin-TM interaction was studied by a functional method, based on the ability of thrombin-TM adduct to activate protein C, and by evaluation of the binding of thrombin to immobilized TM. Both experimental approaches showed that the affinity of thrombin-TM interaction was decreased by micromolar heparin concentrations. Heparin had no significant effect when a recombinant TM form, lacking the chondroitin sulfate moiety, was used. Furthermore, it was also shown that the inhibitory effect of heparin was directly proportional to the heparin molecular mass (molecular weight range, 3 to 16 kDa), which suggests that the effect was mediated by formation of electrostatic bonds between heparin and thrombin.

Conclusions
—These results indicate that heparin at therapeutic concentrations reduces the affinity of thrombin for TM and the rate of protein C activation. The magnitude of this effect is proportionally linked to the molecular mass of heparin.
Whole-Body Hyperthermia Provides Biphasic Cardioprotection Against Ischemia/Reperfusion Injury in the Rat
Authors: Yamashita Nobushige , Hoshida Shiro , Taniguchi Naoyuki , Kuzuya Tsunehiko , Hori Masatsugu
Published: June 2012

Background
—Hyperthermia increases cardiac tolerance to ischemia/reperfusion injury 24 hours after the heat stress. Free radicals and redox mechanisms have been implicated in such tolerance. However, the time course and its relation to the induction of antioxidative enzymes in the protection induced by whole-body hyperthermia against ischemia/reperfusion injury are unknown.

Methods and Results
—Hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. After the defined recovery interval(s) at room temperature, ischemia was induced by occlusion of the left coronary artery for 20 minutes, followed by reperfusion for 48 hours. The exposure to hyperthermia led to a recovery interval– dependent, biphasic reduction in the incidence of ventricular fibrillation during ischemia and in the size of the myocardial infarct as determined after 48 hours of reperfusion. The time course of the late-phase (24- to 96-hour recovery interval) but not the early-phase (0.5 hour) cardioprotection depended on the degree of hyperthermia. The time course of the increase in myocardial manganese superoxide dismutase (Mn-SOD) activity corresponded to that of the cardioprotective effects, although an increase in the content of Mn-SOD and of heat shock protein 72 corresponded only to the late-phase effects. Administration of an antioxidant before hyperthermia abolished the early- and late-phase cardioprotection and the increase in Mn-SOD activity.

Conclusions
—The activation of Mn-SOD mediated by free radical production during hyperthermia is important in the acquisition of early-phase and late-phase cardioprotection against ischemia/reperfusion injury in rats.
Gene Therapy With Extracellular Superoxide Dismutase Attenuates Myocardial Stunning in Conscious Rabbits
Authors: Li Qianhong , Bolli Roberto , Qiu Yumin , Tang Xian-Liang , Murphree Sidney S. , French Brent A.
Published: June 2012

Background
—Administration of Cu/Zn superoxide dismutase (SOD) without catalase fails to alleviate myocardial stunning, but extracellular SOD (Ec-SOD) may be more effective because it binds to heparan sulfate proteoglycans on the cellular glycocalyx. We therefore used in vivo gene transfer to increase systemic levels of Ec-SOD and determined whether this gene therapy protects against myocardial stunning.

Methods and Results
—The cDNA for human Ec-SOD was cloned behind the cytomegalovirus (CMV) promoter and incorporated into a replication-deficient adenovirus (Ad5/CMV/Ec-SOD). Injection of this virus (2×10
8
pfu/kg IV) produced high levels of Ec-SOD in the liver, which could be redistributed to the heart and other organs by injection of heparin. Conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days starting 3 days after intravenous injection of Ad5/CMV/Ec-SOD or Ad5/CMV/nls/LacZ (negative control). Both groups were given heparin (2000 U/kg IV) 2 hours before the first sequence of occlusions. The severity of myocardial stunning was measured as the total deficit of LV wall thickening after the last reperfusion. On day 1, the total deficit of wall thickening was markedly decreased in Ad5/CMV/Ec-SOD rabbits versus controls and similar to that seen on days 2 and 3 in controls.

Conclusions
—The results demonstrate that in vivo gene transfer of the cDNA encoding Ec-SOD provides the heart with substantial protection against myocardial stunning without the need for concomitant administration of catalase. The present observations provide the basis for controlling gene therapy at the posttranslational level and for simultaneously protecting multiple organs from oxidant stress.
Impaired Platelet Production of Nitric Oxide Predicts Presence of Acute Coronary Syndromes
Authors: Freedman Jane E. , Ting Brian , Hankin Beth , Loscalzo Joseph , Keaney John F. , Vita Joseph A.
Published: June 2012

Background
—Thrombus formation within a coronary vessel is the acute precipitating event in most acute coronary syndromes. Recently, constitutive nitric oxide synthase (cNOS) has been identified in human platelets, and platelet-derived nitric oxide has been shown to inhibit platelet recruitment after aggregation. However, its role in regulating platelet responses under normal or pathologic conditions has not yet been elucidated.

Methods and Results
—We examined nitric oxide (NO) production by platelets isolated from 87 patients undergoing coronary angiography, 37 with stable angina and 50 with unstable angina or a myocardial infarction within 2 weeks. After stimulation with 5 μmol/L ADP, platelet aggregation and NO production were simultaneously measured with an NO-selective microelectrode adapted for use in a standard platelet aggregometer. Mean (±SEM) platelet-derived NO production was 1.78±0.36 pmol/10
8
and 0.26±0.05 pmol/10
8
platelets in coronary patients with stable angina and acute coronary syndromes, respectively (
P
=0.0001). By logistic regression analysis, heparin treatment (odds ratio 6.6, CI 1.9 to 22.8,
P
=0.003), lower platelet-NO production (odds ratio 4.0, CI 1.3 to 11.5,
P
=0.01), and extent of atherosclerosis (odds ratio 1.5, CI 1.1 to 2.0,
P
=0.02) were independent predictors of an acute coronary syndrome. In the subset of patients with angiographic evidence of atherosclerosis (n=83), logistic regression demonstrated that platelet NO production (odds ratio 3.9, CI 1.3 to 11.1,
P
=0.01) and heparin treatment (odds ratio 6.4, CI 1.9 to 22.0,
P
=0.004) were independent predictors of an acute coronary syndrome, whereas extent of atherosclerosis was not.

Conclusions
—In summary, aggregating platelets from patients with acute coronary syndromes produce less NO. Since platelet aggregation and thrombus formation are implicated in unstable angina and myocardial infarction, impaired platelet-derived NO production may contribute to the development of acute coronary syndromes.
Gross and Microscopic Pathological Changes Associated With Nonthoracotomy Implantable Defibrillator Leads
Authors: Epstein Andrew E. , Kay G. Neal , Plumb Vance J. , Dailey Sharon M. , Anderson Peter G.
Published: June 2012

Background
—Although the effects of epicardial implantable cardioverter-defibrillator (ICD) leads on underlying cardiac tissue have been reported, the gross and microscopic changes associated with endocardial ICD leads are less well described. This study describes the gross and microscopic changes associated with endocardial ICD leads in humans.

Methods and Results
—The hearts from 8 patients were examined. At the time of ICD implantation, the patients’ mean age was 47±11 years, and the left ventricular ejection fraction was 0.24±0.10. Four patients had ischemic heart disease, and 4 had dilated cardiomyopathy. Five hearts were examined after transplantation; 3, after death. The electrode-myocardial interfaces were characterized by intense endocardial fibrosis and were remarkably consistent. Each lead was encased by a ring of fibroelastic tissue, and there was fibrosis of the right ventricular myocardium adjacent to the leads. Fibrosis involved the tricuspid valve in 5 patients, and 1 had perforation of the valve by the lead. Microscopically, interstitial fibrosis was adjacent to each lead in the current path of ICD shocks. Acute cell injury was present only in the hearts that had received recent shocks.

Conclusions
—The ICD electrode-myocardial interface is characterized by intense fibrosis. The fibrosis associated with endocardial ICD leads and the cumulative acute damage produced by defibrillation discharges may explain changes in the defibrillation and pacing thresholds and the difficulty of lead extraction that can be encountered with transvenous ICD systems.
Recombinant Cardiac ATP-Sensitive K
+
Channel Subunits Confer Resistance To Chemical Hypoxia-Reoxygenation Injury
Authors: Jovanović Aleksandar , Jovanović Sofija , Lorenz Eva , Terzic Andre
Published: June 2012

Background
—Opening of cardiac ATP-sensitive K
+
(K
ATP
) channels has emerged as a promising but still controversial cardioprotective mechanism. Defining K
ATP
channel function at the level of recombinant channel proteins is a necessary step toward further evaluation of the cardioprotective significance of this ion conductance.

Methods and Results
—K
ATP
channel–deficient COS-7 cells were found to be vulnerable to chemical hypoxia-reoxygenation injury that induced significant cytosolic Ca
2+
loading (from 97±3 to 236±11 nmol/L). In these cells, the potassium channel opener pinacidil (10 μmol/L) did not prevent Ca
2+
loading (from 96±3 nmol/L before to 233±12 nmol/L after reoxygenation) or evoked membrane current. Cotransfection with
Kir6.2/SUR2A
genes, which encode cardiac K
ATP
channel subunits, resulted in a cellular phenotype that, in the presence of pinacidil (10 μmol/L), expressed K
+
current and gained resistance to hypoxia-reoxygenation (Ca
2+
concentration from 99±7 to 127±11 nmol/L;
P
>0.05). Both properties were abolished by the K
ATP
channel blocker glyburide (1 μmol/L). In COS-7 cells transfected with individual channel subunits
Kir6.2
or
SUR2A
, which alone do not form functional cardiac K
ATP
channels, pinacidil did not protect against hypoxia-reoxygenation.

Conclusions
—The fact that transfer of cardiac K
ATP
channel subunits protected natively K
ATP
channel–deficient cells provides direct evidence that the cardiac K
ATP
channel protein complex harbors intrinsic cytoprotective properties. These findings validate the concept that targeting cardiac K
ATP
channels should be considered a valuable approach to protect the myocardium against injury.
Randomized Multicenter Comparison of Conventional Anticoagulation Versus Antiplatelet Therapy in Unplanned and Elective Coronary Stenting
Authors: Bertrand Michel E. , Legrand Victor , Boland Jean , Fleck Eckart , Bonnier Johannes , Emmanuelson Hakan , Vrolix Matty , Missault Luc , Chierchia Sergio , Casaccia Michele , Niccoli Luigi , Oto Ali , White Christopher , Webb-Peploe Michael , Van Belle Eric , McFadden Eugène P.
Published: June 2012

Background
—Dual therapy with ticlopidine and aspirin has been shown to be as effective as or more effective than conventional anticoagulation in patients with an optimal result after implantation of intracoronary metallic stents. However, the safety and efficacy of antiplatelet therapy alone in an unselected population has not been evaluated.

Methods
—Patients were randomized to conventional anticoagulation or to treatment with antiplatelet therapy alone. Indications for stenting were classified as elective (decided before the procedure) or unplanned (to salvage failed angioplasty or to optimize the results of balloon angioplasty). After stenting, patients received aspirin and either ticlopidine or conventional anticoagulation (heparin or oral anticoagulant). The primary end point was the occurrence of bleeding or peripheral vascular complications; secondary end points were cardiac events (death, infarction, or stent occlusion) and duration of hospitalization.

Results
—In 13 centers, 236 patients were randomized to anticoagulation and 249 to antiplatelet therapy. Stenting was elective in 58% of patients and unplanned in 42%. Stent implantation was successfully achieved in 99% of patients. A primary end point occurred in 33 patients (13.5%) in the antiplatelet group and 48 patients (21%) in the anticoagulation group (odds ratio=0.6 [95% CI 0.36 to 0.98],
P
=0.03). Major cardiac-related events in electively stented patients were less common (odds ratio=0.23 [95% CI 0.05 to 0.91],
P
=0.01) in the antiplatelet group (3 of 123, 2.4%) than the anticoagulation group (11 of 111, 9.9%). Hospital stay was significantly shorter in the antiplatelet group (4.3±3.6 versus 6.4±3.7 days,
P
=0.0001).

Conclusions
—Antiplatelet therapy after coronary stenting significantly reduced rates of bleeding and subacute stent occlusion compared with conventional anticoagulation.
Doppler Estimation of Left Ventricular Filling Pressure in Sinus Tachycardia
Authors: Nagueh Sherif F. , Mikati Issam , Kopelen Helen A. , Middleton Katherine J. , Quiñones Miguel A. , Zoghbi William A.
Published: June 2012

Background
—Doppler echocardiography is frequently used to predict filling pressures in normal sinus rhythm, but it is unknown whether it can be applied in sinus tachycardia, with merging of E and A velocities. Tissue Doppler imaging (TDI) can record the mitral annular velocity. The early diastolic velocity (E
a
) behaves as a relative load-independent index of left ventricular relaxation, which corrects the influence of relaxation on the transmitral E velocity.

Methods and Results
—We evaluated 100 patients 64±12 years old with simultaneous Doppler and invasive hemodynamics. Mitral inflow was classified into 3 patterns: complete merging of E and A velocities (pattern A), discernible velocities with A dominance (B), or E dominance (C). The Doppler data were analyzed at the mitral valve tips for E, acceleration and deceleration times of E, and isovolumic relaxation time. In patterns B and C, the A velocity, E/A ratio, and atrial filling fraction were derived. Pulmonary venous flow velocities were also measured, and TDI was used to acquire E
a
and A
a
. Weak significant relations were observed between pulmonary capillary wedge pressure (PCWP) and sole parameters of mitral flow, pulmonary venous flow, and annular measurements. These were better for patterns A and C. E/E
a
ratio had the strongest relation to PCWP [
r
=0.86, PCWP=1.55+1.47(E/E
a
)], irrespective of the pattern and ejection fraction. This equation was tested prospectively in 20 patients with sinus tachycardia. A strong relation was observed between catheter and Doppler PCWP (
r
=0.91), with a mean difference of 0.4±2.8 mm Hg.

Conclusions
—The ratio of transmitral E velocity to E
a
can be used to estimate PCWP with reasonable accuracy in sinus tachycardia, even with complete merging of E and A velocities.
Apoptosis and Cell Proliferation After Porcine Coronary Angioplasty
Authors: Malik Nadim , Francis Sheila E. , Holt Cathy M. , Gunn Julian , Thomas Graham L. , Shepherd Lynda , Chamberlain Janet , Newman Christopher M. H. , Cumberland David C. , Crossman David C.
Published: June 2012

Background
—Angioplasty initiates a number of responses in the vessel wall including cellular migration, proliferation, and matrix accumulation, all of which contribute to neointima formation and restenosis. Cellular homeostasis within a tissue depends on the balance between cell proliferation and apoptosis.

Methods and Results
—Profiles of apoptosis and proliferation were therefore examined in a porcine PTCA injury model over a 28-day period. Forty-two arteries from 21 pigs, harvested at the site of maximal injury at 1, 6, and 18 hours, and 3, 7, 14, and 28 days after PTCA, were examined (n=3 animals per time point). Uninjured arteries were used as controls. Apoptosis was demonstrated by the terminal uridine nick-end labeling (TUNEL) method, transmission electron microscopy (TEM), and DNA fragmentation. Cells traversing the cell cycle were identified by immunostaining for proliferating cell nuclear antigen (PCNA). Apoptosis was not detected in control vessels at all time points nor at 28 days after PTCA. Apoptotic cells were identified at all early time points with a peak at 6 hours (5.1±0.26%; compared to uninjured artery,
P
<0.001) and confirmed by characteristic DNA ladders and TEM findings. Regional analysis showed apoptosis within the media, adventitia, and neointima peaked at 18 hours, 6 hours, and 7 days after PTCA, respectively. In comparison, PCNA staining peaked at 3 days after PTCA (7.16±0.29%; compared to 1.78±0.08% PCNA-positive cells in the uninjured artery,
P
<0.001). Profiles of apoptosis and cell proliferation after PTCA were discordant in all layers of the artery except the neointima. These profiles also differed between traumatized and nontraumatized regions of the arterial wall. Immunostaining with cell-type specific markers and TEM analysis revealed that apoptotic cells included vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts.

Conclusions
—These results suggest that the profile of apoptosis and proliferation after PTCA is regional and cell specific, and attempts to modulate either of these events for therapeutic benefit requires recognition of these differences.
Reduced Pulmonary Clearance of Endothelin-1 Contributes to the Increase of Circulating Levels in Heart Failure Secondary to Myocardial Infarction
Authors: Dupuis Jocelyn , Rouleau Jean-L. , Cernacek Peter
Published: June 2012

Background
—The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations.

Methods and Results
—Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with
125
I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63±1.5% to 41±4.5% (mean±SEM,
P
<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV−aortic levels, 0.21±0.12 pg/mL) but not in lungs of HF rats (0.01±0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (
P
<0.001).

Conclusions
—HF is associated with reduced pulmonary ET-1 clearance that contributes to the increase in circulating levels.
Differential Regulation of Cardiac Angiotensin Converting Enzyme Binding Sites and AT
1
Receptor Density in the Failing Human Heart
Authors: Zisman Lawrence S. , Asano Koji , Dutcher Darrin L. , Ferdensi Anthony , Robertson Alastair D. , Jenkin Matthew , Bush Erik W. , Bohlmeyer Teresa , Perryman M. Benjamin , Bristow Michael R.
Published: June 2012

Background
—The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT
1
) receptor in the failing human heart are not understood.

Methods and Results
—Radioligand binding with
3
H-ramiprilat was used to measure ACE protein in membrane preparations of hearts obtained from 36 subjects with idiopathic dilated cardiomyopathy (IDC), 8 subjects with primary pulmonary hypertension (PPH), and 32 organ donors with normal cardiac function (NF hearts).
125
I-Ang II formation was measured in a subset of hearts. Saralasin (
125
I-{Sar
1
,Ile
8
}-Ang II) was used to measure total Ang II receptor density. AT
1
and AT
2
receptor binding were determined with the AT
1
receptor antagonist losartan. Maximal ACE binding (
B
max
) was 578±47 fmol/mg in IDC left ventricle (LV), 713±97 fmol/mg in PPH LV, and 325±27 fmol/mg in NF LV (
P
<0.001, IDC or PPH versus NF). In IDC, PPH, and NF right ventricles (RV), ACE
B
max
was 737±78, 638±137, and 422±49 fmol/mg, respectively (
P
=0.02, IDC versus NF;
P
=0.08, PPH versus NF).
125
I-Ang II formation correlated with ACE binding sites (
r
=0.60,
P
=0.00005). There was selective downregulation of the AT
1
receptor subtype in failing PPH ventricles: 6.41±1.23 fmol/mg in PPH LV, 2.37±0.50 fmol/mg in PPH RV, 5.38±0.53 fmol/mg in NF LV, and 7.30±1.10 fmol/mg in NF RV (
P
=0.01, PPH RV versus PPH LV;
P
=0.0006, PPH RV versus NF RV).

Conclusions
—ACE binding sites are increased in both failing IDC and nonfailing PPH ventricles. In PPH hearts, the AT
1
receptor is downregulated only in the failing RV.
Electrical Conduction Between the Right Atrium and the Left Atrium via the Musculature of the Coronary Sinus
Authors: Antz Matthias , Otomo Kenichiro , Arruda Mauricio , Scherlag Benjamin J. , Pitha Jan , Tondo Claudio , Lazzara Ralph , Jackman Warren M.
Published: June 2012

Background
—The purpose of this study was to determine whether the coronary sinus (CS) musculature has electrical connections to the right atrium (RA) and left atrium (LA) and forms an RA-LA connection.

Methods and Results
—Six excised dog hearts were perfused in a Langendorff preparation. A 20-electrode catheter (2-4-2-mm spacing center to center) was placed along the CS. Excision of the pulmonary veins provided access to the LA, and a second 20-electrode catheter was placed along the LA endocardium opposite the CS catheter. An incision opened the CS longitudinally, and microelectrodes were inserted into the CS musculature and adjacent LA myocardium. Continuous CS musculature was visible along a 35±9-mm length of the CS beginning at the ostium. During lateral LA pacing, CS electrodes recorded double potentials, a rounded, low-frequency potential followed by a sharp potential. The rounded initial potential propagated in the lateral-to-septal direction and represented “far-field” LA activation (timing coincided with adjacent LA potentials and with action potentials recorded from microelectrodes in adjacent LA cells). The sharp potential represented CS activation (timing coincided with action potentials recorded from CS musculature). A distal LA-CS connection (earliest sharp potential in the CS during lateral LA pacing) was located 26±7 mm from the ostium. During RA pacing posterior to the CS ostium, CS electrodes recorded septal-to-lateral activation of the high-frequency potential, with slightly later activation of the rounded potential (LA activation). Incisions surrounding the CS ostium isolating the ostium from the RA had no effect on the CS musculature and LA potentials during RA pacing within the isolated segment containing the CS ostium. RA pacing outside the isolated segment delayed activation of the CS musculature until after LA activation, confirming that the RA-CS connection was located in the region of the CS ostium as well as confirming the presence of the LA-CS connection.

Conclusions
—In canine hearts, the CS musculature is electrically connected to the RA and the LA and forms an RA-LA connection.
Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction
Authors: Böger Rainer H. , Bode-Böger Stefanie M. , Szuba Andrzej , Tsao Philip S. , Chan Jason R. , Tangphao Oranee , Blaschke Terrence F. , Cooke John P.
Published: June 2012

Background
—Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous
l
-arginine.

Methods and Results
—We measured plasma levels of
l
-arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of
l
-arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by >100% (2.17±0.15 versus 1.03±0.09 μmol/L;
P
<0.05) in HC subjects compared with NC adults.
l
-Arginine levels were similar, resulting in a significantly decreased
l
-arginine/ADMA ratio in HC subjects (27.7±2.4 versus 55.7±5.4;
P
<0.05). In 8 HC subjects, intravenous infusion of
l
-arginine significantly increased the
l
-arginine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation (
R
=0.762,
P
<0.01) and urinary nitrate excretion rates (
R
=0.534,
P
<0.01).

Conclusions
—We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. This abnormality is reversed by administration of
l
-arginine. ADMA may be a novel risk factor for endothelial dysfunction in humans.
Skeletal Muscle Metabolism Limits Exercise Capacity in Patients With Chronic Heart Failure
Authors: Okita Koichi , Yonezawa Kazuya , Nishijima Hirotaka , Hanada Akiko , Ohtsubo Mitsunori , Kohya Tetsuro , Murakami Takeshi , Kitabatake Akira
Published: June 2012

Background
—Several studies have indicated that skeletal muscle is important in determining the exercise capacity of patients with chronic heart failure (CHF). However, this theory has been investigated only in experiments based on local exercise involving a small muscle mass. We investigated skeletal muscle metabolism during maximal systemic exercise to determine whether muscle metabolism limits exercise capacity in patients with CHF. We also studied the relationship between muscle metabolic abnormalities during local and systemic exercise.

Methods and Results
—Skeletal muscle metabolism was measured during maximal systemic exercise on a bicycle ergometer by a combination of the metabolic freeze method and
31
P magnetic resonance spectroscopy in 12 patients with CHF and 7 age- and size-matched normal subjects. We also evaluated skeletal muscle metabolism during local exercise while subjects performed unilateral plantar flexion. Muscle phosphocreatine (PCr) was nearly depleted during maximal systemic exercise in patients with CHF and normal subjects (12.5±0.04% and 12.3±0.07%, respectively, of initial level). PCr depletion occurred at a significantly lower peak oxygen uptake (peak V̇
o
2
) in patients with CHF than in normal subjects (CHF, 20.2±3.0 versus normal, 31.8±3.7 mL · min
−1
· kg
−1
,
P
<0.0001). Muscle metabolic capacity, evaluated as the slope of PCr decrease in relation to increasing workload, was correlated with peak V̇
o
2
during maximal systemic exercise in patients with CHF (
r
=0.83,
P
<0.001). Muscle metabolic capacity during local exercise was impaired in patients with CHF and was correlated with capacity during systemic exercise (
r
=0.76,
P
<0.01) and with peak V̇
o
2
(
r
=0.83,
P
<0.001).

Conclusions
—These results suggest that impaired muscle metabolism associated with early metabolic limitation determines exercise capacity during maximal systemic exercise in patients with CHF. There was a significant correlation between muscle metabolic capacity during systemic and local exercise in patients with CHF.
Novel Therapeutic Strategy for Atherosclerosis
Authors: Morishita Ryuichi , Yamada Shingo , Yamamoto Kei , Tomita Naruya , Kida Iwao , Sakurabayashi Ikunosuke , Kikuchi Akira , Kaneda Yasufumi , Lawn Richard , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Background
—Because mechanisms of atherosclerosis by lipoprotein(a) [Lp(a)] have been postulated in the decrease in active transforming growth factor-β conversion by decreased plasmin, selective decrease in apolipoprotein(a) [apo(a)] independent of plasminogen may have therapeutic values. Although antisense can decrease apo(a), its application may be difficult because of very high homology of apo(a) gene to plasminogen. Thus we used ribozyme strategy that actively cleaves targeted genes to selectively inhibit apo(a) expression.

Methods and Results
—We constructed ribozyme oligonucleotides containing phosphorothioate DNA- and RNA-targeted kringle 4 of the apo(a) gene that showed 80% homology to plasminogen. Transfection of human apo(a) gene produced Lp(a) in medium of HepG2 cells, whereas Lp(a) could not be detected in control cells. Cotransfection of ribozyme and apo(a) gene resulted in the decrease in mRNA of apo(a) but not plasminogen. Moreover, marked decrease in Lp(a) was also observed in the medium transfected with ribozyme and apo(a) gene compared with apo(a) gene alone (
P
<0.01), whereas there was no significant change in plasminogen level between ribozyme-transfected and control cells. Incubation of human vascular smooth muscle cells (VSMC) with conditioned medium from apo(a)–transfected HepG2 cells resulted in a significant increase in VSMC number, whereas addition of conditioned medium from cells cotransfected with ribozyme oligonucleotides and apo(a) gene resulted in no VSMC growth (
P
<0.01). DNA-based control oligonucleotides and mismatched ribozyme oligonucleotides did not have an inhibitory effect on Lp(a) production.

Conclusions
—Overall, our data revealed that transfection of ribozyme against the apo(a) gene resulted in the selective inhibition of the apo(a) but not the plasminogen gene, providing novel therapeutic strategy for treatment of high Lp(a), a risk factor for atherosclerosis.