bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic Treatment With Carbachol Sensitizes the Myocardium to cAMP-Induced Arrhythmia
Authors: Eschenhagen Thomas , Mende Ulrike , Diederich Matthias , Hertle Boris , Memmesheimer Christian , Pohl Andreas , Schmitz Wilhelm , Scholz Hasso , Steinfath Markus , Böhm Michael , Michel Martin C. , Brodde Otto-Erich , Raap Achim
Published: June 2012

Background
The present study investigated biochemical and functional consequences of chronic activation of the inhibitory G
iα
-coupled adenylyl cyclase pathway in the heart.

Methods and Results
Rats (220 to 260 g) were treated with 4-day infusions of the M-cholinoceptor agonist carbachol (9.6 mg/kg per day) or vehicle. An additional group that received the β-adrenoceptor agonist isoprenaline (2.4 mg/kg per day) served as control. The main finding was that chronic infusion of carbachol led to a marked increase in isoprenaline- or forskolin-induced arrhythmia in electrically driven papillary muscles (in vitro). Compared with control, the potency of isoprenaline and forskolin to induce arrhythmia in cardiac preparations from carbachol-treated rats was increased 36- and 2.2-fold and the efficacy was increased 7.3- and 2.3-fold, respectively. The potency of carbachol to antagonize the isoprenaline- and forskolin-induced arrhythmia was decreased 30-fold. These changes were accompanied by a decrease in left ventricular M-cholinoceptor density by 15% (
P
<.05) and a decrease in pertussis toxin–sensitive G proteins (G
iα
) by 26% (
P
<.05) without a decrease in the corresponding mRNAs. β-Adrenoceptor density and basal and stimulated adenylyl cyclase activity remained unchanged. In contrast, isoprenaline infusion induced a decrease in arrhythmogenic potency of forskolin (
P
=NS), which was accompanied by a decrease in β-adrenoceptor density, an increase in G
iα
protein and mRNA levels, and a decrease in basal and stimulated adenylyl cyclase activity.

Conclusions
Chronic parasympathetic activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes may be due to quantitative alterations in functional G
iα
.
Processing of Chimeric Antisense Oligonucleotides by Human Vascular Smooth Muscle Cells and Human Atherosclerotic Plaque
Authors: Pickering J. Geoffrey , Isner Jeffrey M. , Ford Carol M. , Weir Lawrence , Lazarovits Andrew , Rocnik Edward F. , Chow Lawrence H.
Published: June 2012

Background
Antisense oligonucleotides have been used in animals to inhibit the accumulation of vascular smooth muscle cells (VSMCs) after arterial injury. This has raised prospects for an oligonucleotide-mediated approach to prevent restenosis in patients undergoing angioplasty. However, little is known about the processing of oligonucleotides by human VSMCs or their bioavailability in human atherosclerotic tissue.

Methods and Results
Oligonucleotides were synthesized with a mixture of unmodified and sulfur-modified linkages (S-chimeric oligonucleotides). These were more stable than unmodified oligonucleotides and could be recovered from within human VSMCs after 36 hours. Oligonucleotide antisense to human proliferating cell nuclear antigen mRNA specifically reduced DNA synthesis (
P
<.01) and proliferating cell nuclear antigen protein content (
P
<.05) in human VSMCs. Confocal microscopy of both live and fixed cells showed modest oligonucleotide uptake that was primarily nuclear. Surprisingly, cationic liposomes did not enhance nuclear uptake but led to extensive, punctated cytoplasmic loading without an enhanced antisense effect. Oligonucleotides incubated with human coronary atherosclerosis fragments associated with cells within 1 hour, despite the presence of abundant extracellular matrix.

Conclusions
S-chimeric oligonucleotides are stable and can specifically inhibit gene expression in human VSMCs. Nuclear transport is a feature of oligonucleotide processing by human VSMCs, indicating a potential influence at the nuclear level rather than with cytoplasmic mRNA. Cationic liposomes increased oligonucleotide uptake but not intracellular bioavailability, and S-chimeric oligonucleotides can be incorporated into cells within human atherosclerotic plaque, despite the presence of a dense extracellular matrix.
Mechanism of Action of OPC-8490 in Human Ventricular Myocardium
Authors: Focaccio Amelia , Peeters George , Movsesian Matthew , Roden Robert , Eki Yutaka , Krall Judith , Bristow Michael R.
Published: June 2012

Background
The quinolinone compounds OPC-8212 (vesnarinone), OPC-18790, and OPC-8490 are members of a family of unique positive inotropic compounds that have no positive chronotropic effects. In subjects with heart failure, the prototypic compound OPC-8212 may reduce morbidity and mortality at low doses but increase mortality at high doses.

Methods and Results
To further characterize the inotropic mechanism(s) of action of these compounds, we investigated the effects of OPC-8490, a water-soluble quinolinone, on the inotropic response, inhibition of phosphodiesterase (PDE), and action potential in human ventricular myocardial preparations. In isolated right ventricular trabeculae and membranes prepared from left ventricular myocardium, OPC-8490 produced dose-related positive inotropic effects, inhibited type III PDE activity, and prolonged action potential. Comparative experiments with other PDE inhibitors, sodium channel agonists, and potassium channel antagonists indicated that the positive inotropic effects are due to PDE inhibition, whereas the action potential effects of OPC-8490 are due to effects on ion channels.

Conclusions
We conclude that OPC-8490 produces selective positive inotropic effects because of type III PDE inhibition combined with ion channel effects, with the latter property inhibiting the positive chronotropic response usually associated with agents that increase intracellular cAMP concentrations.
Atrioventricular Node Reentry With ‘Smooth’ AV Node Function Curves
Authors: Sheahan Richard G. , Klein George J. , Yee Raymond , Le Feuvre Catherine A. , Krahn Andrew D.
Published: June 2012

Background
Some patients with otherwise typical AV node reentry do not manifest discontinuous AV node function curves. We examined the effects of an ablation in the slow-pathway region in patients with smooth AV node function curves.

Methods and Results
Fifteen patients with AV node reentrant tachycardia (AVNRT) and discontinuous AV node function curves were compared with 15 patients with AVNRT and smooth AV node function curves. In the group with a discontinuous curve, the “net” anterograde effective refractory period (AERP) of the AV node increased (270±28 versus 304±37 ms,
P
=.03) and AERP of the remaining fast pathway decreased (367±100 versus 304±37 ms,
P
=.026) after the ablation. In the group with a smooth curve, the AERP of the AV node increased (266±42 versus 299±76 ms,
P
=.07) and the anterograde Wenckebach cycle length increased (336±66 versus 379±86 ms,
P
=.008) after the ablation. Retrograde conduction over the AV node was similar in both groups and was unchanged after ablation. The longest attainable AH interval (AH
max
) measured during atrial extrastimulus testing was more prolonged in patients with a discontinuous curve than in patients with a smooth curve (326±48 versus 250±70 ms,
P
=.002). The AH
max
shortened in both groups after ablation (326±48 versus 173±34 ms,
P
<.0001, and 250±70 versus 179±34 ms,
P
<.0003, respectively) and were similar. Successful ablation in the slow-pathway zone in patients with a smooth AV node function curve resulted in the loss of the “tail” of the curve representing the slow pathway.

Conclusions
These data suggest that the smooth AV node function curve consists of two distinct components representing both fast and slow AV node pathways even when the typical discontinuity is absent.
Heparins Designed to Specifically Inhibit Platelet Interactions With von Willebrand Factor
Authors: Sobel Michael , Bird Karyn E. , Tyler-Cross Ruth , Marques Dalila , Toma Naoto , Edward Conrad H. , Harris Robert B.
Published: June 2012

Background
Platelet interactions with the injured vessel wall may contribute significantly to the early and late failures of many cardiovascular interventions; the adhesive protein von Willebrand factor (vWF) is thought to play an important role. Previously, we demonstrated that heparin interfered with platelet/vWF hemostatic mechanisms by binding to vWF within the protein’s domain responsible for binding the platelet vWF receptor, glycoprotein Ib. The purpose of the present study was to develop and refine heparins with greater potency to inhibit platelet/vWF interactions.

Methods and Results
Immobilized synthetic peptides based on a known heparin-binding domain of vWF were used to yield novel fractions of standard heparin that demonstrated a sevenfold increase in their ability to inhibit vWF-dependent platelet agglutination and vWF/platelet binding. The high vWF affinity heparin showed enhanced anti–factor Xa activity but comparable activated partial thromboplastin time activity. Chemical modification of a standard heparin by periodate oxidation and borohydride reduction enhanced its ability to inhibit platelet/vWF interactions by threefold, while eliminating more than 90% of its activated partial thromboplastin time and anti–factor Xa activity. Affinity chromatography of the chemically modified heparin yielded a heparin with an eightfold higher inhibitory potency than the original heparin.

Conclusions
Subspecies of heparin can be developed with significantly enhanced potency to inhibit vWF/platelet interactions. The vWF-inhibiting property of heparin can be dissociated from its antithrombin-binding activity. Based on a growing understanding of heparin/vWF interactions, combinations of affinity separations and chemical modifications could be designed to yield heparins uniquely suitable for prevention of arterial thrombosis.
Basis for Increased Microtubules in Pressure-Hypertrophied Cardiocytes
Authors: Tagawa Hirofumi , Rozich John D. , Tsutsui Hiroyuki , Narishige Takahiro , Kuppuswamy Dhandapani , Sato Hiroshi , McDermott Paul J. , Koide Masaaki , Cooper George
Published: June 2012

Background
We have shown on the levels of the sarcomere and the cardiocyte that a persistent increase in microtubule density accounts to a remarkable degree for the contractile dysfunction seen in pressure-overload right ventricular hypertrophy. In the present study, we have asked whether these linked phenotypic and contractile abnormalities are an immediate and direct effect of load input into the cardiocyte or instead a concomitant of hypertrophic growth in response to pressure overloading.

Methods and Results
The feline right ventricle was pressure-overloaded by pulmonary artery banding. The quantity of microtubules was estimated from immunoblots and immunofluorescent micrographs, and their mechanical effects were assessed by measuring sarcomere motion during microtubule depolymerization. The biogenesis of microtubules was estimated from Northern and Western blot analyses of tubulin mRNAs and proteins. These measurements were made in control cats and in operated cats during and after the completion of right ventricular hypertrophy; the left ventricle from each heart served as a normally loaded same-animal control. We have shown that the alterations in microtubule density and sarcomere mechanics are not an immediate consequence of pressure overloading but instead appear in parallel with the load-induced increase in cardiac mass. Of potential mechanistic importance, both these changes and increases in tubulin poly A
+
mRNA and protein coexist indefinitely after a new, higher steady state of right ventricular mass is reached.

Conclusions
Because we find persistent increases both in microtubules and in their biosynthetic precursors in pressure-hypertrophied myocardium, the mechanisms for this cytoskeletal abnormality must be sought through studies of the control both of microtubule stability and of tubulin synthesis.
Normalization of Abnormal Coronary Vasomotion by Calcium Antagonists in Patients With Hypertension
Authors: Frielingsdorf Jürgen , Seiler Christian , Kaufmann Philipp , Vassalli Giuseppe , Suter Thomas , Hess Otto M.
Published: June 2012

Background
Endothelial dysfunction with a loss of endothelium-dependent vasodilation has been reported in patients with arterial hypertension. The purpose of the present study was to evaluate coronary vasomotor response to dynamic exercise in patients with coronary artery disease with and without arterial hypertension and to determine the effect of calcium antagonists on coronary vasomotion.

Methods and Results
Cross-sectional areas of a normal and a stenotic coronary vessel segment were examined in 79 patients with coronary artery disease at rest and during supine bicycle exercise (Ex). Change in luminal area after acute administration of a calcium antagonist (diltiazem or nicardipine), during exercise, and after sublingual nitroglycerin (percent change compared with rest=100%) was assessed by biplane quantitative coronary arteriography. Patients were divided into two groups: Group 1 (control) consisted of 48 patients without (normotensive subjects, n=30; hypertensive subjects, n=18) and group 2 of 31 patients with (normotensive subjects, n=15; hypertensive subjects, n=16) pretreatment with a calcium antagonist immediately before exercise. The groups did not differ with regard to clinical characteristics or hemodynamic data measured during exercise. Mean aortic pressure at rest, however, was significantly increased in hypertensive patients compared with normotensive subjects in group 1 (103 mm Hg versus 92 mm Hg,
P
<.01) and group 2 (110 mm Hg versus 98 mm Hg,
P
<.025). In group 1, exercise-induced vasomotor response was significantly different between normotensive and hypertensive patients in normal (+20% versus +1%,
P
<.003) and stenotic vessels (−5% versus −20%,
P
<.025). However, in group 2 there was coronary vasodilation in normotensive and hypertensive patients for both normal (ΔEx +23% versus +21%,
P
=NS) and stenotic vessel segments (+24% versus +26%,
P
=NS).

Conclusions
Abnormal coronary vasomotion during exercise can be observed in hypertensive patients with reduced vasodilator response in normal arteries and enhanced vasoconstrictor response in stenotic arteries. Calcium antagonists prevent the abnormal response of normal and stenotic coronary arteries to exercise in hypertensive patients and thus may compensate for endothelial dysfunction with reduced vasodilator response to exercise.
New Insights Into the Pathophysiology of Carotid Sinus Syndrome
Authors: Hak Tea Say , Mansourati Jacques , L’Heveder Gildas , Mabin Dominique , Blanc Jean-Jacques
Published: June 2012

Background
The pathophysiology of carotid sinus syndrome remains poorly understood. Currently, two main hypotheses are provided: a lesion at the level of carotid sinus receptors or a central defect at the level of the nuclei of the autonomic nervous system. The objective of our study was to present arguments in favor of one of these two hypotheses.

Methods and Results
Test selection was guided by the following hypothesis: a degenerative central or local lesion could be associated with dysfunctions in the structures surrounding or comprising the baroreflex centers or their pathways. To test this hypothesis, brain stem auditory–evoked potentials; somatosensory–evoked potentials; blink reflexes; sympathetic skin responses; and styloglossus, sternocleidomastoid, and superior trapezius muscle electromyography were systematically performed from the right and left sides in 17 patients with carotid sinus syndrome and in 17 sex- and age-matched control subjects. Similar responses were found in the two groups for the “central” tests. Contrasting with this result, the electromyographic analysis of the sternocleidomastoid muscle differed significantly between the groups: 13 (76%) had pathological responses in the carotid sinus syndrome group compared with only 4 (23.5%) in the control group (
P
<.01). Furthermore, the abnormality was found on the right and left sides in 9 patients (53%) in the study group and in none of the control group (
P
<.005).

Conclusions
This study strongly suggests that the neuromuscular structures surrounding the carotid mechanoreceptors are involved in the carotid sinus syndrome; however, the exact mechanism remains speculative.
Ischemic Stroke and the Gene for Angiotensin-Converting Enzyme in Japanese Hypertensives
Authors: Kario Kazuomi , Kanai Nobuyuki , Saito Ken , Nago Naoki , Matsuo Takefumi , Shimada Kazuyuki
Published: June 2012

Background
The
ACE
insertion/deletion (
I/D
) polymorphism is reported to be associated with myocardial infarction in both whites and Japanese. However, there have been no reports on the association of this polymorphism with stroke in each race. Furthermore, there are some racial differences in the demographics of cardiovascular diseases. In Japanese, stroke (especially that which occurs in preexisting hypertension) is more common and coronary artery disease much less common than in whites. We propose that the
ACE I/D
polymorphism might be associated with hypertensive cerebrovascular disease in Japanese.

Methods and Results
To study the association between the
ACE I/D
polymorphism and hypertensive cerebrovascular disease, we identified the
ACE I/D
genotype in 228 hypertensive and 104 normotensive Japanese subjects. Compared with its frequency (0.31) in the 90 hypertensives without lacunae detected by magnetic resonance imaging, the
ACE*D
allele frequency was significantly higher (0.47;
P
<.001) in the 138 hypertensives with silent or clinically overt ischemic stroke, whereas there was no significant difference between its frequency in hypertensives without lacunae and in 104 normotensive control subjects (0.34). The positive association between the
ACE I/D
genotype and ischemic stroke in hypertensive patients was independent of other risk factors.

Conclusions
We found a positive association between the
ACE*D
allele and ischemic stroke in Japanese hypertensives in our study. The
ACE*D
allele may be an independent risk factor for the development of cerebrovascular disease in hypertensive patients.
Electrophysiological Mechanisms in Successful Radiofrequency Catheter Modification of Atrioventricular Junction for Patients With Medically Refractory Paroxysmal Atrial Fibrillation
Authors: Chen Shih-Ann , Lee Shih-Huang , Chiang Chern-En , Tai Chin-Tai , Wu Tsu-Juey , Cheng Chen-Chuan , Wen Zu-Chi , Chiou Chuen-Wang , Ueng Kwo-Chang , Chang Mau-Song
Published: June 2012

Background
Mechanisms and changes of electrophysiological (EP) characteristics in successful radiofrequency (RF) modification of right midseptal and posteroseptal areas for controlling rapid ventricular response to atrial fibrillation (Af) are not clear.

Methods and Results
We studied 50 patients with medically refractory paroxysmal Af. Group 1 consisted of 40 patients without dual atrioventricular (AV) node physiology with modification sites located in the mid/posteroseptal area. Of the 40 patients, 36 had successful modification (follow-up of 14±8 months), and 3 had AV block. Late follow-up electrophysiological study (98±10 days) showed pattern 1 (67%) with prolongation of AV node effective refractory period (ERP, ≥40 milliseconds) and Wenckebach block cycle length (WBCL, ≥40 milliseconds); pattern 2 (22%) with prolongation of AH interval (≥20 milliseconds), ERP, and WBCL; and pattern 3 (11%) without any change in AV node conduction parameter. Change in ventricular rate negatively correlated with change of WBCL in patterns 1 (
r
=−.691,
P
=.019) and 2 (
r
=−.90,
P
=.01). Group 2 consisted of 10 patients with dual AV node pathway; elimination of slow pathway property was performed. Late follow-up electrophysiological study (92±7 days) showed that change in ventricular rate negatively correlated with change in AV node ERP (
r
=−.926,
P
=.0001) and WBCL (
r
=−.969,
P
=.0001). Four patients without significant modification effect had success after RF energy was delivered to higher levels (follow-up, 15±7 months).

Conclusions
RF modification of right mid/posteroseptal area is feasible in 92% of patients with paroxysmal Af. Mechanisms of successful modification might be elimination of posterior input and/or partial injury of the compact node. Furthermore, simple elimination of slow pathway might be inadequate for control of ventricular rate in patients with little difference in conduction properties between fast and slow pathways.
Oxidized LDL Decreases
l
-Arginine Uptake and Nitric Oxide Synthase Protein Expression in Human Platelets
Authors: Chen L.Y. , Mehta P. , Mehta J.L.
Published: June 2012

Background
Oxidized LDL (ox-LDL) promotes vasoconstriction and platelet activation. The present study was undertaken to determine the involvement of the
l
-arginine–nitric oxide (NO) pathway in ox-LDL–mediated platelet activation.

Methods and Results
Washed human platelets were incubated with native LDL or ox-LDL for 1 hour at 37°C followed by measurement of platelet function and indexes of the
l
-arginine–NO pathway. Ox-LDL but not native LDL caused a concentration-dependent increase in thrombin-induced platelet aggregation and
14
C-serotonin release. These effects of ox-LDL were inhibited by pretreatment of platelets with
l
-arginine, the precursor of NO. Ox-LDL also caused a concentration-dependent reduction in the uptake of
3
H-
l
-arginine by platelets. In addition, NO synthase activity, measured as conversion of
3
H-
l
-arginine to
3
H-
l
-citrulline, decreased on incubation of platelet cytosol with ox-LDL. Nitrite production was also reduced by treatment of platelets with ox-LDL. These effects of ox-LDL on NO synthase activity and nitrite production were reversed by pretreatment of platelets with
l
-arginine. Concurrent with the decrease in NO production, cytosolic cGMP was inhibited in ox-LDL–treated platelets. The inhibitory effects of ox-LDL were dependent in part on the increase of cholesterol in the platelets. Western blot analysis demonstrated ≈50% reduction in the expression of NO synthase protein in platelets treated with ox-LDL.

Conclusions
These observations indicate that the
l
-arginine–NO pathway is involved in the effects of ox-LDL on platelet function and that ox-LDL stimulates platelet function primarily by diminishing NO synthase expression as well as decreasing the uptake of
l
-arginine.
Aortocaval Fistulae
Authors: Boudghène Frank , Sapoval Marc , Bonneau Michel , Bigot Jean-Michel
Published: June 2012

Background
Treatment of aortocaval fistulae (ACFs) by open surgery is known to be a high-risk procedure. In this experimental study, we developed a percutaneous model of ACF to test a new nonsurgical method of treatment of ACF using endovascular stent grafts.

Methods and Results
An ACF was created percutaneously in eight sheep. Via a combined venous and arterial femoral approach, angioplasty balloons were inserted to occlude the infrarenal aorta and inferior vena cava (IVC). The IVC was punctured through the lateral aortic wall with a transjugular liver biopsy needle. The fistulous tract was then dilated with an 8-mm angioplasty balloon, and the animal was heparinized. Two weeks later, a 10-mm Cragg-Endopro-Stent was inserted into the aorta at the level of the fistula via a percutaneous femoral approach. ACFs were successfully created in all animals, with rapid dye shunt through the fistula and a 20% increase in cardiac pulsations. Follow-up angiograms at 2 weeks showed a patent ACF, and stent implantation excluded the fistula in every case. Angiographic and pathological examinations up to 6 months demonstrated normal aortic patency and persistent exclusion of the fistulae.

Conclusions
ACFs were effectively treated by endovascular grafting of the aorta. The animal model and the stenting procedures were both performed percutaneously.
Coronary Heart Disease Risk Factors in Men and Women Aged 60 Years and Older
Authors: Frost Philip H. , Davis Barry R. , Burlando Alfredo J. , David Curb J. , Guthrie Gordon P. , Isaacsohn Jonathan L. , Wassertheil-Smoller Sylvia , Wilson Alan C. , Stamler Jeremiah
Published: June 2012

Background
Coronary heart disease (CHD) is the most common cause of death in men and women aged 60 years and older. Although a number of studies support the concept that CHD risk factors that have been defined in younger adults are significantly associated with CHD events in older adults, others do not support this thesis, and further definition of the risk-factor concept in older adults is required.

Methods and Results
The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years); 14% were black, and 43% were men. Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. About 13% of participants were current smokers; 10% had a history of diabetes; 5%, a prior myocardial infarction; 5%, angina pectoris; 2.3%, intermittent claudication; and 7%, a carotid bruit. Mean total cholesterol value was 6.11 mmol/L. Mean follow-up was 4.5 years. In multivariate Cox regression analyses for CHD, variables that were significant were baseline total cholesterol value, smoking, history of diabetes, presence of carotid bruit, and treatment group in the trial. Active treatment yielded a 27% reduction in CHD risk. For each 1.03 mmol/L increase in total cholesterol value, there was an increase in risk of about 20%. Current smokers had a 73% increase, diabetics a 121% increase, and those with carotid bruit a 113% increase in CHD risk.

Conclusions
The results of this study support the concept that CHD risk factors are important in older men and women with isolated systolic hypertension.
Aspirin-Stimulated Nitric Oxide Production by Neutrophils After Acute Myocardial Ischemia in Rabbits
Authors: Lo´pez-Farre´ Antonio , Riesco Amparo , Digiuni Enzo , Mosquera Juan R. , Caramelo Carlos , de Miguel Lourdes S. , Milla´s Inmaculada , de Frutos Trinidad , Cernadas Maria R. , Monto´n Mercedes , Alonso Javier , Casado Santos
Published: June 2012

Background
In recent studies, it has been hypothesized that the protective anti-ischemic effects of aspirin outweigh the effects of inhibition of platelet thromboxane A
2
synthesis. Recently, we have found that the antiaggregating effects of aspirin significantly affect nitric oxide (NO) generation by neutrophils.

Methods and Results
The present study used circulating neutrophils from myocardial ischemic rabbits to assess the effect of aspirin on the circulating neutrophil–derived NO production and, subsequently, on the modulation of platelet activation. Neutrophils were obtained after 60 minutes of coronary artery occlusion followed by 60 minutes of reperfusion. Sham-operated animals were used as controls. The results demonstrated that aspirin stimulated the production of NO by neutrophils obtained from both sham-operated rabbits and rabbits with myocardial ischemia. However, neutrophils isolated from animals with myocardial ischemia showed an enhanced ability to generate NO in the presence of aspirin. As a functional in vitro marker, we observed that neutrophils had a NO-dependent, platelet-antiactivating effect in the presence of aspirin. In the absence of aspirin, ischemic neutrophils did not modify platelet activation, even though they produced increased amounts of NO. An inhibitory role of superoxide anion on the neutrophil-related antiplatelet effect was suggested because superoxide dismutase induced significant platelet inhibition by myocardial ischemic neutrophils in the absence of aspirin.

Conclusions
Our results show that myocardial ischemia/reperfusion stimulates production of NO by circulating neutrophils, an effect that was enhanced in the presence of aspirin. These results suggest a novel interpretation of the protective effect of aspirin on myocardial ischemia damage.
Arterial Thrombin Activity After Angioplasty in an Atherosclerotic Rabbit Model
Authors: Barry William L. , Gimple Lawrence W. , Humphries John E. , Powers Eric R. , McCoy Kyle W. , Sanders John M. , Owens Gary K. , Sarembock Ian J.
Published: June 2012

Background
A 2-hour infusion of the direct thrombin inhibitor hirudin at the time of balloon angioplasty limits restenosis in the focally atherosclerotic rabbit. Although short-term administration of hirudin may have a prolonged biological effect, the effect of hirudin on vessel thrombin activity has not been previously studied in an animal model of angioplasty. We hypothesized that a short intravenous infusion of hirudin would result in prolonged inhibition of arterial wall–associated thrombin activity (ATA) after angioplasty.

Methods and Results
Sixty-one rabbits received recombinant hirudin (r-hirudin) (1 mg/kg bolus plus 1 mg · kg
−
1
· h
−
1
×2 hours) or bolus heparin (controls, 150 U/kg) intravenously at the time of femoral balloon angioplasty. ATA was measured through exposure of arterial segments ex vivo to fibrinogen and conducting an assay for fibrinopeptide A (FPA). ATA was low in nonballooned, atherosclerotic vessels (FPA=0.5±0.3 ng · mL
−
1
· mg
−
1
) but increased significantly at 24 hours after angioplasty in the heparin group (3.7±0.9 ng · mL
−
1
· mg
−
1
,
P
<.01 versus baseline, n=9) but not in the hirudin group (FPA=1.4±0.3;
P
=NS versus baseline,
P
<.02 versus heparin controls, n=8). The time course of ATA after angioplasty was assessed in 44 rabbits. Thrombin activity peaked at 48 hours and declined to baseline at 72 hours and 7 days. FPA values between the heparin and r-hirudin groups were similar at these later time points.

Conclusions
A 2-hour intravenous infusion of r-hirudin suppressed ATA measured 24 hours after angioplasty in the focally atherosclerotic rabbit. This prolonged biological effect may account, in part, for the reduction in restenosis seen in this model.
Elucidating the Mechanisms of Atrial Flutter Cycle Length Variability Using Power Spectral Analysis Techniques
Authors: Stambler Bruce S. , Ellenbogen Kenneth A.
Published: June 2012

Background
The mechanism of the small beat-to-beat variations in cycle length of atrial flutter in humans has not been fully explained. We investigated the beat-to-beat control of atrial flutter cycle length using time and frequency analysis techniques.

Methods and Results
Mean, SD, and power spectra of atrial cycle lengths were calculated from atrial recordings in 28 patients with type I atrial flutter. In control patients, mean and SD values of atrial cycle length were 265±37 and 4.9±1.7 ms. Power spectra contained two or three major peaks with 10.6±9.2% in band 1 (0.0 to 0.18 Hz), 26.7±15.9% in band 2 (0.18 to 0.6 Hz), and 63.1±17.7% in band 3 (0.6 to 2.2 Hz). Isoproterenol infusion (n=8) increased percentage of total power in band 1 (7.1±5.6% to 25.7±18.9%,
P
<.001). Percentage of total power in band 1 was less in patients receiving (n=5) versus not receiving (n=18) oral β-blockers (2.2±1.9% versus 10.6±9.2%,
P
=.003). Standard deviation (2.5±1.3 versus 4.9±1.7 ms,
P
=.009) and total power (2025±1350 versus 9768±8874 ms
2
,
P
=.005) were less in heart transplant recipients (n=5) than control patients. Increases in respiratory rate (n=6) shifted band 2 frequency peak to higher frequencies (0.26±0.13 to 0.38±0.18 Hz,
P
<.05). Atrial cycle length was longer and monophasic action potential duration was shorter during inspiration than during expiration. Band 3 frequency peak was correlated with heart rate (
r
=.797,
P
<.0001).

Conclusions
Atrial flutter cycle length variability has an underlying periodic pattern that is detected by spectral analysis. Atrial flutter is modulated on a beat-to-beat basis by an interplay between the autonomic nervous and respiratory systems and the ventricular rate.
Effects of Low-Dose Heparin Infusion on Arterial Endothelin-1 Release in Humans
Authors: Piatti P.M. , Monti L.D. , Valsecchi G. , Conti M. , Nasser R. , Guazzini B. , Fochesato E. , Phan C.V. , Pontiroli A.E. , Pozza G.
Published: June 2012

Background
The aim of this study was to evaluate the effect of low-dose heparin infusion on arterialized endothelin-1 (ET-1) release in the presence of fasting or high insulin levels in healthy humans.

Methods and Results
Eleven normal subjects underwent two tests in random order lasting 240 minutes. A primed (250 IU), continuous heparin (600 IU/h) infusion was performed in test 1; saline was infused in test 2 as control. At 120 minutes, a euglycemic hyperinsulinemic clamp (25 mU·kg
−1
·h
−1
) was started that lasted 2 hours in both tests. Two hours after heparin infusion (test 1), ET-1 levels decreased by 32% (3.52±0.60 to 3.02±0.73 pg/mL), while nitric oxide (NO) and forearm blood flow increased by 29% and 14%, respectively. During saline infusion, ET-1, nitric oxide, and forearm blood flow remained unchanged. There was a significant interaction between the effect of decreasing ET-1 levels and the heparin treatment (
F
, 4.06;
df
, 3.30;
P
<.01). The decrease in ET-1 levels was significantly correlated with the increase in forearm blood flow in test 1 (
r
=.74;
P
<.01) but not in test 2. During the heparin/insulin period, ET-1 increased by 25%, returning to fasting values; nitric oxide levels increased by 12%; and forearm blood flow remained unchanged.

Conclusions
The present study showed that it is possible to decrease ET-1 levels by use of low-dose heparin infusion in humans. This effect seems mediated by a simultaneous increase in nitric oxide levels and is completely reversed by a mild increase in insulin concentrations.
Myocardial Ultrasonic Tissue Characterization in Pediatric and Adult Patients With Hypertrophic Cardiomyopathy
Authors: Vitale Dino F. , Bonow Robert O. , Calabro` Raffaele , De Cristofaro Margherita , Pacileo Giuseppe , Caso Pio , Gerundo Giusto , Bordini Carlo , Losi Maria Angela , Rengo Carlo , Rengo Franco
Published: June 2012

Background
Hypertrophic cardiomyopathy (HCM) has different clinical and prognostic aspects in young than in adult patients. This study was undertaken to determine whether these reported differences are reflected by changes in ultrasonic backscatter parameters and whether oral treatment with verapamil modifies backscatter variables in children with HCM.

Methods and Results
Sixty-eight subjects underwent backscatter analysis to assess the ultrasonic myocardial reflectivity and the amplitude of the cardiac cycle–dependent variation of the backscatter power curve. Subjects were divided into four groups: 10 HCM and 23 normal subjects <10 years old and 17 HCM and 18 normal adults. Myocardial reflectivity and amplitude of the cyclic variation were assessed in the septum and in the posterior wall of all subjects. The children with HCM were restudied after long-term oral administration of verapamil. Both children and adult patients, compared with the normal control groups, showed a significant reduction in the amplitude of the cyclic variation both in the septum and in the posterior wall. In contrast, myocardial reflectivity, although significantly increased in adult HCM patients, was unchanged in the young HCM group. Verapamil administration did not significantly alter the results in the children with HCM.

Conclusions
These data demonstrate that in young HCM patients, the ultrasonic myocardial reflectivity is normal, in contrast to the significant increase observed in adult patients affected by the same disease. This observation is in accord with the different clinical manifestations reported in young HCM patients and indicates an age-dependent difference in the echogenic structure of the hypertrophied myocardium in HCM.
Preserved Vasodilatory Response to Nitroglycerin in Saphenous Vein Bypass Grafts
Authors: Berglund Hans , Luo Huai , Nishioka Toshihiko , Eigler Neal L. , Kim Chong-Jin , Tabak Steven W. , Siegel Robert J.
Published: June 2012

Background
Uncertainty exists regarding the effects of nitroglycerin on atherosclerotic segments of coronary arteries, and information on vasoreactivity of saphenous vein bypass grafts is sparse. Intravascular ultrasound enables identification of atherosclerosis in angiographically normal segments and allows continuous determination of alterations in cross-sectional lumen areas.

Methods and Results
Patients with documented coronary atherosclerosis were studied. Vessel morphology and lumen area at baseline and after 100 to 200 μg nitroglycerin were assessed at 10-second intervals for 60 seconds in vessel segments without angiographically apparent lesions. Coronary artery saphenous vein bypass grafts from 11 patients were compared with native coronary arteries in 16 different patients. Atherosclerosis was present in all vessel segments studied. There was a rapid increase in lumen area compared with baseline after intravascular nitroglycerin in both native coronary arteries and saphenous vein bypass grafts. Maximum lumen area dilatation was 19.6±12.2% in saphenous vein bypass grafts and 19.7±13.1% in native coronary arteries. An earlier peak response in saphenous vein bypass grafts (34.5±6.9 seconds) compared with native coronary arteries (44.7±8.5 seconds;
P
=.003) was found. Vessel wall area remained constant during vasodilation, but there was a significant reduction in measured wall thickness (
P
=.034).

Conclusions
In patients with documented coronary artery disease, intravascular ultrasound reveals substantial atherosclerosis in angiographically normal vessel segments. In these vessel segments, both native coronary arteries and saphenous vein bypass grafts exhibit prompt vasodilation with the intravascular administration of nitroglycerin. The vasodilatory capacity in response to nitroglycerin seems to be preserved in transposed, denervated, and devascularized saphenous veins.
17β-Estradiol Prevents Dysfunction of Canine Coronary Endothelium and Myocardium and Reperfusion Arrhythmias After Brief Ischemia/Reperfusion
Authors: Kim Young D. , Chen Barbara , Beauregard John , Kouretas Peter , Thomas George , Farhat Michel Y. , Myers Adam K. , Lees David E.
Published: June 2012

Background
Brief myocardial ischemia is associated with myocardial and coronary endothelial dysfunction caused by oxygen free radicals released during reperfusion. Estrogen, known to have antioxidant activity, may prevent these complications.

Methods and Results
We assessed the effect of 2 weeks of treatment with 17β-estradiol (E, 100 μg·kg
−1
·d
−1
, n=12) or placebo (P, n=15) on myocardial and coronary endothelial function during the first 2 hours of reperfusion in dogs subjected to 15 minutes of ischemia induced by occlusion of the left anterior descending coronary artery (LAD). Our results show that the incidence of ventricular arrhythmias significantly decreased in E (3 of 12) compared with P (11 of 15). Systolic shortening, significantly depressed in P during early reperfusion, was maintained at preischemic levels in E. During reperfusion, the increase in LAD flow to acetylcholine, attenuated in P (60±6%), was preserved in E (151±28%) and was associated with increased serum nitrite/nitrate concentration.
n
-Pentane in exhaled gas in vivo, an index of lipid peroxidation, increased significantly during early reperfusion in P (from 9.1±1.9 to 41.6±13.0 ppb,
P
<.05) but not in E (23.0±6.9 ppb). In vitro, arterial segments from E generated significantly less superoxide anion after hypoxia/reoxygenation than those from P. Ischemic/reperfused LAD segments from E also revealed a better preservation of endothelium-dependent relaxation in vitro (maximum relaxation, 42±4% versus 24±4% in P;
P
<.05).

Conclusions
Estrogen protects against endothelial and myocardial dysfunction resulting from brief ischemia/reperfusion. This protection may relate to an antioxidant effect of estrogen.
Persistent Expression of Cytokine in the Chronic Stage of Viral Myocarditis in Mice
Authors: Shioi Tetsuo , Matsumori Akira , Sasayama Shigetake
Published: June 2012

Background
Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure of unknown origin. One possible cause of DCM is considered to be a sequel to myocarditis. However, the mechanism of progression from viral myocarditis to DCM is still not clear.

Methods and Results
The expression of the immunoregulatory cytokines interferon (IFN)-γ and interleukin (IL)-2 and the proinflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α in the heart tissue was studied in a murine model of postmyocarditis DCM induced by encephalomyocarditis virus. IFN-γ, IL-1β, and TNF-α mRNA increased 3 days after virus inoculation. IL-2 mRNA was detectable 7 days after inoculation. The peak expression of all cytokine genes examined was seen 7 days after inoculation. The expression of these cytokine genes decreased thereafter but persisted 80 days after inoculation. IL-1β gene expression in the chronic stage was relatively high compared with other cytokines and was correlated with the ratio of heart weight to body weight and the extent of fibrotic lesions. Immunohistochemical analysis revealed that some of the mononuclear cells, endothelial cells, and interstitial macrophages were positive for IL-1β or TNF-α and fibroblasts were positive for IL-1β in the heart tissue of mice 80 days after inoculation.

Conclusions
Persistent expression of cytokines was seen in a murine model of postmyocarditis DCM. These cytokines may have important implications in the pathogenesis of DCM.
Macrophages, Smooth Muscle Cells, and Tissue Factor in Unstable Angina
Authors: Moreno Pedro R. , Bernardi Vi´ctor H. , Lo´pez-Cue´llar Julio , Murcia Alvaro M. , Palacios Igor F. , Gold Herman K. , Mehran Roxana , Sharma Samin K. , Nemerson Yale , Fuster Valenti´n , Fallon John T.
Published: June 2012

Background
Macrophage expression of tissue factor may be responsible for coronary thrombogenicity in patients with plaque rupture. In patients without plaque rupture, smooth muscle cells may be the thrombogenic substrate. This study was designed to identify the cellular correlations of tissue factor in patients with unstable angina.

Methods and Results
Tissue from 50 coronary specimens (1560 pieces) from patients with unstable angina and 15 specimens from patients with stable angina were analyzed. Total and segmental areas (in square millimeters) were identified with trichrome staining. Macrophages, smooth muscle cells, and tissue factor were identified by immunostaining. Tissue factor content was larger in unstable angina (42±3%) than in stable angina (18±4%) (
P
=.0001). Macrophage content was also larger in unstable angina (16±2%) than in stable angina (5±2%) (
P
=.002). The percentage of tissue factor located in cellular areas was larger in coronary samples from patients with unstable angina (67±8%) than in samples from patients with stable angina (40±5%) (
P
=.00007). Multiple linear stepwise regression analysis showed that coronary tissue factor content correlated significantly (
r
=.83,
P
<.0001) with macrophage and smooth muscle cell areas only in tissue from patients with unstable angina, with a strong relationship between tissue factor content and macrophages in the atheromatous gruel (
r
=.98,
P
<.0001).

Conclusions
Tissue factor content is increased in unstable angina and correlates with areas of macrophages and smooth muscle cells, suggesting a cell-mediated thrombogenicity in patients with acute coronary syndromes.
Nonsustained Ventricular Tachycardia in Severe Heart Failure
Authors: Doval Hernan C. , Nul Daniel R. , Grancelli Hugo O. , Varini Sergio D. , Soifer Saul , Corrado Gianni , Dubner Sergio , Scapin Omar , Perrone Sergio V.
Published: June 2012

Background
The goal of the study was to determine the prognostic value of nonsustained ventricular tachycardia (NSVT) in total mortality in severe congestive heart failure (CHF) and in death modes. NSVT is associated with an increased mortality in CHF. However, the predictive value of NSVT as a marker for sudden death or death due to progressive heart failure has not been determined.

Methods and Results
Five hundred sixteen patients from the GESICA trial (33.4% with NSVT) were initially studied with the results of 24-hour Holter and 2 years of follow-up. Within 2 years, 87 of 173 patients (50.3%) with NSVT and 106 of 343 patients (30.9%) without NSVT died. Relative risk (RR) was 1.69 (95% confidence interval [CI], 1.27 to 2.24;
P
<.0002), and Cox proportional hazard analysis was 1.62 (95% CI, 1.22 to 2.16;
P
<.001). Sudden death increased from 8.7% (30 of 343) to 23.7% (41 of 173) in patients with NSVT (RR, 2.77; 95% CI, 1.78 to 4.44;
P
<.001). Progressive heart failure death was also increased from 17.5% (60 of 343) to 20.8% (36 of 173) (
P
=.22). Quantitative analysis of 24-hour Holter (first 295 patients) demonstrated that couplets had a similar RR to that of NSVT for both total mortality (RR, 1.81; 95% CI, 1.22 to 2.66;
P
<.002) and sudden death (RR, 3.37; 95% CI, 1.57 to 7.25;
P
<.0005). Couplets and/or NSVT (ventricular repetitive beats) were even more predictive for sudden death (RR, 10.1; 95% CI, 1.91 to 52.7;
P
<.01).

Conclusions
In patients with CHF, NSVT is an independent marker for increased overall mortality rate and sudden death. The absence of NSVT and ventricular repetitive beats in a 24-hour Holter indicates a low probability of sudden death.
Inadvertent Atrioventricular Block During Radiofrequency Catheter Ablation
Authors: Schaffer Michael S. , Silka Michael J. , Ross Bertrand A. , Kugler John D.
Published: June 2012

Background
Inadvertent atrioventricular block is a complication of radiofrequency ablation. The present study is an analysis of the incidence, significance, and factors associated with inadvertent atrioventricular block during radiofrequency catheter ablation in childhood and adolescence.

Methods and Results
The records of the Pediatric Radiofrequency Ablation Registry were reviewed. Between January 1, 1991, and April 1, 1994, atrioventricular block occurred in 23 of 1964 radiofrequency ablations (1.2%): 14 as third-degree block (3 transient) and 9 as second-degree block (5 transient). Atrioventricular block occurred from 5 seconds to 2 months (mean, 4.1 days; median, 15 seconds) after the onset of the energy application. Eight transient cases lasted 1 hour to 1 month (mean, 9.4 days; median, 7 days). Inadvertent atrioventricular block was related to the ablation anatomic site: 3 of 111 (2.7%) anteroseptal, 11 of 106 (10.4%) midseptal, and 2 of 197 (1.0%) right posteroseptal sites (
P
=.0007 for anteroseptal,
P
=.0001 for midseptal, and
P
=.17 for right posteroseptal versus nonright septal sites). Five of 314 (1.6%) ablations for atrioventricular nodal reentrant tachycardia resulted in atrioventricular block (
P
=.004 versus nonright septal sites). Compared with a matched subgroup, radiofrequency ablation experience was the only significant risk factor (32.7 versus 106.6,
P
=.002) for the occurrence of atrioventricular block.

Conclusions
Inadvertent atrioventricular block may occur during or late after radiofrequency catheter ablation. It is associated with ablations for (1) anterior and midseptal accessory pathways and atrioventricular nodal reentry and (2) relative institutional inexperience.