bluuebunny/crossref_metadata_2025 huggingface dataset:
Dobutamine-Atropine Stress Echocardiography for the Detection of Coronary Artery Disease in Patients With Left Ventricular Hypertrophy
Authors: Smart Steven C. , Knickelbine Thomas , Malik Fayaz , Sagar Kiran B.
Published: June 2012

Background
—Left ventricular hypertrophy is a heterogeneous disorder with distinct morphologies. Changes in wall thickness, left ventricular chamber diameter, and mass alter systolic wall stress of the left ventricle and may influence ischemic threshold. Thus, the goal of this study was to investigate the effect of the different patterns of left ventricular hypertrophy on the accuracy of dobutamine-atropine stress echocardiography.

Methods and Results
—Three-hundred eighty-six patients underwent multistage dobutamine-atropine stress echocardiography and diagnostic angiography. Echocardiograms were measured for mean and relative wall thicknesses, chamber size, left ventricular mass, and end-systolic wall stress. The patterns of ventricular hypertrophy were concentric hypertrophy (increased wall thickness and mass), eccentric hypertrophy (normal wall thickness and increased mass), and concentric remodeling (increased wall thickness and normal mass). The overall sensitivity, specificity, and accuracy of dobutamine-atropine stress echocardiography for the detection of coronary artery disease were 85%, 87%, and 86%, respectively. Increased left ventricular mass index alone did not affect accuracy. Sensitivity was markedly reduced (36%) only in those with concentric remodeling. The univariate predictors of false-negative studies were single-vessel left circumflex disease, increased wall thickness, small chamber size, hyperdynamic ejection fraction, and left ventricular concentric remodeling. Multivariate predictors were concentric remodeling (
P
<0.0001; odds ratio, 13.5), left ventricular ejection fraction >2 SD above normal (
P
<0.0001), and single-vessel left circumflex disease (
P
<0.0007; odds ratio, 7.6). Sensitivity was excellent in patients with small ventricles and normal wall thickness and in those with normal or large chambers regardless of wall thickness.

Conclusions
—Dobutamine-atropine stress echocardiography is an accurate test in most patients with left ventricular hypertrophy, but it is insensitive in the small subset with concentric remodeling.
Cost-Effectiveness of Catheter Ablation in Patients With Ventricular Tachycardia
Authors: Calkins Hugh , Bigger J. Thomas , Ackerman Stacey J. , Duff Steven B. , Wilber David , Kerr Robert A. , Bar-Din Miriam , Beusterien Kathleen M. , Strauss Michael J.
Published: June 2012

Background
—This study evaluated the cost-effectiveness of catheter ablation therapy versus amiodarone for treating ventricular tachycardia (VT) in patients with structural heart disease. The analysis used a societal perspective for a hypothetical cohort of VT patients with implantable cardioverter-defibrillators, who were experiencing frequent shocks.

Methods and Results
—We calculated incremental cost-effectiveness of ablation relative to amiodarone over 5 years after treatment initiation. Event probabilities were from the Chilli randomized clinical trial (Chilli Cooled Ablation System, Cardiac Pathways Corporation, Sunnyvale, Calif), the literature, and a consensus panel. Costs were from 1998 national Medicare reimbursement schedules. Quality-of-life weights (utilities) were estimated using an established preference measurement technique. In a hypothetical cohort of 10 000 patients, 5-year costs were higher for patients undergoing ablation compared with amiodarone therapy ($21 795 versus $19 075). Ablation also produced a greater increase in quality of life (2.78 versus 2.65 quality-adjusted life-years [QALYs]). This yielded a cost-effectiveness ratio of $20 923 per QALY gained for ablation compared with amiodarone. Results were relatively insensitive to assumptions about ablation success and durability. In less severe patients with good ejection fractions who suffer their first VT episode, the incremental cost-effectiveness ratio was $6028 per QALY gained. These cost-effectiveness ratios are within the range generally thought to warrant technology adoption.

Conclusions
—This study demonstrates that, from a societal perspective, catheter ablation appears to be a cost-effective alternative to amiodarone for treating VT patients.
Nifedipine-Induced Coronary Vasodilation in Ischemic Hearts Is Attributable to Bradykinin- and NO-Dependent Mechanisms in Dogs
Authors: Kitakaze Masafumi , Asanuma Hiroshi , Takashima Seiji , Minamino Tetsuo , Ueda Yasunori , Sakata Yasuhiko , Asakura Masanori , Sanada Shoji , Kuzuya Tsunehiko , Hori Masatsugu
Published: June 2012

Background
—Dihydropyridine calcium channel blockers protect endothelial cells against ischemia and reperfusion injury, suggesting that nifedipine may increase the in vivo cardiac NO level and thus coronary blood flow (CBF) in ischemic hearts. We tested this hypothesis.

Methods and Results
—In open-chest dogs, coronary perfusion pressure (CPP) was reduced in the left anterior descending coronary artery so that CBF decreased to one third of the control level, and thereafter CPP was maintained constant (103±8 to 43±3 mm Hg, n=9). We obtained fractional shortening (FS) and lactate extraction ratio (LER) as indices of regional myocardial contraction and metabolism. Both FS (26.4±2.1% to 6.7±2.0%, n=9,
P
<0.001) and LER (32±6% to −37±5%, n=9,
P
<0.001) showed a decrease when CPP was reduced. After intracoronary infusion of nifedipine (4 μg · kg
−1
· min
−1
), CBF increased from 30±1 to 48±4 mL · 100 g
−1
· min
−1
(
P
<0.01) without a change of CPP (n=9). Both FS (14.0±1.9%, n=9) and LER (−9±7%, n=9) also increased (
P
<0.01). Nifedipine increased the difference in the level of metabolites of NO (nitrate+nitrite; 9±3 to 25±5 nmol/mL, n=9,
P
<0.01) and bradykinin (22±5 to 58±4 pmol/mL, n=9,
P
<0.01) between coronary venous and arterial blood. L-NAME (an NO synthase inhibitor) or HOE-140 (a bradykinin receptor antagonist) attenuated (
P
<0.05) the increase in CBF (29±3 and 35±2 mL · 100 g
−1
· min
−1
, n=5 each), FS (4.8±0.6% and 6.9±1.7%, n=5 each), LER (−47±8% and −35±9%, n=5 each), and nitrate+nitrite (3±2 and 8±4 nmol/mL, n=5 each) due to nifedipine infusion.

Conclusions
—These results indicate that the calcium channel blocker nifedipine mediates coronary vasodilation and improves myocardial ischemia through both bradykinin/NO-dependent and -independent mechanisms.
Intracoronary Adenovirus-Mediated Delivery and Overexpression of the β
2
-Adrenergic Receptor in the Heart
Authors: Shah Ashish S. , Lilly R. Eric , Kypson Alan P. , Tai Oliver , Hata Jonathan A. , Pippen Anne , Silvestry Scott C. , Lefkowitz Robert J. , Glower Donald D. , Koch Walter J.
Published: June 2012

Background
—Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β
2
-adrenergic receptors (β
2
ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β
2
AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery.

Methods and Results
—Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β
2
AR (Adeno-β
2
AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex– and right coronary artery–mediated delivery of Adeno-β
2
AR resulted in ≈10-fold overexpression in a chamber-specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β
2
ARs in the LV improved global LV contractility, as measured by dP/dt
max
, at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery.

Conclusions
—Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β
2
AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.
Lamin A/C Gene Mutation Associated With Dilated Cardiomyopathy With Variable Skeletal Muscle Involvement
Authors: Brodsky Gary L. , Muntoni Francesco , Miocic Snjezana , Sinagra Gianfranco , Sewry Caroline , Mestroni Luisa
Published: June 2012

Background
—Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. Familial transmission of the disease is frequently observed, and genetic heterogeneity is indicated by clinical and morphological variability in the disease phenotype. In the family MDDC1 reported here, the disease phenotype is severe and characterized by an autosomal dominant pattern of transmission. In addition, the majority of affected family members show signs of mild skeletal muscle involvement.

Methods and Results
—On the basis of the clinical observation of both cardiac and skeletal muscle abnormalities in the MDDC1 family, the lamin A/C gene was examined in this kindred. Coding regions were polymerase chain reaction–amplified from genomic DNA and sequenced. A single nucleotide deletion was identified within exon 6, and all affected individuals were found to be heterozygous for this deletion.

Conclusions
—Heterozygosity for a single nucleotide deletion in exon 6 of lamin A/C segregates with both the cardiac and skeletal abnormalities observed in the MDDC1 family.
The Pressor Response to Water Drinking in Humans
Authors: Jordan Jens , Shannon John R. , Black Bonnie K. , Ali Yasmine , Farley Mary , Costa Fernando , Diedrich Andre , Robertson Rose Marie , Biaggioni Italo , Robertson David
Published: June 2012

Background
—Water drinking increases blood pressure profoundly in patients with autonomic failure and substantially in older control subjects. The mechanism that mediates this response is not known.

Methods and Results
—We studied the effect of drinking tap water on seated blood pressure in 47 patients with severe autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure patients [PAF]). Eleven older controls and 8 young controls served as control group. We also studied the mechanisms that could increase blood pressure with water drinking. Systolic blood pressure increased profoundly with water drinking, reaching a maximum of 33±5 mm Hg in MSA and 37±7 in PAF mm Hg after 30 to 35 minutes. The pressor response was greater in patients with more retained sympathetic function and was almost completely abolished by trimethaphan infusion. Systolic blood pressure increased by 11±2.4 mm Hg in elderly but not in young controls. Plasma norepinephrine increased in both groups. Plasma renin activity, vasopressin, and blood volume did not change in any group.

Conclusions
—Water drinking significantly and rapidly raises sympathetic activity. Indeed, it raises plasma norepinephrine as much as such classic sympathetic stimuli as caffeine and nicotine. This effect profoundly increases blood pressure in autonomic failure patients, and this effect can be exploited to improve symptoms due to orthostatic hypotension. Water drinking also acutely raises blood pressure in older normal subjects. The pressor effect of oral water is an important yet unrecognized confounding factor in clinical studies of pressor agents and antihypertensive medications.
Effectiveness and Limitations of β-Blocker Therapy in Congenital Long-QT Syndrome
Authors: Moss Arthur J. , Zareba Wojciech , Hall W. Jackson , Schwartz Peter J. , Crampton Richard S. , Benhorin Jesaia , Vincent G. Michael , Locati Emanuela H. , Priori Silvia G. , Napolitano Carlo , Medina Aharon , Zhang Li , Robinson Jennifer L. , Timothy Katherine , Towbin Jeffrey A. , Andrews Mark L.
Published: June 2012

Background
—β-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of β-blockers in this disorder have not been evaluated.

Methods and Results
—The study population comprised 869 LQTS patients treated with β-blockers. Effectiveness of β-blockers was analyzed during matched periods before and after starting β-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed β-blockers. After initiation of β-blockers, there was a significant (
P
<0.001) reduction in the rate of cardiac events in probands (0.97±1.42 to 0.31±0.86 events per year) and in affected family members (0.26±0.84 to 0.15±0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before β-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during β-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed β-blockers. Patients with a history of aborted cardiac arrest before starting β-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed β-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on β-blockers.

Conclusions
—β-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed β-blockers, particularly in those who were symptomatic before starting this therapy.
Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development
Authors: Verstraete Marc
Published: June 2012

Abstract
—Activation of the platelet glycoprotein (GP IIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GP IIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic and nonpeptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as 2 weeks, whereas synthetic GP IIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion, but some have the advantage of also being orally active. In the secondary prevention of atherothrombosis, large-scale trials were successfully conducted with aspirin, dipyridamole, ticlopidine, and clopidogrel. In the first large-scale trials with GP IIb/IIIa inhibitors, abciximab was investigated. In aggregate, synthetic GP IIb/IIIa inhibitors, combined with aspirin and heparin, were shown to reduce ischemic events in patients with high- and low-risk coronary intervention, stents, unstable angina, and non–Q-wave infarction. With short-term use of synthetic GP IIb/IIIa inhibitors, there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses currently used, bleeding occurs more often with the synthetic GP IIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours), but there are no direct comparisons between these drugs.
Prevention of High Incidence of Neurally Mediated Ventricular Arrhythmias by Afferent Nerve Stimulation in Dogs
Authors: Zhou Xiaohong , Vance Frank L. , Sims Anthony L. , Sreenan Catherine M. , Ideker Raymond E.
Published: June 2012

Background
—This study tested the hypothesis that the high incidence of ventricular arrhythmias caused by hypothalamic stimulation during acute myocardial ischemia could be attenuated by afferent nerve stimulation and investigated the cardiac mechanisms for those effects.

Methods and Results
—In 18 anesthetized dogs, stimulating electrodes were implanted in the hypothalamus and in the isolated left peroneal nerve. The chest was opened and approximately 100 plunge needles were inserted into the ventricles for 3-D activation mapping. Each animal underwent 4 episodes of 2.5 minutes of acute myocardial ischemia. The first and fourth episodes served as controls. During the second and third episodes, animals received either hypothalamic stimulation, peroneal nerve stimulation, or both. Hypothalamic stimulation significantly increased the incidence of ventricular arrhythmias. This high incidence was reduced 34% by simultaneous stimulation of the hypothalamus and peroneal nerve. 3-D mapping showed a focal origin for all ventricular arrhythmias. Hypothalamic stimulation increased the number of arrhythmic beats and decreased the coupling interval between each arrhythmic beat and the preceding beat. These effects were reduced by peroneal nerve stimulation.

Conclusions
—Alteration in autonomic tone by hypothalamic stimulation causes a high incidence of ventricular arrhythmias during acute myocardial ischemia that can be decreased by afferent nerve stimulation.
Elevated Levels of Shed Membrane Microparticles With Procoagulant Potential in the Peripheral Circulating Blood of Patients With Acute Coronary Syndromes
Authors: Mallat Ziad , Benamer Hakim , Hugel Bénédicte , Benessiano Joëlle , Steg P. Gabriel , Freyssinet Jean-Marie , Tedgui Alain
Published: June 2012

Background
—Apoptotic microparticles are responsible for almost all tissue factor activity of the plaque lipid core. We hypothesized that elevated levels of procoagulant microparticles could also circulate in the peripheral blood of patients with recent clinical signs of plaque disruption and thrombosis.

Methods and Results
—We studied 39 patients with coronary heart disease, including 12 patients with stable angina and 27 patients with acute coronary syndromes (ACS), and 12 patients with noncoronary heart disease. We isolated the circulating microparticles by capture with annexin V and determined their procoagulant potential with a prothrombinase assay. The cell origins of microparticles were determined in an additional 22 patients by antigenic capture with specific antibodies. The level of procoagulant microparticles did not differ between stable angina patients and noncoronary patients (10.1±1.6 nmol/L phosphatidylserine [PS] equivalent versus 9.9±1.6 nmol/L PS equivalent, respectively). However, procoagulant microparticles were significantly elevated in patients with ACS (22.2±2.7 nmol/L PS equivalent) compared with other coronary (
P
<0.01) or noncoronary (
P
<0.01) patients. Microparticles of endothelial origin were significantly elevated in patients with ACS (
P
<0.01), which suggests an important role for endothelial injury in inducing the procoagulant potential.

Conclusions
—High levels of procoagulant endothelial microparticles are present in the circulating blood of patients with ACS and may contribute to the generation and perpetuation of intracoronary thrombi.
Transcatheter Closure of Atrial Septal Defects Without Fluoroscopy
Authors: Ewert Peter , Berger Felix , Daehnert Ingo , van Wees John , Gittermann Matthias , Abdul-Khaliq Hashim , Lange Peter E.
Published: June 2012

Background
—In an effort to reduce x-ray exposure, we developed a technique for transcatheter closure of atrial septal defects under echocardiographic guidance without fluoroscopy. To assess the efficiency of this procedure for routine use, we compared our initial results with those for the conventional procedure.

Methods and Results
—Twenty-two randomly selected patients (median age 18 years; range 2 to 66 years) with atrial septal defects (n=13) or patent foramen ovale (n=9) underwent cardiac catheterization for possible interventional defect closure with echocardiography as the only imaging tool. Median stretched diameter was 9 mm (range 6 to 26 mm); median left-to-right shunt over the atrial septal defects was Qp/Qs=1.8 (range 1.5 to 2.6). An Amplatzer septal occluder was successfully implanted in 19 defects without fluoroscopy and in 3 with the help of radiography. After 1 month, complete defect closure was documented in all patients. Compared with the conventional procedure of a control group of 131 patients, procedure times were not significantly different (88 versus 100 minutes;
P
=0.09). However, the study group received significantly higher doses of propofol for sedation (9.9 versus 5.6 mg/kg body weight;
P
=0.002) owing to extended transesophageal echocardiography.

Conclusions
—In the majority of patients in whom transcatheter closure of interatrial communications with the Amplatzer septal occluder is possible, the procedure can be safely performed under echocardiographic guidance without fluoroscopy.
Influence of the Menstrual Cycle on Sympathetic Activity, Baroreflex Sensitivity, and Vascular Transduction in Young Women
Authors: Minson Christopher T. , Halliwill John R. , Young Tamica M. , Joyner Michael J.
Published: June 2012

Background
—Our goal was to test sympathetic and cardiovagal baroreflex sensitivity and the transduction of sympathetic traffic into vascular resistance during the early follicular (EF) and midluteal (ML) phases of the menstrual cycle.

Methods and Results
—Sympathetic baroreflex sensitivity was assessed by lowering and raising blood pressure with intravenous bolus doses of sodium nitroprusside and phenylephrine. It was defined as the slope relating muscle sympathetic nerve activity (MSNA; determined by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. Vascular transduction was evaluated during ischemic handgrip exercise and postexercise ischemia, and it was defined as the slope relating MSNA and calf vascular resistance (determined by plethysmography). Resting MSNA (EF, 1170±151 U/min; ML, 2252±251 U/min;
P
<0.001) and plasma norepinephrine levels (EF, 240±21 pg/mL; ML, 294±25 pg/mL;
P
=0.025) were significantly higher in the ML than in the EF phase. Furthermore, sympathetic baroreflex sensitivity was greater during the ML than the EF phase in every subject (MSNA/diastolic blood pressure slopes: EF, −4.15; FL, −5.42;
P
=0.005). No significant differences in cardiovagal baroreflex sensitivity or vascular transduction were observed.

Conclusions
—The present study suggests that the hormonal fluctuations that occur during the normal menstrual cycle may alter sympathetic outflow but not the transduction of sympathetic activity into vascular resistance.
Detection of Atrial Fibrillation and Flutter by a Dual-Chamber Implantable Cardioverter-Defibrillator
Authors: Swerdlow Charles D. , Schšls Wolfgang , Dijkman Barbara , Jung Werner , Sheth Nirav V. , Olson Walter H. , Gunderson Bruce D. , Investigators for the Worldwide Jewel AF
Published: June 2012

Background
—To distinguish prolonged episodes of atrial fibrillation (AF) that require cardioversion from self-terminating episodes that do not, an atrial implantable cardioverter-defibrillator (ICD) must be able to detect AF continuously for extended periods. The ICD should discriminate between atrial tachycardia/flutter (AT), which may be terminated by antitachycardia pacing, and AF, which requires cardioversion.

Methods and Results
—We studied 80 patients with AT/AF and ventricular arrhythmias who were treated with a new atrial/dual-chamber ICD. During a follow-up period lasting 6±2 months, we validated spontaneous, device-defined AT/AF episodes by stored electrograms in all patients. In 58 patients, we performed 80 Holter recordings with telemetered atrial electrograms, both to validate the continuous detection of AT/AF and to determine the sensitivity of the detection of AT/AF. Detection was appropriate in 98% of 132 AF episodes and 88% of 190 AT episodes (98% of 128 AT episodes with an atrial cycle length <300 ms). Intermittent sensing of far-field R waves during sinus tachycardia caused 27 inappropriate AT/AF detections; these detections lasted 2.6±2.0 minutes. AT/AF was detected continuously in 27 of 28 patients who had spontaneous episodes of AT/AF (96%). The device memory recorded 90 appropriate AT/AF episodes lasting >1 hour, for a total of 2697 hours of continuous detection of AT/AF. During Holter monitoring, the sensitivity of the detection of AT/AF (116 hours) was 100%; the specificity of the detection of non-AT/AF rhythms (1290 hours) was 99.99%. Of 166 appropriate episodes detected as AT, 45% were terminated by antitachycardia pacing.

Conclusions
—A new ICD detects AT/AF accurately and continuously. Therapy may be programmed for long-duration AT/AF, with a low risk of underdetection. Discrimination of AT from AF permits successful pacing therapy for a significant fraction of AT.
Percutaneous Closure of Patent Foramen Ovale in Patients With Paradoxical Embolism
Authors: Windecker Stephan , Wahl Andreas , Chatterjee Tushar , Garachemani Ali , Eberli Franz R. , Seiler Christian , Meier Bernhard
Published: June 2012

Background
—Patients with a patent foramen ovale (PFO) and paradoxical embolism are at risk for recurrent thromboembolic events. This study investigated the long-term risk of recurrent thromboembolic events in patients with PFO and paradoxical embolism after percutaneous PFO closure.

Methods and Results
—Since 1994, a total of 80 patients with PFO and at least 1 paradoxical embolic event (transient ischemic attack [TIA], cerebrovascular accident [CVA], peripheral embolism) have undergone percutaneous PFO closure with 5 different devices. There were 30 women and 50 men, with a mean age of 52±12 years. Sixty patients had only a PFO, whereas 20 patients had both a PFO and an atrial septal aneurysm. The implantation procedure was successful in 78 patients (98%). During 5 years of follow-up (mean, 1.6±1.4 years; range, 0.1 to 5.0 years), the actuarial annual risk to suffer a recurrent thromboembolic event was 2.5% for TIA, 0% for CVA, 0.9% for peripheral emboli, and 3.4% for the combined end point of TIA, CVA, or peripheral embolism. A postprocedural shunt was a predictor of recurrent paradoxical embolism (RR, 4.2; 95% CI, 1.1 to 17.8;
P
=0.03). The risk for recurrent thromboembolic events in patients with both atrial septal aneurysm and PFO was not significantly increased compared with patients with only PFO (RR, 1.0; 95% CI, 0.2 to 4.7;
P
=0.95).

Conclusions
—Percutaneous PFO closure appears to be a promising technique in the prevention of recurrent systemic thromboembolism in patients with a PFO after a first event. Prospective studies comparing percutaneous PFO closure with antithrombotic medications or surgery must define its therapeutic value.
Alteration in Left Ventricular Diastolic Filling and Accumulation of Myocardial Collagen at Insulin-Resistant Prediabetic Stage of a Type II Diabetic Rat Model
Authors: Mizushige Katsufumi , Yao Li , Noma Takahisa , Kiyomoto Hideyasu , Yu Yang , Hosomi Naohisa , Ohmori Koji , Matsuo Hirohide
Published: June 2012

Background
—Considerable controversy exists regarding impairment of cardiac function in diabetes mellitus (DM). We investigated the serial changes in left ventricular (LV) histopathology and LV filling dynamics in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have been established as an animal model of type II DM.

Methods and Results
—In 54 OLETF and 54 non-DM rats, body weight, blood pressure, heart rate, and transmitral pulsed Doppler examinations were performed from 5 to 47 weeks of age. An oral glucose tolerance test was performed at 10, 20, and 30 weeks of age. The hearts were excised for histopathology, including immunohistochemistry and histomorphometry of collagen, and measurement of hydroxyproline at baseline and each stage of developing DM. In the prediabetic stage (15 weeks of age), in which fast blood glucose remained normal, OLETF rats manifested mild obesity, postprandial hyperglycemia, and hyperinsulinemia, and early diastolic transmitral inflow exhibited prolonged deceleration time (OLETF, 59±10 ms versus non-DM, 49±8 ms,
P
<0.01) and low peak velocity (OLETF, 73±11 cm/s versus non-DM, 88±11 cm/s,
P
<0.01). Histopathology revealed extracellular fibrosis and abundant transforming growth factor-β
1
receptor II in LV myocytes of OLETF rats. At 15 weeks of age, the ratio of collagen area/visual field of LV wall in OLETF rats (8.3±1.3%) was larger than that in non-DM rats (4.9±1.8%,
P
<0.0001), and the collagen content/dry tissue weight ratio of heart was significantly higher in OLETF (2.0±0.5 mg/g) than non-DM (1.3±0.2 mg/g,
P
<0.01) rats.

Conclusions
—A metabolic abnormality present in the prestage of type II DM may produce LV fibrosis and alteration in cardiac function.
Hemodialysis Impairs Endothelial Function via Oxidative Stress
Authors: Miyazaki Hiroshi , Matsuoka Hidehiro , Itabe Hiroyuki , Usui Michiaki , Ueda Seiji , Okuda Seiya , Imaizumi Tsutomu
Published: June 2012

Background
—Patients who undergo hemodialysis experience accelerated atherosclerosis and premature death. Recent evidence suggests that endothelial dysfunction proceeds to and exacerbates atherosclerosis. It remains unknown whether hemodialysis per se causes endothelial dysfunction.

Methods and Results
—We evaluated endothelial function estimated by flow-mediated vasodilation during reactive hyperemia using high-resolution ultrasound Doppler echocardiography before and after a single session in patients on maintenance hemodialysis. Several studies have shown that the imbalance between pro-oxidant and antioxidant activities in hemodialyzed patients results in high oxidative stress, which causes lipid peroxidation and endothelial injury. Accordingly, we investigated the effects of antioxidative modification during hemodialysis on endothelial function using a vitamin E–coated cellulose membrane dialyzer. Nonspecific endothelium-independent vasodilation was measured after administration of a sublingual glyceryl trinitrate spray (0.3 mg). A single session of hemodialysis by noncoated dialyzer impaired flow-mediated vasodilation (
P
<0.05) associated with increased plasma levels of oxidized LDL (
P
<0.05), an index of oxidative stress. Hemodialysis by vitamin E–coated membrane prevented dialysis-induced endothelial dysfunction and increases in oxidized LDL. Plasma levels of oxidized LDL were inversely correlated with the magnitudes of flow-mediated vasodilation (
r
=−0.53,
P
< 0.001). Hemodialysis by noncoated or vitamin E–coated membrane did not affect glyceryl trinitrate–induced endothelium-independent vasodilation.

Conclusions
—Our findings indicate that hemodialysis per se impairs endothelial function, possibly by increasing oxidative stress.
Crucial Role of Endogenous Interleukin-10 Production in Myocardial Ischemia/Reperfusion Injury
Authors: Yang Zequan , Zingarelli Basilia , Szabó Csaba
Published: June 2012

Background
—The anti-inflammatory cytokine interleukin-10 (IL-10) has been detected in the plasma of patients with myocardial ischemia/reperfusion. The aim of our study was to investigate the role of endogenously produced IL-10 in myocardial ischemia/reperfusion.

Methods and Results
—In the present study, we used wild-type and IL-10–deficient mice subjected to myocardial ischemia/reperfusion. Significant levels of IL-10 were produced in wild-type mice at 2 to 6 hours after myocardial reperfusion. The genetic deletion of IL-10 enhanced neutrophil infiltration into the reperfused tissues at 6 hours after reperfusion and increased infarct size and myocardial necrosis. Furthermore, in the absence of IL-10, an enhancement of the inflammatory response was seen, as demonstrated by increased plasma levels of tumor necrosis factor-α, nitrite/nitrate (breakdown products of NO), and increased tissue expression of intercellular adhesion molecule-1. Reperfusion for 24 hours was associated with a 75% mortality rate in IL-10–deficient mice, whereas no deaths occurred in the wild-type animals.

Conclusions
—The present findings provide the first direct evidence that endogenous IL-10 inhibits the production of tumor necrosis factor-α and NO and serves to protect the ischemic and reperfused myocardium through the suppression of neutrophil recruitment.
Proximal Atrioventricular Bundle, Atrioventricular Node, and Distal Atrioventricular Bundle Are Distinct Anatomic Structures With Unique Histological Characteristics and Innervation
Authors: Racker Darlene K. , Kadish Alan H.
Published: June 2012

Background
—Direct 3D analysis (ie, stereotaxic analysis of 3 planes) has shown that the atrioventricular (AV) node (AVN) is continuous with only specialized myocardium of the proximal AV bundle (PAVB) and distal AV bundle (DAVB) or His bundle. The purpose of the present study was to determine whether the PAVB, AVN, and DAVB possess histological features distinct from each other and from the ordinary myocardium.

Methods and Results
—A protocol that preserves the cytoplasmic and interstitial integrity of the tissue and permits serial sections of the AV junction region to be made in 3 orthogonal planes showed that the PAVB, AVN, and DAVB are characterized by myocardium aggregated into fascicles containing ≈8 myofibers. Myofibers within the fascicles are coiled or spiraled about each other; and spiraling is most compact in the PAVB. Collagen encases individual fascicles and segregates primary fascicles into secondary fascicles. Fascicles, and not myofibers, are in parallel array in the PAVB, interwoven in the AVN, and parallel in the DAVB. Narrow junctions of parallel fascicles separate the AVN from the PAVB and DAVB. Myocytes, which are largest in DAVB, possess clear perinuclear regions; thin finger-like end processes, which are most numerous in the AVN; uniform, delicate cross-striations; and intercalated disks, which are broader in the PAVB and form short stacks in the AVN. Sheaves of nerve terminals, including boutons, are as found in skeletal muscle.

Conclusions
—The PAVB, AVN, and DAVB have distinct histological features. Collagen septation of primary and secondary fascicles presents natural barriers within the tissues and to surrounding myocardium and structures. These findings confirm that the AV junction region contains a specialized conduction system that is anatomically isolated from ordinary myocardium.
Randomized Trial Comparing Intravenous Nitroglycerin and Heparin for Treatment of Unstable Angina Secondary to Restenosis After Coronary Artery Angioplasty
Authors: Doucet Serge , Malekianpour Mehrdad , Théroux Pierre , Bilodeau Luc , Côté Gilles , Pierre de Guise  , Dupuis Jocelyn , Joyal Michel , Gosselin Gilbert , Tanguay Jean-François , Juneau Martin , Harel François , Nattel Stanley , Tardif Jean-Claude , Lespérance Jacques
Published: June 2012

Background
—The treatment of unstable angina targets the specific pathophysiological thrombotic process at the site of the active culprit lesion. In unstable angina due to a restenotic lesion, smooth muscle cell proliferation and increased vasoreactivity may play a more important role than thrombus formation. Therefore, the relative benefits of nitroglycerin and heparin might differ in unstable angina associated with restenosis compared with classic unstable angina.

Methods and Results
—We randomized 200 patients hospitalized for unstable angina within 6 months after angioplasty (excluding those with intracoronary stents) to double-blind administration of intravenous nitroglycerin, heparin, their combination, or placebo for 63±30 hours. Recurrent angina occurred in 75% of patients in the placebo and heparin-alone groups, compared with 42.6% of patients in the nitroglycerin-alone group and 41.7% of patients in the nitroglycerin-plus-heparin group (
P
<0.003). Refractory angina requiring angiography occurred in 22.9%, 29.2%, 4.3%, and 4.2% of patients, respectively (
P
<0.002). The odds ratios for being event free were 0.24 (95% CI, −0.13 to 0.45,
P
=0.0001) for nitroglycerin versus no nitroglycerin and 0.98 (95% CI, −0.55 to 1.73,
P
=NS) for heparin versus no heparin. No patient died or suffered myocardial infarction.

Conclusions
—Intravenous nitroglycerin is highly effective in preventing adverse ischemic events (recurrent or refractory angina) in patients with unstable angina secondary to restenosis, whereas heparin has no effect.
Fast Determination of Regional Myocardial Strain Fields From Tagged Cardiac Images Using Harmonic Phase MRI
Authors: Garot Jérôme , Bluemke David A. , Osman Nael F. , Rochitte Carlos E. , McVeigh Elliot R. , Zerhouni Elias A. , Prince Jerry L. , Lima João A. C.
Published: June 2012

Background
—Tagged MRI of the heart is difficult to implement clinically because of the lack of fast analytical techniques. We investigated the accuracy of harmonic phase (HARP) imaging for rapid quantification of myocardial strains and for detailed analysis of left ventricular (LV) function during dobutamine stimulation.

Methods and Results
—Tagged MRI was performed in 10 volunteers at rest and during 5 to 20 μg
−1
· kg
−1
· min
−1
dobutamine and in 9 postinfarct patients at rest. We compared 2D myocardial strains (circumferential shortening, Ecc; maximal shortening, E
2
; and E
2
, direction) as assessed by a conventional technique and by HARP. Full quantitative analysis of the data was 10 times faster with HARP. For pooled data, the regression coefficient was
r
=0.93 for each strain (
P
<0.001). In volunteers, Ecc and E
2
were greater in the free wall than in the septum (
P
<0.01), but recruitable myocardial strain at peak dobutamine was greater in the LV septum (
P
<0.01). E
2
orientation shifted away from the circumferential direction at peak dobutamine (
P
<0.01). HARP accurately detected subtle changes in myocardial strain fields under increasing doses of dobutamine. In patients, HARP-determined Ecc and E
2
values were dramatically reduced in the asynergic segments as compared with remote (
P
<0.001), and E
2
direction shifted away from the circumferential direction (
P
<0.001).

Conclusions
—HARP MRI provides fast, accurate assessment of myocardial strains from tagged MR images in normal subjects and in patients with coronary artery disease with wall motion abnormalities. HARP correctly indexes dobutamine-induced changes in strains and has the potential for on-line quantitative monitoring of LV function during stress testing.
Brief Antecedent Ischemia Enhances Recombinant Tissue Plasminogen Activator–Induced Coronary Thrombolysis by Adenosine-Mediated Mechanism
Authors: Przyklenk Karin , Whittaker Peter
Published: June 2012

Background
—Clinical studies have implicated preinfarct angina (brief antecedent ischemia/reperfusion [I/R]) as a predictor of more rapid thrombolysis and lower rates of reocclusion. However, the effects of antecedent ischemia on the efficacy of thrombolysis have not been rigorously assessed. Using a canine model of coronary thrombosis, we aimed to (1) reproduce these clinical findings and (2) determine whether release of adenosine (a potent inhibitor of platelet aggregation via stimulation of platelet A
2
receptors) during brief I/R contributes to this improved patency.

Methods and Results
—To address our first objective, we compared the time required to achieve lysis with recombinant tissue plasminogen activator and patency during the first 2 hours after lysis in dogs in which 1-hour thrombotic occlusion was preceded by brief I/R (10-minute coronary occlusion/10-minute reperfusion) versus 20-minute uninterrupted perfusion (controls). Time to lysis was accelerated in the I/R group versus the control group (11±1 versus 35±6 minutes,
P
=0.004). In addition, the duration of subsequent reocclusion was reduced (17±12 versus 30±11 minutes), and the area of the flow-time profile (normalized to baseline flow×120 minutes) was increased (64±12% versus 35±7%,
P
=0.04) in the I/R cohort. The protocol was then repeated, but all dogs were pretreated with the adenosine A
2
/A
1
antagonist CGS 15943 (CGS, 1.5 mg/kg). Time to lysis (38 versus 39 minutes) and subsequent patency were comparable in the CGS+control group versus the CGS+I/R group.

Conclusions
—Brief antecedent I/R enhances the efficacy of coronary thrombolysis in this canine model, which is due, at least in part, to an adenosine-mediated mechanism.
Short- and Intermediate-Term Clinical Outcomes From Direct Myocardial Laser Revascularization Guided by Biosense Left Ventricular Electromechanical Mapping
Authors: Kornowski Ran , Baim Donald S. , Moses Jeffrey W. , Hong Mun K. , Laham Roger J. , Fuchs Shmuel , Hendel Robert C. , Wallace Deborah , Cohen David J. , Bonow Robert O. , Kuntz Richard E. , Leon Martin B.
Published: June 2012

Background
—Direct myocardial revascularization (DMR) has been examined as an alternative treatment for patients with chronic refractory myocardial ischemic syndromes who are not candidates for conventional coronary revascularization.

Methods and Results
—We used left ventricular electromagnetic guidance in 77 patients with chronic refractory angina (56 men, mean age 61±11 years, ejection fraction 0.48±0.11) to perform percutaneous DMR with an Ho:YAG laser at 2 J/pulse. Procedural success (laser channels placed in prespecified target zones) was achieved in 76 of 77 patients with an average of 26±10 channels (range 11 to 50 channels). The rate of major in-hospital cardiac adverse events was 2.6%, with no deaths or emergency operations, 1 patient with postprocedural pericardiocentesis, and 1 patient with minor embolic stroke. The rate of out-of-hospital adverse cardiac events (up to 6 months) was 2.6%, with 1 patient with myocardial infarction and 1 patient with stroke. Exercise duration after DMR increased from 387±179 to 454±166 seconds at 1 month and to 479±161 seconds at 6 months (
P
=0.0001). The time to onset of angina increased from 293±167 to 377±176 seconds at 1 month and to 414±169 seconds at 6 months (
P
=0.0001). Importantly, the time to ST-segment depression (≥1 mm) also increased from 327±178 to 400±172 seconds at 1 month and to 436±175 seconds at 6 months (
P
=0.001). Angina (Canadian Cardiovascular Society classification) improved from 3.3±0.5 to 2.0±1.2 at 6 months (
P
<0.001). Nuclear perfusion imaging studies with a dual-isotope technique, however, showed no significant improvements at 1 or 6 months.

Conclusions
—Percutaneous DMR guided by left ventricular mapping is feasible and safe and reveals improved angina and prolonged exercise duration for up to a 6-month follow-up.
Response to Antihypertensive Therapy in Older Patients With Sustained and Nonsustained Systolic Hypertension
Authors: Fagard Robert H. , Staessen Jan A. , Thijs Lutgarde , Gasowski Jerzy , Bulpitt Christopher J. , Clement Denis , de Leeuw Peter W. , Dobovisek Jurij , Jääskivi Matti , Leonetti Gastone , O’Brien Eoin , Palatini Paolo , Parati Gianfranco , Rodicio José L. , Vanhanen Hannu , Webster John
Published: June 2012

Background
—The goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension.

Methods and Results
—Patients who were ≥60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (≥160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (
P
<0.001) and, during follow-up, a lower incidence of stroke (
P
<0.05) and of cardiovascular complications (
P
=0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (
P
<0.001). The influence of active treatment on ECG voltages (
P
<0.05) and on the incidence of stroke (
P
<0.05) and cardiovascular events (
P
=0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension.

Conclusions
—Patients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.
Analysis of 12-Lead T-Wave Morphology for Risk Stratification After Myocardial Infarction
Authors: Zabel Markus , Acar Burak , Klingenheben Thomas , Franz Michael R. , Hohnloser Stefan H. , Malik Marek
Published: June 2012

Background
—The stratification of post–myocardial infarction (MI) patients at risk of sudden cardiac death remains important. The aim of the present study was to assess the prognostic value of novel T-wave morphology descriptors derived from resting 12-lead ECGs.

Methods and Results
—In 280 consecutive post-MI patients, a 12-lead ECG was recorded before discharge, optically scanned, and digitized. For the present study, 5 T-wave morphology descriptors were automatically calculated after singular value decomposition of the ECG signal. The total cosine R-to-T (TCRT [describes the global angle between repolarization and depolarization wavefront]) and the T-wave loop dispersion were univariately associated (
P
=0.0002 and
P
<0.002, respectively,
U
test) with 27 prospectively defined clinical events in 261 patients (mean follow-up 32±10 months). Kaplan-Meier event probability curves for strata above and below the median confirmed the strong risk discrimination by TCRT and T-wave loop dispersion (
P
<0.003 and
P
<0.001, respectively, log-rank test). On Cox regression analysis, with the entering of age, left ventricular ejection fraction, heart rate, QRS width, reperfusion therapy, β-adrenergic–blocker treatment, and standard deviation of R-R intervals on 24-hour Holter monitoring, TCRT (
P
<0.03) yielded independent predictive value, whereas T-wave loop dispersion was of borderline independence (
P
=0.064). Heart rate (
P
<0.02), left ventricular ejection fraction (
P
<0.02), and reperfusion therapy (
P
<0.02) also remained in the final model.

Conclusions
—Computerized T-wave morphology analysis of the 12-lead resting ECG permits independent assessment of post-MI risk and an improved risk stratification when combined with other risk markers.