bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiarrhythmic Actions of Intravenous Ibutilide Compared With Procainamide During Human Atrial Flutter and Fibrillation
Authors: Stambler Bruce S. , Wood Mark A. , Ellenbogen Kenneth A.
Published: June 2012

Background
The selective class III antiarrhythmic agent ibutilide prolongs action potential duration and terminates atrial flutter (AFL) and fibrillation (AF), but the mechanism of its antiarrhythmic efficacy in humans has not been fully characterized. This study compared the antiarrhythmic effects of ibutilide with the class IA agent procainamide in humans during AFL and AF. Antiarrhythmic drug actions and electrophysiological characteristics of AFL and AF that enhanced pharmacological termination were investigated.

Methods and Results
Right atrial monophasic action potentials were recorded during 148 episodes of AFL (n=89) or AF (n=59) in 136 patients treated with intravenous ibutilide (n=73) or placebo (n=22) as participants in randomized, double-blinded comparative studies or intravenous procainamide (n=53) in a concurrent open-label study. The conversion rates in AFL with ibutilide, procainamide, and placebo were 64% (29 of 45 patients), 0% (0 of 33), and 0% (0 of 11), respectively, whereas in AF the rates were 32% (9 of 28), 5% (1 of 20), and 0% (0 of 11), respectively. In AFL, ibutilide increased atrial monophasic action potential duration (MAPD) more (30% versus 18%,
P
<.001) and prolonged atrial cycle length (CL) less (16% versus 26%,
P
<.001) than procainamide. Ibutilide shortened and procainamide prolonged action potential diastolic interval during AFL (−12% versus 51%,
P
<.001). Ibutilide increased MAPD/CL ratio, whereas procainamide tended to decrease this ratio (13% versus −6%,
P
<.01). In AF, ibutilide and procainamide induced similar increases in atrial CL (48% versus 45%), but ibutilide induced a greater increase in MAPD (52% versus 37%,
P
<.05). Independent electrophysiological predictors of pharmacological arrhythmia termination were increase in MAPD/CL ratio (
P
=.005) in AFL and longer baseline mean MAPD (
P
=.011) in AF. Termination of AFL with ibutilide was characterized by significant increases in beat-to-beat atrial CL, MAPD, and diastolic interval variability. Ibutilide was significantly more effective in converting AF when the mean atrial CL was ≥160 ms (64% versus 0%,
P
<.001) or MAPD was ≥125 ms (57% versus 0%,
P
=.002) at baseline.

Conclusions
Enhanced conversion efficacy of ibutilide compared with procainamide in AFL is correlated with a relatively greater prolongation of atrial MAPD than atrial CL, and termination of AFL by ibutilide is characterized by oscillations in atrial CL and MAPD. Conversion of AF by ibutilide is enhanced by a longer baseline mean atrial CL or MAPD.
Relationship Between Progressive Microvascular Damage and Intramyocardial Hemorrhage in Patients With Reperfused Anterior Myocardial Infarction
Authors: Asanuma Toshihiko , Tanabe Kazuaki , Ochiai Koichi , Yoshitomi Hiroyuki , Nakamura Ko , Murakami Yo , Sano Kazuya , Shimada Toshio , Murakami Rinji , Morioka Shigefumi , Beppu Shintaro
Published: June 2012

Background
Recent studies indicated that ischemic microvascular damage may be reversible or progressive after coronary reflow. Intramyocardial hemorrhage is a phenomenon that reflects severe microvascular injury. We examined the relationship between temporal changes in microvascular perfusion patterns detected by myocardial contrast echocardiography (MCE) and intramyocardial hemorrhage detected by magnetic resonance imaging (MRI) in patients with acute myocardial infarction (AMI).

Methods and Results
The study population consisted of 24 patients with anterior AMI. All patients underwent MCE shortly after reflow and in the chronic stage (a mean of 31 days after reflow). Wall motion score (WMS) was determined as the sum of 16 segmental scores (dyskinetic/akinetic=3 to normal=0) at days 1 and 31. Gradient-echo acquisition and gadolinium-DTPA–enhanced spin-echo MRI were performed within 10 days after reflow. In MCE shortly after reflow, 16 patients (67%) showed contrast enhancement and the other 8 patients (33%) showed a sizable contrast defect. In the chronic stage, a persistent contrast defect was observed in 7 of 8 patients with a contrast defect shortly after reflow. Consistent contrast enhancement was observed in 12 of 16 patients (75%) with contrast enhancement shortly after reflow, indicating that a contrast defect newly appeared in 4 patients (25%). Intramyocardial hemorrhage was detected in 9 patients (38%): 5 of 7 patients with a persistent contrast defect and in all 4 patients with a new appearance of a contrast defect during the chronic stage. The patients without hemorrhage showed a significant improvement in WMS compared with patients with hemorrhage at day 31 (5±5 versus 19±6,
P
<.0005).

Conclusions
These results suggest that irreversible microvascular damage to the ischemic myocardium may cause intramyocardial hemorrhage after reflow, associated with impaired recovery of left ventricular function. Contrast enhancement within the risk area shortly after reflow does not necessarily indicate long-term microvascular salvage.
Late Regression of the Dilated Site After Coronary Angioplasty
Authors: Ormiston John A. , Stewart Fiona M. , Roche Antony H. G. , Webber Bruce J. , Whitlock Ralph M. L. , Webster Mark W. I.
Published: June 2012

Background
Limited data are available on the changes that occur at the dilated site late after coronary angioplasty. The aim of this study was to evaluate with quantitative angiography the natural history of changes that occur in the dilated segment between “early” (≈6 months) and “late” (≈5 years) follow-up after angioplasty.

Methods and Results
Of 127 consecutive patients (174 lesions) with successful angioplasty, 125 underwent early angiography. Three patients subsequently died, and 24 underwent revascularization surgery or repeated angioplasty, giving a study-eligible population of 98 patients. Quantitative angiographic analysis was performed before and immediately after angioplasty and at early and late follow-up in the study population of 84 patients (115 lesions), which was 86% of study-eligible patients. Mean lesion diameter stenosis decreased from 36.3±14.2% at early to 29.6±13.5% at late follow-up (
P
<.0001). No lesion developed late restenosis by the 50% diameter loss criterion. Late regression was related to stenosis severity at early angiography (
r
=−.58,
P
<.001). Subgroups at early angiography of 40% to 49% stenosis and ≥50% stenosis showed significant regression at late angiography.

Conclusions
Lesion regression at the dilated site is common late after angioplasty. The more severe a stenosis is at early angiography, the more likely the chance that there will be late regression. A strategy of watchful waiting may be appropriate for patients with restenotic lesions of borderline severity.
Downregulation of Cyclin G1 Expression by Retrovirus-Mediated Antisense Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
Authors: Zhu Nian Ling , Wu Lingtao , Liu Peng Xuan , Gordon Erlinda M. , Anderson W. French , Starnes Vaughn A. , Hall Frederick L.
Published: June 2012

Background
The contemporary treatment of coronary athero-occlusive disease by percutaneous transluminal coronary angioplasty is hampered by maladaptive wound healing, resulting in significant failure rates. Morbid sequelae include smooth muscle cell (SMC) hyperplasia and restenosis due to vascular neointima formation.

Methods and Results
In this study, we examined the inhibitory effects of a concentrated retroviral vector bearing an antisense cyclin G1 gene on aortic SMC proliferation in vitro and on neointima formation in vivo in a rat carotid injury model of restenosis. Retroviral vectors bearing an antisense cyclin G1 construct inhibited the proliferation of transduced aortic SMCs in 2- to 6-day cultures, concomitant with downregulation of cyclin G1 protein expression and decreased [
3
H]thymidine incorporation into DNA. Morphological examination showed evidence of cytolysis, giant syncytia formation, and apoptotic changes evidenced by overt cell shrinkage, nuclear fragmentation, and specific immunostaining of nascent 3′-OH DNA ends generated by endonuclease-mediated DNA fragmentation. Pronounced “bystander effects” including neighboring cells were noted in aortic SMCs transduced with the antisense cyclin G1 vector, as determined by quantitative assays and fluorescent labeling of nontransduced cells. In an in vitro tissue injury model, the proliferation and migration of antisense cyclin G1 vector–transduced aortic SMCs were inhibited. Moreover, in vivo delivery of high-titer antisense cyclin G1 vector supernatant to the balloon-injured rat carotid artery in vivo resulted in a significant reduction in neointima formation.

Conclusions
These findings represent the first demonstration of the inhibitory effects of an antisense cyclin G1 retroviral vector on nonneoplastic cell proliferation. Taken together, these data affirm the potential utility of antisense cyclin G1 constructs in the development of novel gene therapy approaches to vascular restenosis.
Coronary Angiographic Characteristics of Patients With Permanent Artificial Pacemakers
Authors: Mosseri Morris , Izak Tami , Rosenheck Shimon , Lotan Chaim , Rozenman Yoseph , Zolti Einat , Admon Dan , Gotsman Mervyn S.
Published: June 2012

Background
The cause of severe cardiac conduction disturbances is often uncertain. The aim of this study was to examine a group of patients with permanent pacemakers who underwent coronary arteriography to determine the extent of coronary atherosclerotic disease that might be responsible for the conduction disturbances.

Methods and Results
Forty-three consecutive patients with a permanent pacemaker and 36 matched control patients were investigated. The coronary angiographic study included measurement of diameter and stenosis severity, qualitative assessment of flow, and classification of pathological anatomy, particularly the blood supply to territories supplying the different segments of the conduction system. Among 43 patients with a permanent pacemaker, 27 had ischemic heart disease (17 after coronary artery bypass graft surgery). The conduction disturbance was infranodal in 28 patients, sinus nodal in 6, AV nodal in 4, and complete AV block of unspecified origin in 5. Patients with permanent pacemakers had a coronary artery pathology compromising blood flow to the septal branches and the right coronary artery (type IV anatomy). This pattern was significantly different from the matched control patients, in whom the most prevalent coronary anatomy was the combination of right coronary artery with distal left anterior descending artery (not involving the septal branches) lesions (
P
=.007).

Conclusions
Patients with coronary artery disease and severe conduction disturbances that require implantation of permanent pacemakers are more likely to have a specific pathological coronary anatomy that combines a compromised blood flow to the septal branches of the left anterior descending artery with right coronary artery lesions. The location of lesions in the coronary tree rather than severe diffuse atherosclerosis appears to be responsible for the conduction disturbances.
Changes in Phasic Coronary Blood Flow Velocity Profile and Relative Coronary Flow Reserve in Patients With Hypertrophic Obstructive Cardiomyopathy
Authors: Kyriakidis Michael K. , Dernellis John M. , Androulakis Aristides E. , Kelepeshis Glafkos A. , Barbetseas John , Anastasakis Aristides N. , Trikas Athanasios G. , Tentolouris Costas A. , Gialafos John E. , Toutouzas Pavlos K.
Published: June 2012

Background
In this study, we both investigated coronary flow velocity in hypertrophic obstructive cardiomyopathy (HOCM) and tested the hypothesis of differing coronary flow reserve (CFR) of coronary arteries perfusing left ventricular regions with nonuniform myocardial hypertrophy by measuring the relative CFR.

Methods and Results
Coronary flow velocity was assessed in left anterior descending coronary (LAD) and left circumflex (LCx) arteries in 18 patients with HOCM and marked hypertrophy only in the ventricular septum, in 13 patients without obstruction (HCM), and in 9 age- and sex-matched normal subjects at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 μg/kg per minute). Relative CFR was estimated as the ratio between absolute CFR of the LAD and absolute CFR of the LCx (LAD/LCx
CF
). At the peak of rapid atrial pacing and during dobutamine stress, LAD/LCx
CF
was reversed in HOCM patients (from 1.25±0.11 to 0.82±0.07 and 0.79±0.06, respectively), whereas it remained unchanged in control subjects (from 1.0±0.1 to 1.0±0.05 and 1.0±0.05, respectively;
P
<.001). In HCM patients, LAD/LCx
CF
at rest was 1.10±0.11, whereas during rapid atrial pacing and dobutamine stress, it was 0.92±0.08 and 0.90±0.09, respectively. Relative CFR was 0.62±0.05 in HOCM patients and 1.05±0.05 (
P
<.001) in normal subjects. There was an inverse correlation between relative CFR and peak systolic outflow tract gradient (
r
2
=.74,
P
<.001).

Conclusions
Regional distribution of hypertrophy in some patients with HOCM resulted in regional impairment of coronary flow. Relative CFR can be used to estimate regional disturbances of coronary flow and may help in patient selection for new interventional therapeutic techniques.
Regional Disparities in the Incidence of Elevated Blood Pressure Among Young Adults
Authors: Kiefe Catarina I. , Williams O. Dale , Bild Diane E. , Lewis Cora E. , Hilner Joan E. , Oberman Albert
Published: June 2012

Background
Within the United States, little is known about regional disparities in blood pressure (BP), their changes over time, or explanations for their existence.

Methods and Results
A population-based cohort of 5115 black and white men and women, 18 to 30 years old in 1985-1986 (balanced on age, race, sex, and education), was followed up for 7 years in four centers: Birmingham, Ala; Chicago, Ill; Minneapolis, Minn; and Oakland, Calif. Differences in elevated BP (EBP) prevalence among centers at years 0, 2, 5, and 7 and in 7-year incidence of EBP were assessed. Sociodemographic and dietary variables, physical activity, weight, smoking, and alcohol were considered. At year 0, no regional differences were seen. Seven years later, there was marked variability in prevalence of EBP overall and for both black and white men, from a low in Chicago (9% for black men and 5% for white men) to a high in Birmingham (25% for black men and 14% for white men). Birmingham also had the highest 7-year incidence (11%) and overall prevalence at year 7 (14%). The adjusted odds ratios, with Birmingham as referent (95% CIs), for 7-year incidence of EBP overall were 0.38 (0.24, 0.60) for Chicago, 0.37 (0.24, 0.57) for Minneapolis, and 0.74 (0.52, 1.07) for Oakland.

Conclusions
Regional disparities are absent at baseline but become apparent as the cohort ages. These differences are not fully explained by the available behavioral and sociodemographic characteristics.
Dietary
l
-Arginine Reduces the Progression of Atherosclerosis in Cholesterol-Fed Rabbits
Authors: Böger Rainer H. , Bode-Böger Stefanie M. , Brandes Ralf P. , Phivthong-ngam Laddaval , Böhme Michael , Nafe Reinhold , Mügge Andreas , Frölich Jürgen C.
Published: June 2012

Background
We investigated whether
l
-arginine induces regression of preexisting atheromatous lesions and reversal of endothelial dysfunction in hypercholesterolemic rabbits, whether similar effects can be obtained by cholesterol-lowering therapy with lovastatin, and which mechanism leads to these effects.

Methods and Results
Rabbits were fed 1% cholesterol for 4 weeks and 0.5% cholesterol for an additional 12 weeks. Two groups of cholesterol-fed rabbits were treated with
l
-arginine (2.0% in drinking water) or lovastatin (10 mg/d) during weeks 5 through 16. Systemic nitric oxide (NO) formation was assessed as the urinary excretion rates of nitrate and cGMP in weekly intervals. Cholesterol feeding progressively reduced urinary nitrate excretion to ≈40% of baseline (
P
<.05) and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthesis inhibitor. Dietary
l
-arginine reversed the reduction in plasma
l
-arginine/ADMA ratio and partly restored urinary excretion of nitrate and cGMP (each
P
<.05 vs cholesterol) but did not change plasma cholesterol levels.
l
-Arginine completely blocked the progression of carotid intimal plaques, reduced aortic intimal thickening, and preserved endothelium-dependent vasodilator function. Lovastatin treatment reduced plasma cholesterol by 32% but did not improve urinary nitrate or cGMP excretion or endothelium-dependent vasodilation. Lovastatin had a weaker inhibitory effect on carotid plaque formation and aortic intimal thickening than
l
-arginine.
l
-Arginine inhibited but lovastatin potentiated superoxide radical generation in the atherosclerotic vascular wall.

Conclusions
Dietary
l
-arginine improves NO-dependent vasodilator function in cholesterol-fed rabbits and completely blocks the progression of plaques via restoration of NO synthase substrate availability and reduction of vascular oxidative stress. Lovastatin treatment has a weaker inhibitory effect on the progression of atherosclerosis and no effect on vascular NO elaboration, which may be due to its stimulatory effect on vascular superoxide radical generation.
Amiodarone Inhibits Production of Tumor Necrosis Factor-α by Human Mononuclear Cells
Authors: Matsumori Akira , Ono Koh , Nishio Ryosuke , Nose Yoshisuke , Sasayama Shigetake
Published: June 2012

Background
Recent studies suggest that cytokines such as tumor necrosis factor (TNF)-α and interleukins (ILs) are capable of modulating cardiovascular function and that drugs used in the treatment of heart failure have various modulatory effects on the production of cytokines. This study was performed to examine the effects of amiodarone (a drug shown to be beneficial in some patients suffering from heart failure) versus other antiarrhythmic agents on the production of cytokines in vitro.

Methods and Results
Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured with 0.1, 1, and 10 μmol/L of amiodarone, quinidine, disopyramide, and lidocaine in the presence of lipopolysaccharide. After 24 hours’ incubation, TNF-α, IL-1β, and IL-6 were measured in the culture supernatants by an enzyme-linked immunosorbent assay. TNF-α production was inhibited by amiodarone but stimulated by quinidine in a concentration-dependent manner. Disopyramide and lidocaine tended to increase TNF-α production. IL-6 production was decreased by amiodarone in all concentrations but was increased significantly by disopyramide. Modulation of IL-1β production by amiodarone was biphasic and significantly increased at a concentration of 10 μmol/L.

Conclusions
These previously unrecognized immunomodulatory effects of amiodarone may contribute to its beneficial effects in heart failure patients.
Highly Localized Arterial Remodeling in Patients With Coronary Atherosclerosis
Authors: Berglund Hans , Luo Huai , Nishioka Toshihiko , Fishbein Michael C. , Eigler Neal L. , Tabak Steven W. , Siegel Robert J.
Published: June 2012

Background
Preservation of luminal area and symmetry in the presence of irregular plaques necessitates local expansion of the artery wall.

Methods and Results
Cross-sectional dimensions of coronary arteries in 65 patients were measured with the use of intravascular ultrasound. A total of 104 arterial segments were studied, of which 88 had atherosclerosis; 16 served as nonatherosclerotic control segments. Three features of atherosclerotic arterial segments were classified: (1) plaque formation, (2) lumen shape, and (3) shape of arterial external elastic lamina. With our intravascular ultrasound–based three-level classification system, we identified three patterns that accounted for 89% of all atherosclerotic arterial segments: (1) concentric plaque with a circular lumen and a circular external elastic lamina (n=17), (2) eccentric plaque with a circular lumen and an oval external elastic lamina (n=35), and (3) eccentric plaque with an oval lumen and a circular external elastic lamina (n=26). A circular lumen was preserved in 66% of all atherosclerotic arterial segments. Arterial segments with a circular lumen in the presence of an eccentric plaque had a significantly larger lumen area than the other two main groups (
P
<.05).

Conclusions
With our intravascular ultrasound–based classification, we provided information regarding the local remodeling response in the coronary artery wall. In a majority of cases, a circular lumen is maintained. Failure of this highly localized response to be operative may contribute to the development of stenotic lesions at a specific site in the artery.
Effects of Octreotide Treatment on Restenosis After Coronary Angioplasty
Authors: von Essen Rainer , Ostermaier Ralf , Grube Eberhard , Mäurer Wolfgang , Tebbe Ulrich , Erbel Raimund , Roth Michael , Oel Werner , Brom Joachim , Weidinger Gottfried
Published: June 2012

Background
The VERAS study (VErringerung der Re- stenoserate nach Angioplastie durch ein Somatostatin-analogon [Prevention of Restenosis Following Angioplasty With a Somatostatin Analogue]) was a placebo-controlled trial to evaluate the effects of octreotide for the prevention of restenosis after coronary angioplasty. Octreotide is a somatostatin analogue with antiproliferative properties on smooth muscle cell growth in vitro that limits myointimal thickening of arteries in balloon injury models.

Methods and Results
Patients received either octreotide or placebo, starting 1 hour before angioplasty and continued for 3 weeks. The minimal luminal diameters before and after angioplasty and at 6-month follow-up were analyzed with a digital quantitative algorithm. Of the initial 274 patients recruited, 217 (108 in the octreotide group and 109 in the placebo group) could be analyzed after a complete 6-month evaluation: the minimal luminal diameters were 1.67±0.57 mm in the oc-treotide-treated group and 1.66±0.64 mm in the placebo group (two-paired
P
=.70), and the relative losses were 0.16±0.22 and 0.13±0.21 (two-paired
P
=.27). The restenosis rates were also identical in both treatment groups: final diameter stenosis ≥50% (34.3% versus 33.9%, two-paired
P
=1.0), loss of ≥50% of the initial gain (34.3% versus 33.9%, two-paired
P
=1.0), and absolute reduction of minimal luminal diameter >0.72 mm (29.6% versus 24.8%, two-paired
P
=.45). Likewise, there was no difference with regard to the incidence of clinical events (death, myocardial infarction, bypass operations, reintervention). Octreotide was well tolerated, with the exception of gastrointestinal side effects, which were three times more common than in the placebo group.

Conclusions
Octreotide did not reduce the angiographically determined restenosis rate or the incidence of major clinical events after coronary angioplasty.
Modulation of Cytokine Production and Protection Against Lethal Endotoxemia by the Cardiac Glycoside Ouabain
Authors: Matsumori Akira , Ono Koh , Nishio Ryosuke , Igata Hideki , Pharm B , Shioi Tetsuo , Matsui Shigeo , Furukawa Yutaka , Iwasaki Atsushi , Nose Yoshisuke , Sasayama Shigetake
Published: June 2012

Background
Recent studies have shown that cytokines are capable of modulating cardiovascular function and that some drugs used in the treatment of heart failure variably modulate the production of cytokines. To examine whether cardiac glycosides also modulate cytokine production, we evaluated the effects of ouabain on the production of cytokines in vitro and in vivo.

Methods and Results
Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured with or without ouabain in the presence or absence of lipopolysaccharide (LPS). Ouabain induced the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in PBMC and induced mRNA of these cytokines, an induction apparently at the transcriptional level. Amiloride, staurosporin, and genistein inhibited cytokine production, and protein kinase C and tyrosine kinase appeared to be involved in the modulation of cytokine production induced by ouabain. However, when PBMC were stimulated with LPS, ouabain suppressed the production of IL-6 and TNF-α. To investigate whether ouabain modulates cytokine production in vivo, we evaluated the effects of ouabain in LPS-treated mice. Ouabain was found to protect against LPS-induced lethal toxicity in mice and decreased circulating IL-6 and TNF-α levels in vivo.

Conclusions
These previously unrecognized immunomodulating effects of a cardiac glycoside may explain either the beneficial or the detrimental effects of these drugs in heart failure patients.
Cost Comparison of Radiofrequency Modification and Ablation of the Atrioventricular Junction in Patients With Chronic Atrial Fibrillation
Authors: Knight Bradley P. , Weiss Raul , Bahu Marwan , Souza Joseph , Zivin Adam , Goyal Rajiva , Daoud Emile , Man K. Ching , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
Because it is not clear which technique is less expensive, the purpose of this study was to compare the cost of radiofrequency modification and ablation of the atrioventricular (AV) node in drug-refractory patients with atrial fibrillation and an uncontrolled ventricular rate.

Methods and Results
The initial nominal charges for a successful procedure were compared in 10 patients with chronic atrial fibrillation who underwent modification of the AV node ($13 109±2002) and 14 similar patients who underwent ablation and pacemaker implantation ($28 302±2023,
P
<.001). On the basis of the long-term follow-up of patients who underwent each procedure, it was assumed that 31% of patients selected for the modification procedure would require a permanent pacemaker for inadvertent AV block or because of AV nodal ablation after a failed modification procedure and that the recurrence rate after AV node ablation would be 2%. The annual charges during follow-up were predicted and adjusted for recurrences and the need for additional procedures. The adjusted total charges at 1 year of follow-up were significantly lower for the modification procedure ($19 389±2002) than for the ablation procedure ($28 485±2023,
P
<.001). After 10 years of follow-up, the cumulative, adjusted charges for modification were $20 016 (42%) less than for ablation.

Conclusions
The initial charges generated by AV node modification are significantly lower than for AV node ablation in patients with chronic atrial fibrillation. Even when adjusted for higher failure and recurrence rates, the modification procedure retains a major cost advantage over ablation during long-term follow-up.
Hysteresis of the RT Interval With Exercise
Authors: Krahn Andrew D. , Klein George J. , Yee Raymond
Published: June 2012

Background
The diagnosis of the long-QT syndrome (LQTS) may be difficult to establish in patients with normal or borderline prolongation of the QT interval. Noninvasive markers are needed to identify patients with LQTS.

Methods and Results
Fourteen patients with known LQTS, 9 unaffected family members, and 40 control subjects underwent modified Bruce protocol exercise testing. The RT interval (peak of R wave to peak of T wave) and rate-corrected RT interval (RTc) were measured during exercise and recovery. The RT interval at 1 minute into recovery was subtracted from the RT interval at a similar heart rate during exercise (ΔRT). The RTc shortened by 61 milliseconds (ms) in the LQTS patients compared with 23 to 26 ms in the other two groups (
P
=.003 by ANOVA). The RT interval shortened in a linear fashion in all patients but demonstrated persistent shortening during recovery in the LQTS patients. This was manifested as a hysteresis loop in the curve relating the RT interval to cycle length. The hysteresis loop was present in 13 of 14 LQTS patients and only 4 of 40 control subjects. ΔRT >25 ms had a sensitivity of 73%, a specificity of 92%, a positive predictive value of 79%, and a negative predictive value of 90% for LQTS.

Conclusions
Hysteresis of the RT interval with exercise may be useful for the diagnosis of LQTS.
Circadian Rhythms of Cardiovascular Functions Are Modulated by the Baroreflex and the Autonomic Nervous System in the Rat
Authors: Makino Mitsutaka , Hayashi Hiroshi , Takezawa Hiroto , Hirai Makoto , Saito Hidehiko , Ebihara Shizufumi
Published: June 2012

Background
We assessed the hypothesis that the baroreflex and the autonomic nervous system are important in the control of the circadian rhythms of cardiovascular functions.

Methods and Results
We continuously measured blood pressure (BP), heart rate (HR), and locomotor activity in sinoaortic denervated (SAD), sympathectomized, and atropine-injected rats by use of a radiotelemetry system. The circadian rhythm of mean blood pressure (MBP) was selectively disrupted in SAD rats under 12-hour light-dark (LD12:12) cycles as a result of an increase in MBP during the light period and disappeared under constant darkness (DD). The locomotor activity and HR were not remarkably affected by SAD. The circadian rhythm of MBP was suppressed in sympathectomized rats by a decrease in the MBP during the dark period, and the abrupt changes in MBP when the lighting was altered were not seen under LD. Under DD, an MBP rhythm similar to that observed under LD was obtained. Sympathectomized rats also showed lower HR levels during the dark period than intact rats under LD cycles. In atropine-injected rats, the MBP and HR increased, especially during the light period, resulting in a reduction of light-dark differences in MBP and HR. The locomotor activity showed an apparent 24-hour variation in the sympathectomized and atropine-injected rats.

Conclusions
The disruption of the baroreflex selectively eliminates the circadian rhythm of BP, and the circadian rhythms of BP and HR are modulated by the autonomic nervous system in rats. The circadian rhythms of BP and HR are regulated by different mechanisms involving the autonomic nervous system.
High Homocysteine Levels Are Independently Related to Isolated Systolic Hypertension in Older Adults
Authors: Sutton-Tyrrell Kim , Bostom Andrew , Selhub Jacob , Zeigler-Johnson Charnita
Published: June 2012

Background
The association between homocysteine and isolated systolic hypertension in older adults was evaluated using a case-control design, and the relationship between homocysteine and clinical or subclinical atherosclerosis was explored.

Methods and Results
Cases were 179 adults ≥60 years with a systolic blood pressure of ≥160 mm Hg and diastolic blood pressure <90 mm Hg. One hundred seventy-one control subjects had the same criteria except systolic blood pressures were <160 mm Hg. All had normal creatinine levels. Homocysteine levels were performed on fasting blood samples that had been stored at −70°C. Atherosclerosis was defined as either a history of clinical disease, an internal carotid stenosis of ≥40% by duplex scan, or an ankle/arm pressure ratio of <0.9. The median homocysteine value was 11.5 μmol/L for cases and 9.9 for control subjects (
P
<.001). After control for potential confounders, homocysteine remained significantly associated with systolic hypertension (
P
=.019). For the hypertensive group, there was no apparent association between level of homocysteine and prevalence of atherosclerosis. However, among the normotensive group, the prevalence of atherosclerosis went from 22% in the lowest quintile of homocysteine values to 53% in the fifth quintile, with an odds ratio of 4.1 (fifth quintile in comparison to the first,
P
<.05). After adjustment for age, sex, systolic blood pressure, cholesterol, and smoking, this odds ratio increased to 6.4 (
P
<.01).

Conclusions
Elevated levels of homocysteine may be related to the cause of isolated systolic hypertension in some individuals. In normotensive older adults, homocysteine appears to be an independent risk factor for atherosclerosis.
Impact of Acute Mental Stress on Sympathetic Nerve Activity and Regional Blood Flow in Advanced Heart Failure
Authors: Middlekauff Holly R. , Nguyen Alison H. , Negrao Carlos E. , Nitzsche Egbert U. , Hoh Carl K. , Natterson Barbara A. , Hamilton Michele A. , Fonarow Gregg C. , Hage Antoine , Moriguchi Jaime D.
Published: June 2012

Background
Evidence is accumulating that specific “triggers,” such as intense psychological stress, may precipitate myocardial infarction and sudden death. Patients with advanced heart failure have increased resting sympathoexcitation, which has been directly related to increased mortality. The impact of triggers on sympathetic nerve activity and regional blood flow in heart failure has not been examined in patients with heart failure.

Methods and Results
Twenty-seven patients with heart failure (NYHA functional class III or IV) and 26 age-matched normal control subjects were studied. Muscle sympathetic nerve activity, heart rate, mean arterial pressure, forearm blood flow, and renal blood flow were measured during mental stress testing with mental arithmetic and Stroop color word test. Patients with heart failure had elevated levels of resting muscle sympathetic nerve activity and heart rate. Mental stress significantly increased muscle sympathetic nerve activity and heart rate in both patients with heart failure and control subjects, although the magnitude of increases tended to be blunted in patients with heart failure. Nevertheless, absolute levels of sympathetic activity in patients with heart failure remained significantly higher than levels in control subjects during mental stress. The decrease in renal blood flow in patients with heart failure was similar to that of control subjects, despite greater resting renal vasoconstriction. The increase in forearm blood flow during mental stress testing in patients with heart failure was blunted compared with that of control subjects.

Conclusions
Patients with heart failure do not have augmented muscle sympathetic nerve activity responses to mental stress, despite elevated resting levels of sympathetic activity, but they do have markedly higher absolute levels of sympathetic nerve activity during mental stress as well as at rest.
Direct Vascular Effects of Furosemide in Humans
Authors: Pickkers Peter , Dormans Tom P. J. , Russel Frans G. M. , Hughes Alun D. , Thien Theo , Schaper Nicolaas , Smits Paul
Published: June 2012

Background
In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein.

Methods and Results
Forearm blood flow in response to infusion of increasing dosages of furosemide into the brachial artery was recorded by venous occlusion plethysmography. Local plasma concentrations of furosemide reached a maximum of 234±40 μg/mL during the highest infused dose but did not significantly affect the ratio of flow in the infused/noninfused arms. Venous distensibility of a dorsal hand vein was measured with a linear variable differential transformer. During precontraction with norepinephrine, five increasing dosages of furosemide (1 to 100 μg/min) were administered locally. Additional experiments using local administration of indomethacin or
N
G
-monomethyl-
l
-arginine (L-NMMA) were carried out to determine whether effects were dependent on local prostaglandin or nitric oxide synthesis, respectively. Also, the effects of systemic administration of furosemide were examined. Local administration of furosemide led to a dose-dependent venorelaxation of 18±6% at the first to 72±16% at the last dose. Indomethacin almost completely abolished furosemide-induced venorelaxation, whereas L-NMMA had no effect. Systemic administration of furosemide resulted in a time-dependent increase of hand vein distensibility, reaching 45±11% after 8 minutes.

Conclusions
Furosemide does not exert any direct arterial vasoactivity in the human forearm, even at supratherapeutic concentrations. In contrast, at concentrations estimated to be in the therapeutic range, we observed a dose-dependent direct venodilator effect on the dorsal hand vein that appears to be mediated by local vascular prostaglandin synthesis.
Stimulated Activation of Platelet-Derived Growth Factor Receptor In Vivo in Balloon-Injured Arteries
Authors: Abe Jun-ichi , Deguchi Jun-o , Matsumoto Takeo , Takuwa Noriko , Noda Masakuni , Ohno Minoru , Makuuchi Masatoshi , Kurokawa Kiyoshi , Takuwa Yoh
Published: June 2012

Background
Growth factors such as platelet-derived growth factor (PDGF) have been postulated to be important mediators of neointimal formation in balloon-injured artery. Binding of growth factors to their receptors activates intrinsic receptor tyrosine kinase, resulting in tyrosine phosphorylation of receptors themselves and cellular substrate proteins. We investigated in vivo activities of growth factors by determining the extent of tyrosine phosphorylation of growth factor receptors and substrate proteins in injured artery.

Methods and Results
Rat balloon-injured carotid artery was analyzed for phosphotyrosine content of PDGF α- and β-receptors, epidermal growth factor (EGF) receptors, and insulin receptor substrate-1 (IRS-1) by immunoprecipitation and anti-phosphotyrosine Western blot. The development of intimal thickening after deendothelializing balloon catheterization of rat carotid artery was accompanied by transient twofold to threefold increases in the extent of tyrosyl phosphorylation of PDGF α- and β-receptors but not EGF receptor or IRS-1. The AT
1
angiotensin II (Ang II) receptor antagonist TCV-116 markedly inhibited both tyrosyl phosphorylation of PDGF α- and β-receptors and intimal thickening. The AT
1
antagonist reduced mRNA levels of both PDGF-A and -B chains in injured arteries.

Conclusions
The present study provides direct evidence for increased PDGF activities in injured artery in situ and the involvement of Ang II in stimulated activation of PDGF receptors. These results are consistent with the pathogenetic role for PDGF in intimal thickening.
Effects of Hypertrophy on Regional Action Potential Characteristics in the Rat Left Ventricle
Authors: Shipsey S. Jane , Bryant Simon M. , Hart George
Published: June 2012

Background
In cardiac hypertrophy, ECG T-wave changes imply an abnormal sequence of ventricular repolarization. We investigated the hypothesis that this is due to changes in the normal regional differences in action potential duration. We assessed the contribution of potassium- and calcium-dependent currents to these differences. Both the altered sequence of ventricular repolarization and the underlying cellular mechanisms may contribute to the increased incidence of ventricular arrhythmias in hypertrophy.

Methods and Results
Rats received daily isoproterenol injections for 7 days. Myocytes were isolated from basal subendocardial (endo), basal midmyocardial (mid), and apical subepicardial (epi) regions of the left ventricular free wall. Action potentials were stimulated with patch pipettes at 37°C. The ratio of heart weight to body weight and mean cell capacitance are increased by 22% and 18%, respectively, in hypertrophy compared with controls (
P
<.001). Normal regional differences in action potential duration at 25% repolarization (APD
25
) are reduced in hypertrophy (control: endo, 11.4±0.9 ms; mid, 8.2±0.9 ms; epi, 5.1±0.4 ms; hypertrophy: endo, 11.6±0.9 ms; mid, 10.4±0.8 ms; epi, 7.8±0.6 ms). The regional differences in APD
25
are still present in 3 mmol/L 4-aminopyridine. Hypertrophy affects APD
75
differently, depending on the region of origin of myocytes (ANOVA
P
<.05). APD
75
is shortened in subendocardial myocytes but is prolonged in subepicardial myocytes (control: endo, 126±7 ms; epi, 96±10 ms; hypertrophy: endo, 91±6 ms; epi, 108±7 ms). These changes in APD
75
are altered by intracellular calcium buffering.

Conclusions
Normal regional differences in APD and the changes observed in hypertrophy are only partially explained by differences in
I
to1
. In hypertrophy, the normal endocardial/epicardial gradient in APD
75
appears to be reversed. This may explain the T-wave inversion observed and will have implications for arrhythmogenesis.
Anti-Ischemic and Anti-Anginal Effects of Thoracic Epidural Anesthesia Versus Those of Conventional Medical Therapy in the Treatment of Severe Refractory Unstable Angina Pectoris
Authors: Olausson Karin , Magnusdottir Helga , Lurje Leon , Wennerblom Bertil , Emanuelsson Håkan , Ricksten Sven-Erik
Published: June 2012

Background
Cardiac sympathetic blockade by thoracic epidural anesthesia (TEA) dilates stenotic coronary arteries and has been used to control pain in patients with unstable angina. The aim of the present study was to evaluate the potential anti-ischemic effects of cardiac sympathetic blockade by TEA in severe, refractory, unstable angina.

Methods and Results
Forty patients with unstable angina refractory to standard anti-anginal therapy were randomized to receive either continuous epidural infusion of bupivacaine (TEA, Th1 to Th5) or to standard anti-anginal therapy including β-blockers, calcium antagonists, aspirin, heparin, and nitroglycerin infusion (control group). The primary end points were number of anginal attacks and severity of myocardial ischemia assessed by 48-hour ambulatory Holter monitoring. The incidence of myocardial ischemia was lower in the TEA group (22% versus 61%;
P
<.05). The number of ischemic episodes per patient was 1.0±0.6 in the TEA group and 3.6±0.9 in the control group (
P
<.05). The episode duration per patient was 4.1±2.5 minutes and 19.7±6.2 minutes in the TEA and the control groups, respectively (
P
<.05). The mean area-under-the-ST-time-curve was 6.8±4.3 and 32.2±14.3 (mm · min) in the TEA and the control groups, respectively (
P
<.05). Fifteen anginal attacks were recorded in the control group and one attack in the TEA group (0.83±0.21 versus 0.06±0.06/patient, respectively,
P
<.01).

Conclusions
The anti-ischemic and anti-anginal effects of continuous TEA are superior to those of conventional therapy in the treatment of refractory unstable angina.
Effect of Serotonin, Thromboxane A
2
, and Specific Receptor Antagonists on Vascular Smooth Muscle Cell Proliferation
Authors: Pakala Rajbabu , Willerson James T. , Benedict Claude R.
Published: June 2012

Background
Restenosis is a major complication that limits the long-term efficacy of coronary angioplasty. Migration and proliferation of activated medial smooth muscle cells (SMCs) is considered an important mechanism in this process. Because at sites of vascular injury, aggregating platelets release both serotonin (5-HT) and thromboxane A
2
(TXA
2
), we examined whether 5-HT and TXA
2
can induce SMC proliferation and whether there is synergistic interaction between these two mediators.

Methods and Results
The mitogenic effects of 5-HT and TXA
2
either alone or in combination was examined in serum-free medium on canine aortic SMCs by [
3
H]thymidine incorporation into DNA and by cell counting. 5-HT induced SMC proliferation at a concentration of 100 nmol/L, whereas the effect of TXA
2
(U46619, a stable TXA
2
mimetic) on inducing proliferation of SMCs was observed at a concentration of 100 nmol/L. When these two mediators were added together, there was a synergistic interaction on inducing SMC proliferation even at subthreshold concentrations. The mitogenic effect of 5-HT and its synergistic interaction with TXA
2
on SMC proliferation was abolished by a 5-HT
2
receptor antagonist, LY281067, without affecting the contribution of TXA
2
. Similarly, the TXA
2
synthase inhibitor/receptor antagonist ridogrel abolished the mitogenic effect of TXA
2
and the interaction between 5-HT and TXA
2
without affecting the response to 5-HT. When LY281067 and ridogrel were used together, they abolished the mitogenic effects of 5-HT and TXA
2
.

Conclusions
At sites of vascular injury, platelet-induced SMC proliferation may also be modulated by nonpeptide growth mediators. A combination of a 5-HT
2
receptor antagonist and TXA
2
synthase inhibitor/receptor may be useful for attenuation of restenosis after angioplasty.
Myocardial
99m
Tc-Tetrofosmin Uptake During Adenosine-Induced Vasodilatation With Either a Critical or Mild Coronary Stenosis
Authors: Glover David K. , Ruiz Mirta , Yang Joo Y. , Smith William H. , Watson Denny D. , Beller George A.
Published: June 2012

Background
Clinical studies have shown a comparable coronary stenosis detection rate between
99m
Tc-tetrofosmin and
201
Tl but with smaller defect magnitudes for
99m
Tc-tetrofosmin. The goals of this study were to measure the first-pass extraction fraction (EF) of
99m
Tc-tetrofosmin in canine myocardium and to compare
99m
Tc-tetrofosmin with
201
Tl uptake during adenosine-induced vasodilatation in dogs with various degrees of coronary stenosis.

Methods and Results
EF was calculated in 4 anesthetized, open-chest dogs after intracoronary administration of
125
I-labeled albumin and
99m
Tc-tetrofosmin. In another 16 dogs with either critical (n=6) or mild (n=10) left anterior descending coronary artery (LAD) stenoses,
201
Tl and
99m
Tc-tetrofosmin were administered during adenosine infusion (250 μg · kg
−1
· min
−1
). Dogs were killed 5 minutes later, and tracer activities were determined by ex vivo imaging of heart slices and by well counting. Mean
99m
Tc-tetrofosmin EF was 54.0±3.7%. In the 6 critical-stenosis dogs, the LAD-to-left circumflex artery (LCx) microsphere flow ratio was 0.22±0.02 with adenosine. The LAD-to-LCx activity ratios were 0.37±0.04 for
201
Tl and 0.67±0.05 for
99m
Tc-tetrofosmin (
P
<.01). For the 10 mild-stenosis dogs, the LAD-to-LCx flow ratio was 0.44±0.05. The
201
Tl activity ratio was 0.58±0.04, compared with 0.81±0.04 for
99m
Tc-tetrofosmin (
P
<.01). Thus, in both groups,
99m
Tc-tetrofosmin uptake underestimated the flow disparity more than
201
Tl. Similarly, magnitudes of ex vivo image defects were significantly greater for
201
Tl than for
99m
Tc-tetrofosmin in both groups.

Conclusions
In this canine model, relative underperfusion with adenosine stress is better resolved with
201
Tl than with
99m
Tc-tetrofosmin and may be explained by the lower EF for
99m
Tc tetrofosmin. With clinical imaging, greater
201
Tl attenuation and redistribution may lessen this advantage.