bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustained Ventricular Arrhythmias in Patients Receiving Thrombolytic Therapy
Authors: Newby Keith H. , Thompson Trevor , Stebbins Amanda , Topol Eric J. , Califf Robert M. , Natale Andrea
Published: June 2012

Background
—Sustained ventricular tachycardia (VT) and fibrillation (VF) occur in up to 20% of patients with acute myocardial infarction (MI) and have been associated with a poor prognosis. The relationships among the type of arrhythmia (VT versus VF or both), time of VT/VF occurrence, use of thrombolytic agents, and eventual outcome are unclear.

Methods and Results
—In the GUSTO-I study, we examined variables associated with the occurrence of VT/VF and its impact on mortality. Of the 40 895 patients with ventricular arrhythmia data, 4188 (10.2%) had sustained VT, VF, or both. Older age, systemic hypertension, previous MI, Killip class, anterior infarct, and depressed ejection fraction were associated with a higher risk of sustained VT and VF (
P
<0.001). In-hospital and 30-day mortality rates were higher among patients with sustained VT/VF than among patients without sustained ventricular arrhythmias (
P
<0.001). Both early (<2 days) and late (>2 days) occurrences of sustained VT and VF were associated with a higher risk of later mortality (
P
<0.001). In addition, patients with both VT and VF had worse outcomes than those with either VT or VF alone (
P
<0.001). Among patients who survived hospitalization, no significant difference was found in 30-day mortality between the VT/VF and no VT/VF groups. However, after 1 year, the mortality rate was significantly higher in the VT alone and VT/VF groups (
P
<0.0001).

Conclusions
—Despite the use of thrombolytic therapy, both early and late occurrences of sustained VT or VF continue to have a negative impact on patient outcome; patients with both VT and VF had the worst outcome; and among patients who survived hospitalization, the 1-year mortality rate was significantly higher in those who experienced VT alone or VT and VF.
Spontaneous Conversion and Maintenance of Sinus Rhythm by Amiodarone in Patients With Heart Failure and Atrial Fibrillation
Authors: Deedwania Prakash C. , Singh Bramah N. , Ellenbogen Kenneth , Fisher Susan , Fletcher Ross , Singh Steven N.
Published: June 2012

Background
—In a multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone on morbidity and mortality in patients with congestive heart failure (CHF) and atrial fibrillation (AF) were evaluated during a 4-year period.

Methods and Results
—Of 667 patients with CHF, 103 (15%) had AF at baseline. Of these, 51 were randomized to amiodarone and 52 to placebo. The group with sinus rhythm and the group in AF were comparable except for a higher proportion of AF in patients with nonischemic versus ischemic cardiomyopathy (41% versus 27%,
P
<0.005). The mean ventricular response (VR) during AF over 24 hours was reduced by amiodarone at 2 weeks (20%,
P
=0.001), at 6 months (18%,
P
=0.001), and at 12 months (16%,
P
=0.006). Maximal VR was reduced 22% (
P
=0.001) at 2 weeks, 19% (
P
=0.001) at 6 months, and 14% (
P
=0.001) at 12 months. Sixteen of 51 patients on amiodarone and 4 of 52 on placebo converted to sinus rhythm during the study (χ
2
=9.23,
P
=0.002). During follow-up, 11 of 268 patients in sinus rhythm on amiodarone at baseline and 22 of the 263 in sinus rhythm on placebo developed AF; the difference was significant (χ
2
=12.88,
P
=0.005). Analysis of total mortality during follow-up showed a significantly lower mortality rate (
P
=0.04) in patients in AF at baseline who subsequently converted to sinus rhythm on amiodarone than in those who did not convert to sinus rhythm on the drug.

Conclusions
—In patients with CHF, amiodarone has a significant potential to spontaneously convert patients in AF to sinus rhythm, with patients who convert having a lower mortality rate than those who do not. The drug prevented the development of new-onset AF and significantly reduced the VR in those with persistent AF.
Laminar Shear Stress–Induced GRO mRNA and Protein Expression in Endothelial Cells
Authors: Hagiwara Hideyuki , Mitsumata Masako , Yamane Tetsu , Jin Xin , Yoshida Yoji
Published: June 2012

Background
—The shear stress induced by blood flow may play a pivotal role in the induction or prevention of atherosclerosis by changing endothelial functions. To disclose the mechanisms of this change, we prepared an endothelial cell (EC) cDNA library to select specific clones expressed in response to shear stress.

Methods and Results
—The mRNA of cultured confluent bovine aortic ECs (BAECs) subjected to steady laminar shear stress (30 dyne/cm
2
) for 4 hours was separated, and a cDNA library was prepared. Nine clones whose expressions were specifically enhanced by the shear stress were selected by use of a differential hybridization method. One clone had 94% homology at the nucleotide sequence level to
Oryctolagus cuniculus
gro (GRO) mRNA and 79% homology at the amino acid sequence level to human GRO-β. The GRO mRNA expression was increased in both BAECs and human umbilical vein ECs (HUVECs) after the ECs were subjected to high (30 dyne/cm
2
) and low (5 dyne/cm
2
) laminar shear stress. GRO-α and/or -β protein expression also increased after the HUVECs and BAECs were subjected to shear stress. Because GRO protein has been shown to function as an adhesion factor of monocytes on the surface of ECs, we studied whether shear stress–induced monocyte adhesion was caused by GRO protein expression on ECs. The 4-hour shear stress enhanced monocyte adhesion to ECs by 2.5-fold over control levels, and this enhancement was inhibited by 53% by anti–GRO-α antibody.

Conclusions
—The present study is the first report that shear stress induced the expression of GRO mRNA and protein in ECs and enhanced the monocyte adhesion on ECs via GRO protein. Further investigations of the functions and participation in atherogenesis of this selected clone may clarify the significance of shear stress on atherogenesis.
Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial Fibrillation
Authors: Olgin Jeffrey E. , Sih Haris J. , Hanish Steven , Jayachandran J. Vijay , Wu Jiashin , Zheng Qi Huang , Winkle Wendy , Mulholland G. Keith , Zipes Douglas P. , Hutchins Gary
Published: June 2012

Background
—Heterogeneous electrophysiological properties, which may be due in part to autonomic innervation, are important in the maintenance of atrial fibrillation (AF). We hypothesized that heterogeneous sympathetic denervation with phenol would create a milieu for sustained AF.

Methods and Results
—After the determination of baseline inducibility, 15 dogs underwent atrial epicardial phenol application and 11 underwent a sham procedure. After 2 weeks of recovery, the animals had repeat attempts at inducing AF and effective refractory period (ERP) testing. Epicardial maps were obtained to determine local AF cycle lengths. ERPs were determined at baseline and during sympathetic, vagal, and simultaneous vagal/sympathetic stimulation. Dogs then underwent PET imaging with either a sympathetic ([
11
C]hydroxyephedrine, HED) or parasympathetic (5-[
11
C]methoxybenzovesamicol, MOBV) nerve label. None of the animals had sustained AF (>60 minutes) at baseline. None of the sham dogs and 14 of 15 phenol dogs had sustained AF at follow-up. Sites to which phenol was applied had a significantly shorter ERP (136±17.6 ms) than those same sites in the sham controls (156±19.1 ms) (
P
=0.01). Although there was no difference in the ERP change with either vagal or sympathetic stimulation alone between phenol and nonphenol sites, the percent decrease in ERP with simultaneous vagal/sympathetic stimulation was greater in the phenol sites (17±8%) than in the nonphenol sites (9±9%) (
P
=0.01). There was a significantly increased dispersion of refractoriness (21±6.4 ms in the sham versus 58±14 ms in the phenol dogs,
P
=0.01) as well as dispersion of AF cycle length (49±10 ms in the sham versus 105±12 ms in the phenol dogs,
P
=0.0001). PET images demonstrated defects of HED uptake in the areas of phenol application, with no defect of MOBV uptake.

Conclusions
—Heterogeneous sympathetic atrial denervation with phenol facilitates sustained AF.
Gender Gap in Aortic Cholesterol Accumulation in Cholesterol-Clamped Rabbits
Authors: Holm Pernille , Andersen Heidi L. , Arrøe Gry , Stender Steen
Published: June 2012

Background
—The purpose of the present study was to investigate plasma lipid–independent mechanisms for the sex difference in the development of atherosclerosis.

Methods and Results
—In the first experiment, 20 male and 20 female rabbits were balloon-injured in the middle thoracic aorta and maintained at the same plasma cholesterol level of ≈25 mmol/L by use of individualized cholesterol feeding for 13 weeks. In the undamaged aorta, female rabbits had accumulated less than half the amount of cholesterol found in male rabbits (
P
<0.05). In the balloon-injured aorta, cholesterol accumulation was 3- to 4-fold higher than in the undamaged aorta, with no difference between groups. When cholesterol accumulation data for the balloon-injured aorta were separately assessed for blue (deendothelialized) and white (reendothelialized) tissue, blue tissue surprisingly revealed a reverse gender gap, ie, a significantly higher accumulation of cholesterol in females than in males (
P
<0.05). White tissue, which constituted the majority of the balloon-injured area, showed no difference in aortic cholesterol accumulation between groups. In the second experiment, 6 male and 6 female rabbits were fed standard rabbit pellets and 6 male and 6 female rabbits were fed a 0.5% cholesterol-enriched chow for 2 weeks. Mononuclear cell binding was 5-fold higher in aortic segments from hypercholesterolemic than from normocholesterolemic rabbits (
P
<0.001). In hypercholesterolemic rabbits, cell binding was significantly lower in female than in male rabbits (
P
<0.05) and showed higher values in atherosclerosis-prone regions. These differences were not found in normocholesterolemic animals.

Conclusions
—The present results suggest that female atheroprotection is independent of sex differences in plasma cholesterol but vitally dependent on the state of the arterial endothelium and involves mononuclear-endothelial cell adhesion as an early step.
Prospective Study of Herpes Simplex Virus, Cytomegalovirus, and the Risk of Future Myocardial Infarction and Stroke
Authors: Ridker Paul M. , Hennekens Charles H. , Stampfer Meir J. , Wang Fred
Published: June 2012

Background
—It has been hypothesized that infection with either herpes simplex virus (HSV) or cytomegalovirus (CMV) is associated with atherogenesis. However, prospective data relating evidence of prior exposure to these agents with risks of future myocardial infarction (MI) and stroke are sparse.

Methods and Results
—In a prospective, nested case-control study of apparently healthy men, the baseline prevalence of antibodies directed against HSV or CMV was similar among 643 men who subsequently developed a first MI or thromboembolic stroke and among 643 age- and smoking-matched men who remained free of reported vascular disease over a 12-year follow-up period. Specifically, the relative risks for future MI and stroke were 0.94 (95% CI, 0.7 to 1.2) for HSV seropositivity and 0.72 (95% CI, 0.6 to 0.9) for CMV seropositivity, after adjustment for other cardiovascular risk factors. These findings were not materially altered in comparisons of early versus late events or in analyses stratified by smoking status. There was no evidence of association between HSV or CMV antibodies and plasma concentration of C-reactive protein, a marker of inflammation that predicts vascular risk in this cohort.

Conclusions
—Among apparently healthy middle-aged men, IgG antibodies directed against HSV or CMV do not appear to be a marker for increased atherothrombotic risk. The observed possible inverse relationship of CMV with MI and stroke was unexpected and may well be due to chance, because the direction of association is not compatible with the a priori hypothesis based on proposed biological mechanisms or previous cross-sectional and retrospective data.
TNK–Tissue Plasminogen Activator Compared With Front-Loaded Alteplase in Acute Myocardial Infarction
Authors: Cannon Christopher P. , Gibson C. Michael , McCabe Carolyn H. , Adgey A. A. Jennifer , Schweiger Marc J. , Sequeira Rafael F. , Grollier Gilles , Giugliano Robert P. , Frey Martin , Mueller Hiltrud S. , Steingart Richard M. , Weaver W. Douglas , Van de Werf Frans , Braunwald Eugene
Published: June 2012

Background
—Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent.

Methods and Results
—In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively,
P
=NS); the rate for the 30-mg dose was significantly lower (54.3%,
P
=0.035) and was 65.8% for the 50-mg dose (
P
=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (
P
=0.001). Similar dose responses were observed for serious bleeding and intracranial hemorrhage, but significantly lower rates were observed for both TNK-tPA and tPA after the heparin doses were lowered and titration of the heparin was started at 6 hours.

Conclusions
—TNK-tPA, given as a single 40-mg bolus, achieved rates of TIMI grade 3 flow similar to those of the 90-minute bolus and infusion of tPA. Weight-adjusting TNK-tPA appears to be important in achieving optimal reperfusion; reduced heparin dosing appears to improve safety for both agents. Together with the safety results from the parallel Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT I) trial, an appropriate dose of this single-bolus thrombolytic agent has been identified for phase III testing.
Increased Formation of Distinct F
2
Isoprostanes in Hypercholesterolemia
Authors: Reilly Muredach P. , Praticò Domenico , Delanty Norman , DiMinno Giovanni , Tremoli Elena , Rader Daniel , Kapoor Shiv , Rokach Joshua , Lawson John , FitzGerald Garret A.
Published: June 2012

Background
—F
2
isoprostanes are stable, free radical–catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo.

Methods and Results
—Specific assays were developed by use of mass spectrometry for the F
2
isoprostanes iPF
2α
-III and iPF
2α
-VI and arachidonic acid (AA). Urinary excretion of the 2 F
2
isoprostanes was significantly increased in hypercholesterolemic patients, whereas substrate AA in urine did not differ between the groups. iPF
2α
-III (pmol/mmol creatinine) was elevated (
P
<0.0005) in homozygous familial hypercholesterolemic (HFH) patients (85±5.5; n=38) compared with age- and sex-matched normocholesterolemic control subjects (58±4.2; n=38), as were levels of iPF
2α
-VI (281±22 versus 175±13;
P
<0.0005). Serum cholesterol correlated with urinary iPF
2α
-III (
r
=0.41;
P
<0.02) and iPF
2α
-VI (
r
=0.39;
P
<0.03) in HFH patients. Urinary excretion of iPF
2α
-III (81±10 versus 59±4;
P
<0.05) and iPF
2α
-VI (195±18 versus 149±20;
P
<0.05) was also increased in moderately hypercholesterolemic subjects (n=24) compared with their controls. Urinary excretion of iPF
2α
-III and iPF
2α
-VI was correlated (
r
=0.57;
P
<0.0001; n=106). LDL iPF
2α
-III levels (ng/mg arachidonate) were elevated (
P
<0.01) in HFH patients (0.32±0.08) compared with controls (0.09±0.02). The concentrations of iPF
2
-III in LDL and urine were significantly correlated (
r
=0.42;
P
<0.05) in HFH patients.

Conclusions
—Asymptomatic patients with moderate and severe hypercholesterolemia have evidence of oxidant stress in vivo.
Dipyridamole Stress Echocardiography for Risk Stratification in Hypertensive Patients With Chest Pain
Authors: Cortigiani Lauro , Paolini Emilio A. , Nannini Eugenio
Published: June 2012

Background
—The noninvasive prognostic assessment of coronary artery disease (CAD) in hypertensive patients represents an unresolved task to date. In this study, we investigated the value of dipyridamole stress echocardiography in risk stratification of hypertensive patients with chest pain and unknown CAD.

Methods and Results
—Dipyridamole stress echocardiography was performed in 257 hypertensives (110 men; age, 63±9 years) complaining of chest pain and without a history of CAD. No major complications occurred. Four tests were interrupted prematurely because of side effects, with 98.4% feasibility of test. A positive echocardiographic response was found in 72 patients (27 during the low-dose [≤0.56 mg/kg] and 45 during the high-dose [>0.56 mg/kg]). During the follow-up (32±18 months), 27 cardiac events occurred: 3 deaths, 8 infarctions, and 16 cases of unstable angina. Moreover, 27 patients underwent coronary revascularization. At multivariate analysis, the positive echocardiographic result (OR, 5.5; 95% CI, 1.4 to 16.6) was the only predictor of hard cardiac events (death, infarction). Considering spontaneous cardiac events (death, infarction, and unstable angina) as end points, the positive echocardiographic result (OR, 4.2; 95% CI, 1.8 to 9.6) and family history of CAD (OR, 4.2; 95% CI, 1.5 to 6.9) were independently associated with prognosis. The 3-year survival rates for the negative and the positive populations were, respectively, 97% and 87% (
P
=0.0019) considering hard cardiac events and 96% and 74% (
P
=0.0000) considering spontaneous cardiac events.

Conclusions
—Dipyridamole stress echocardiography is safe, highly feasible, and effective in risk stratification of hypertensives with chest pain and unknown CAD. At present, it represents an attractive option for prognostic assessment of this clinically defined population.
Prospective Study of Atherosclerotic Disease Progression in the Renal Artery
Authors: Caps Michael T. , Perissinotto Claudio , Zierler R. Eugene , Polissar Nayak L. , Bergelin Robert O. , Tullis Michael J. , Cantwell-Gab Kim , Davidson Robert C. , Strandness D. Eugene
Published: June 2012

Background
—The aim of this study was to determine the incidence of and the risk factors associated with progression of renal artery disease in individuals with atherosclerotic renal artery stenosis (ARAS).

Methods and Results
—Subjects with ≥1 ARAS were monitored with serial renal artery duplex scans. A total of 295 kidneys in 170 patients were monitored for a mean of 33 months. Overall, the cumulative incidence of ARAS progression was 35% at 3 years and 51% at 5 years. The 3-year cumulative incidence of renal artery disease progression stratified by baseline disease classification was 18%, 28%, and 49% for renal arteries initially classified as normal, <60% stenosis, and ≥60% stenosis, respectively (
P
=0.03, log-rank test). There were only 9 renal artery occlusions during the study, all of which occurred in renal arteries having ≥60% stenosis at the examination before the detection of occlusion. A stepwise Cox proportional hazards model included 4 baseline factors that were significantly associated with the risk of renal artery disease progression during follow-up: systolic blood pressure ≥160 mm Hg (relative risk [RR]=2.1; 95% CI, 1.2 to 3.5), diabetes mellitus (RR=2.0; 95% CI, 1.2 to 3.3), and high-grade (>60% stenosis or occlusion) disease in either the ipsilateral (RR=1.9; 95% CI, 1.2 to 3.0) or contralateral (RR=1.7; 95% CI, 1.0 to 2.8) renal artery.

Conclusions
—Although renal artery disease progression is a frequent occurrence, progression to total renal artery occlusion is not. The risk of renal artery disease progression is highest among individuals with preexisting high-grade stenosis in either renal artery, elevated systolic blood pressure, and diabetes mellitus.
Increased Bioavailability of Nitric Oxide After Lipid-Lowering Therapy in Hypercholesterolemic Patients
Authors: John Stefan , Schlaich Markus , Langenfeld Matthias , Weihprecht Horst , Schmitz Gerd , Weidinger Gottfried , Schmieder Roland E.
Published: June 2012

Background
—Impaired endothelium-dependent vasodilation is an early sign of atherosclerosis in hypercholesterolemic patients. We hypothesized that lipid-lowering therapy can improve endothelial function and that this effect is mainly mediated by increased bioavailability of nitric oxide (NO).

Methods and Results
—In a randomized, double-blind, placebo-controlled trial, we studied 29 patients (age, 50±12 years) with hypercholesterolemia (LDL cholesterol ≥160 mg/dL) randomly assigned to receive either fluvastatin (40 mg twice daily; 17 patients) or placebo (12 patients). Forearm blood flow was measured by plethysmography before and after 24 weeks of treatment. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of acetylcholine (ACh; 3, 12, 24, and 48 μg/min) and basal NO synthesis rate by intra-arterial infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA; 1, 2, and 4 μmol/min). Simultaneous intra-arterial infusion of L-NMMA (4 μmol/min) and ACh (12, 24, and 48 μg/min) was used to test whether any increase in endothelium-dependent vasodilation after lipid-lowering therapy could be blocked by this NO synthase inhibitor. Endothelium-dependent vasodilation improved significantly after 24 weeks of lipid-lowering therapy compared with before therapy (ACh 24 μg/min: 240±34% before versus 347±50% after therapy;
P
≤0.01) and placebo (changes between after and before therapy with ACh 24 μg/min: 108±39% for fluvastatin versus −26±32% for placebo;
P
≤0.05). This improvement in endothelium-dependent vasodilation could be blocked by simultaneous administration of L-NMMA (ACh 24 μg/min plus L-NMMA 4 μmol/min: 170±69% before versus 219±47% after treatment;
P
=NS).

Conclusions
—Lipid-lowering therapy with fluvastatin can improve disturbed endothelial function in hypercholesterolemic patients compared with placebo. This improvement is mediated by increased bioavailability of NO.
Quantitative Assessment of Myocardial Viability After Infarction by Dobutamine Magnetic Resonance Tagging
Authors: Geskin Gennady , Kramer Christopher M. , Rogers Walter J. , Theobald Therese M. , Pakstis Diana , Hu Yong-Lin , Reichek Nathaniel
Published: June 2012

Background
—The assessment of return of function within dysfunctional myocardium after acute myocardial infarction (MI) using contractile reserve has been primarily qualitative. Magnetic resonance (MR) myocardial tagging is a novel noninvasive method that measures intramyocardial function. We hypothesized that MR tagging could be used to quantify the intramyocardial response to low-dose dobutamine and relate this response to return of function in patients after first MI.

Methods and Results
—Twenty patients with a first reperfused MI (age, 53±12 years; 16 male; 11 inferior MIs) were studied. Patients underwent breath-hold MR-tagged short-axis imaging on day 4±2 after MI at baseline and during dobutamine infusion at 5 and 10 μg · kg
−1
· min
−1
. At 8±1 weeks after MI, patients returned for a follow-up MR tagging study without dobutamine. Quantification of percent intramyocardial circumferential segment shortening (%S) was performed. Low-dose dobutamine MRI was well tolerated. Overall, mean %S was 15±11% at baseline (n=227 segments), increased to 16±10% at 5 μg · kg
−1
· min
−1
dobutamine (
P
=NS), 21±10% at peak (
P
<0.0001 versus baseline and 5 μg · kg
−1
· min
−1
), and 18±10% at 8 weeks (
P
<0.004 versus baseline and peak). The increase in %S with peak dobutamine was greater in dysfunctional myocardium (103 segments, +9±10%) than in normal tissue (124 segments, +4±12%,
P
<0.0001). In dysfunctional regions, %S also increased from 6±7% at baseline to 14±10% at 8 weeks after MI (
P
<0.0001). In dysfunctional regions that responded normally to peak dobutamine (≥5% increase in %S), the increase in %S from baseline to 8 weeks after MI (+9±9%) was greater than in those regions that did not respond normally (+5±9%,
P
<0.04). Midmyocardial and subepicardial response to dobutamine were predictive of functional recovery, but the subendocardial response was not.

Conclusions
—The response of intramyocardial function to low-dose dobutamine after reperfused MI can be quantified with MR tagging. Dysfunctional tissue after MI demonstrates a larger contractile response to dobutamine than normal myocardium. A normal increase in shortening elicited by dobutamine within dysfunctional midwall and subepicardium predicts greater functional recovery at 8 weeks after MI, but the response within the subendocardium is not predictive.
Mechanism of Acute Mechanical Benefit From VDD Pacing in Hypertrophied Heart
Authors: Pak Peter H. , Maughan W. Lowell , Baughman Kenneth L. , Kieval Robert S. , Kass David A.
Published: June 2012

Background
—Dual-chamber pacing can improve symptoms in hypertrophic cardiomyopathy (HCM), but the mechanism remains unclear. We hypothesized that pacing generates discoordinate contraction and a rightward shift of the end-systolic pressure-volume relation (ESPVR) and that benefits from this mechanism do not depend on the presence of resting outflow pressure gradients or obstruction.

Methods and Results
—Eleven patients with NYHA class III symptoms, 5 with HCM, and 6 with hypertensive hypertrophy and cavity obliteration, were studied by invasive conductance catheter methods. No patient had coronary artery or primary valvular disease. Pressure-volume relations were recorded before and during VDD pacing by use of a short (75-millisecond) PR interval to achieve preexcitation. Left ventricular cavity pressure was simultaneously recorded at basal and apical sites, with pressure at the basal site used to generate the ESPVRs. VDD pacing shifted the ESPVR rightward, increasing end-systolic volume by 45% (range, 17% to 151%;
P
=0.002). Resting and provokable gradients declined by 20% (range, −56% to +3%) and 30% (range, −65% to −12%), respectively (
P
<0.05). Preload declined by 3% to 10% because of the short PR interval. Preload-corrected contractility indexes and myocardial workload declined by ≈10% (
P
<0.001). Diastolic compliance and relaxation time were unchanged. Pacing made apical pressure-volume loops discoordinate, limiting cavity obliteration and reducing distal systolic pressures. Results in both patient groups were similar.

Conclusions
—VDD pacing shifts the ESPVR rightward in HCM patients with cavity obliteration with or without obstruction, increasing end-systolic volumes and reducing apical cavity compression and cardiac work. These effects likely contribute to reduced metabolic demand and improved symptoms.
Cocaine Increases the Endothelial Release of Immunoreactive Endothelin and Its Concentrations in Human Plasma and Urine
Authors: Wilbert-Lampen Ute , Seliger Christian , Zilker Thomas , Arendt Rainer M.
Published: June 2012

Background
—Cocaine-associated vascular events are not completely explained by adrenergic stimulation. The purposes of this study were to investigate whether vasoconstrictive endothelin-1 is released by cocaine and to elucidate the mechanisms involved.

Methods and Results
—Endothelin-1 was measured by radioimmunoassay and high-performance liquid chromatography (1) in the supernatant of porcine aortic endothelial cells after treatment with cocaine (10
−7
to 10
−4
mol/L) and a σ-receptor antagonist, haloperidol (10
−6
mol/L) or ditolylguanidine (10
−5
mol/L) and (2) in plasma and urine of 12 cocaine-intoxicated patients and 13 healthy control subjects. Radioligand binding assays were performed on endothelial membrane preparations. In cell culture, cocaine significantly increased endothelin accumulation above baseline at 3 to 24 hours; endothelin release rates per hour increased dose-dependently, reaching a plateau of 175±23% of control at hour 4 to 5. Coincubation of cocaine with haloperidol or ditolylguanidine abolished or reduced cocaine-induced endothelin release. Endothelial membrane preparations specifically and displaceably bound the highly selective σ-ligand [
3
H]ditolylguanidine (25×10
−9
mol/L), with 1400 binding sites estimated per cell. Endothelin-1 levels in plasma (22.7±5.6 versus 7.3±0.8 pmol/L) and urine (41.5±10.1 versus 12.7±3.8 pmol/L) of cocaine-intoxicated patients were significantly increased compared with control values.

Conclusions
—The data suggest that cocaine increases the endothelin-1 release in vitro and in vivo. The cocaine-induced vasoconstriction/vasospasm may therefore be facilitated by the release of endothelin-1. Cocaine appears to be an exogenous stimulator at endothelial σ-receptors. The endogenous ligands of this antiopioid system may prove to play a role in vasospastic angina, acute myocardial infarction, and sudden cardiac death.
Inverse Relationship Between Electrode Size and Lesion Size During Radiofrequency Ablation With Active Electrode Cooling
Authors: Nakagawa Hiroshi , Wittkampf Fred H. M. , Yamanashi William S. , Pitha Jan V. , Imai Shinobu , Campbell Barclay , Arruda Mauricio , Lazzara Ralph , Jackman Warren M.
Published: June 2012

Background
—Clinical efficacy has driven the use of larger electrodes (7F, length ≥4 mm) for radiofrequency ablation, which reduces electrogram resolution and causes variability in tissue contact depending on electrode orientation. With active cooling, ablation electrode size may be reduced. The purpose of this study was to examine the effect of electrode length on tissue temperature and lesion size with saline irrigation used for active cooling.

Methods and Results
—In 11 anesthetized dogs, the thigh muscle was exposed and bathed with heparinized canine blood. A 7F ablation catheter with a 2- or 5-mm irrigated tip electrode was positioned perpendicular or parallel to the thigh muscle. Radiofrequency current was delivered at constant voltage (50 V) for 30 seconds during saline irrigation (20 mL/min) to 148 sites. Tissue temperature at depths of 3.5 and 7 mm and lesion size were measured. In the perpendicular electrode-tissue orientation, radiofrequency applications at 50 V with the 2-mm electrode compared with the 5-mm electrode resulted in lower power at 50 V (26 versus 36 W) but higher tissue temperatures, larger lesion depth (8.0 versus 5.4 mm), and greater diameter (12.4 mm versus 8.4 mm). Also, in the parallel orientation, overall power was lower with the 2-mm electrode (25 versus 33 W), but tissue temperatures were higher and lesions were deeper (7.3 versus 6.9 mm). Lesion diameter was similar (11.1 versus 11.3 mm) for both electrodes.

Conclusions
—The smaller electrode resulted in transmission of a greater fraction of the radiofrequency power to the tissue and resulted in higher tissue temperature, larger lesions, and lower dependency of lesion size on the electrode orientation.
Abnormalities of the Extracellular Degradation of Collagen Type I in Essential Hypertension
Authors: Laviades Concepción , Varo Nerea , Fernández Javier , Mayor Gaspar , Gil María J. , Monreal Ignacio , Díez Javier
Published: June 2012

Background
—This study was designed to investigate whether collagen type I degradation is altered in patients with essential hypertension and whether this alteration could be related to disturbances in the serum matrix metalloproteinase pathway of collagen degradation. A second aim of the study was to assess whether some relation exists between serum markers of collagen type I degradation and left ventricular hypertrophy in hypertensive patients.

Methods and Results
—We measured serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation, of total matrix metalloproteinase-1 (MMP-1), or collagenase, of total tissue inhibitor of metalloproteinases 1 (TIMP-1), and of MMP-1/TIMP-1 complex in 37 patients with never-treated essential hypertension and in 23 normotensive control subjects. Serum concentrations of free MMP-1 and free TIMP-1 were calculated by subtracting the values of MMP-1/TIMP-1 complex from the values of total MMP-1 and total TIMP-1, respectively. Measurements were repeated in 26 hypertensive patients after 1 year of treatment with the ACE inhibitor lisinopril. Baseline free MMP-1 was decreased (
P
<0.001) and baseline free TIMP-1 was increased (
P
<0.001) in hypertensives compared with normotensives. No significant differences were observed in the baseline values of CITP between the 2 groups of subjects. Hypertensive patients with baseline left ventricular hypertrophy exhibited lower values of free MMP-1 (
P
<0.01) and CITP (
P
<0.05) and higher (
P
<0.001) values of free TIMP-1 than hypertensive patients without baseline left ventricular hypertrophy. Treated patients attained an increase (
P
<0.001) in free MMP-1 and a decrease (
P
<0.05) in free TIMP-1. In addition, serum CITP was increased (
P
<0.05) in treated hypertensives compared with normotensive subjects.

Conclusions
—These findings suggest that systemic extracellular degradation of collagen type I is depressed in patients with essential hypertension and can be normalized by treatment with lisinopril. A depressed degradation of collagen type I may facilitate organ fibrosis in hypertensive patients, namely, in those with left ventricular hypertrophy.
Mechanisms Underlying Very-Low-Frequency RR-Interval Oscillations in Humans
Authors: Taylor J. Andrew , Carr Deborah L. , Myers Christopher W. , Eckberg Dwain L.
Published: June 2012

Background
—Survival of post–myocardial infarction patients is related inversely to their levels of very-low-frequency (0.003 to 0.03 Hz) RR-interval variability. The physiological basis for such oscillations is unclear. In our study, we used blocking drugs to evaluate potential contributions of sympathetic and vagal mechanisms and the renin-angiotensin-aldosterone system to very-low-frequency RR-interval variability in 10 young healthy subjects.

Methods and Results
—We recorded RR intervals and arterial pressures during three separate sessions, with the patient in supine and 40 degree upright tilt positions, during 20-minute frequency (0.25 Hz) and tidal volume–controlled breathing after intravenous injections: saline (control), atenolol (0.2 mg/kg, β-adrenergic blockade), atropine sulfate (0.04 mg/kg, parasympathetic blockade), atenolol and atropine (complete autonomic blockade), and enalaprilat (0.02 mg/kg, ACE blockade). We integrated fast Fourier transform RR-interval spectral power at very low (0.003 to 0.03 Hz), low (0.05 to 0.15 Hz), and respiratory (0.2 to 0.3 Hz) frequencies. β-Adrenergic blockade had no significant effect on very-low- or low-frequency RR-interval power but increased respiratory frequency power 2-fold. ACE blockade had no significant effect on low or respiratory frequency RR-interval power but modestly (≈21%) increased very-low-frequency power in the supine (but not upright tilt) position (
P
<0.05). The most profound effects were exerted by parasympathetic blockade: Atropine, given alone or with atenolol, abolished nearly all RR-interval variability and decreased very-low-frequency variability by 92%.

Conclusions
—Although very-low-frequency heart period rhythms are influenced by the renin-angiotensin-aldosterone system, as low and respiratory frequency RR-interval rhythms, they depend primarily on the presence of parasympathetic outflow. Therefore the prognostic value of very-low-frequency heart period oscillations may derive from the fundamental importance of parasympathetic mechanisms in cardiovascular health.
Asynchronous Electrical Activation Induces Asymmetrical Hypertrophy of the Left Ventricular Wall
Authors: van Oosterhout Matthijs F. M. , Prinzen Frits W. , Arts Theo , Schreuder Jan J. , Vanagt Ward Y. R. , Cleutjens Jack P. M. , Reneman Robert S.
Published: June 2012

Background
—Asynchronous electrical activation, induced by ventricular pacing, causes regional differences in workload, which is lower in early- than in late-activated regions. Because the myocardium usually adapts its mass and structure to altered workload, we investigated whether ventricular pacing leads to inhomogeneous hypertrophy and whether such adaptation, if any, affects global left ventricular (LV) pump function.

Methods and Results
—Eight dogs were paced at physiological heart rate for 6 months (AV sequential, AV interval 25 ms, ventricular electrode at the base of the LV free wall). Five dogs were sham operated and served as controls. Ventricular pacing increased QRS duration from 47.2±10.6 to 113±16.5 ms acutely and to 133.8±25.2 ms after 6 months. Two-dimensional echocardiographic measurements showed that LV cavity and wall volume increased significantly by 27±15% and 15±17%, respectively. The early-activated LV free wall became significantly (17±17%) thinner, whereas the late-activated septum thickened significantly (23±12%). Calculated sector volume did not change in the LV free wall but increased significantly in the septum by 39±13%. In paced animals, cardiomyocyte diameter was significantly (18±7%) larger in septum than in LV free wall, whereas myocardial collagen fraction was unchanged in both areas. LV pressure-volume analysis showed that ventricular pacing reduced LV function to a similar extent after 15 minutes and 6 months of pacing.

Conclusions
—Asynchronous activation induces asymmetrical hypertrophy and LV dilatation. Cardiac pump function is not affected by the adaptational processes. These data indicate that local cardiac load regulates local cardiac mass of both myocytes and collagen.
Antisense
fos
B RNA Inhibits Thrombin-Induced Hypertrophy in Cultured Pulmonary Arterial Smooth Muscle Cells
Authors: Lu Chuanyi , Giordano Frank J. , Bao Xuping , Morris Kemberlyn C. , Rothman Abraham
Published: June 2012

Background
—We have previously reported that
fos
B mRNA is induced by hypertrophic stimuli (thrombin, angiotensin II) but not proliferative stimuli (platelet-derived growth factor, basic fibroblast growth factor) in pulmonary arterial smooth muscle cells (PASMCs) (
J Biol Chem
. 1994;9:6399–6404). Our aim in the present study was to investigate the potential role of FosB in PASMC hypertrophy.

Methods and Results
—Adenoviruses carrying sense or antisense
fos
B RNA expression cassettes were used to infect cultured PASMCs with the aim of increasing or inhibiting
fos
B expression, respectively. We examined whether
fos
B expression modification affected the growth of quiescent PASMCs, thrombin-induced hypertrophy, or platelet-derived growth factor–induced proliferation. PASMC growth was assessed by daily cell number count, determination of [
3
H]leucine incorporation, and quantification of total cellular protein. Neither an increase nor a decrease in FosB protein expression caused a significant change in the growth of quiescent PASMCs over a period of 96 hours, indicating that FosB alone is not sufficient to induce hypertrophy. Modification of FosB levels did not affect platelet-derived growth factor–induced PASMC proliferation. An increase in FosB expression did not augment thrombin-induced hypertrophy; however, inhibition of FosB expression resulted in a diminution of thrombin-induced hypertrophy by 58±6% (
P
<0.005).

Conclusions
—These results suggest that FosB is necessary but not sufficient for thrombin-induced hypertrophy in cultured PASMCs.
Resuscitation Preferences Among Patients With Severe Congestive Heart Failure
Authors: Krumholz Harlan M. , Phillips Russell S. , Hamel Mary Beth , Teno Joan M. , Bellamy Paul , Broste Steven K. , Califf Robert M. , Vidaillet Humberto , Davis Roger B. , Muhlbaier Lawrence H. , Connors Alfred F. , Lynn Joanne , Goldman Lee
Published: June 2012

Background
—We sought to describe the resuscitation preferences of patients hospitalized with an exacerbation of severe congestive heart failure, perceptions of those preferences by their physicians, and the stability of the preferences.

Methods and Results
—Of 936 patients in this study, 215 (23%) explicitly stated that they did not want to be resuscitated. Significant correlates of not wanting to be resuscitated included older age, perception of a worse prognosis, poorer functional status, and higher income. The physician’s perception of the patient’s preference disagreed with the patient’s actual preference in 24% of the cases overall. Only 25% of the patients reported discussing resuscitation preferences with their physician, but discussion of preferences was not significantly associated with higher agreement between the patient and physician. Of the 600 patients who responded to the resuscitation question again 2 months later, 19% had changed their preferences, including 14% of those who initially wanted resuscitation (69 of 480) and 40% of those who initially did not (48 of 120). The physician’s perception of the patient’s hospital resuscitation preference was correct for 84% of patients who had a stable preference and 68% of those who did not.

Conclusions
—Almost one quarter of patients hospitalized with severe heart failure expressed a preference not to be resuscitated. The physician’s perception of the patient’s preference was not accurate in about one quarter of the cases, but communication was not associated with greater agreement between the patient and the physician. A substantial proportion of patients who did not want to be resuscitated changed their minds within 2 months of discharge.
Prospective Study of C-Reactive Protein and the Risk of Future Cardiovascular Events Among Apparently Healthy Women
Authors: Ridker Paul M. , Buring Julie E. , Shih Jessie , Matias Mathew , Hennekens Charles H.
Published: June 2012

Background
—C-reactive protein (CRP) predicts risk of myocardial infarction (MI) and stroke among apparently healthy men, but in women, virtually no data are available.

Methods and Results
—CRP was measured in baseline blood samples from 122 apparently healthy participants in the Women’s Health Study who subsequently suffered a first cardiovascular event and from 244 age- and smoking-matched control subjects who remained free of cardiovascular disease during a 3-year follow-up period. Women who developed cardiovascular events had higher baseline CRP levels than control subjects (
P
=0.0001), such that those with the highest levels at baseline had a 5-fold increase in risk of any vascular event (RR=4.8; 95% CI, 2.3 to 10.1;
P
=0.0001) and a 7-fold increase in risk of MI or stroke (RR=7.3; 95% CI, 2.7 to 19.9;
P
=0.0001). Risk estimates were independent of other risk factors, and prediction models that included CRP provided a better method to predict risk than models that excluded CRP (all
P
values <0.01). In stratified analyses, CRP was a predictor among subgroups of women with low as well as high risk as defined by other cardiovascular risk factors.

Conclusions
—In these prospective data among women, CRP is a strong independent risk factor for cardiovascular disease that adds to the predictive value of risk models based on usual factors alone.
Accuracy and Impact of Presumed Cause in Patients With Cardiac Arrest
Authors: Kürkciyan Istepan , Meron Giora , Behringer Wilhelm , Sterz Fritz , Berzlanovich Andrea , Domanovits Hans , Müllner Marcus , Bankl Hans C. , Laggner Anton N.
Published: June 2012

Background
—International guidelines recommend differentiation between cardiac and noncardiac causes of cardiac arrest. The aim of this study was to find the rate of agreement between primarily postulated and definitive causes of cardiac arrest.

Methods and Results
—We retrospectively analyzed the primarily presumed cause of cardiac arrest as determined by the emergency room physician on admission in all patients admitted to the emergency department of one urban tertiary care hospital. This was compared with the definitive cause as established by clinical evidence or autopsy. Within 4 years, the initially presumed cause was unclear in 24 (4%) of 593 patients. In the remaining 569 patients, the presumed cause was correct in 509 (89%) and wrong in 60 (11%) cases. Cardiac origin was presumed in 421 (71%) and the definitive cause in 408 (69%) cases. Noncardiac origin was presumed in 148 (25%) and the definitive cause in 185 (31%) patients. Presumed cardiac cause was sensitive (96%) but less specific (77%). Noncardiac causes such as pulmonary embolism, cerebral disorders, or exsanguination were those most frequently overlooked. Asystole occurred significantly more often in patients in whom presumed cause remained undetermined or differed from the definitive cause.

Conclusions
—Cause of cardiac arrest is not as easily recognized as anticipated, especially when the initial rhythm is different from ventricular fibrillation. This might affect comparability of study results, therapeutic strategies, prognosis, and outcome. Patients in whom the presumed cause was confirmed as being correct had significantly better survival and neurological outcome.
Preformed IgG Antibodies Against Major Histocompatibility Complex Class II Antigens Are Major Risk Factors for High-grade Cellular Rejection in Recipients of Heart Transplantation
Authors: Itescu Silviu , Tung Thomas C. , Burke Elizabeth M. , Weinberg Alan , Moazami Nader , Artrip John H. , Suciu-Foca Nicole , Rose Eric A. , Oz Mehmet C. , Michler Robert E.
Published: June 2012

Background
—Preformed anti-HLA antibodies reacting specifically with donor lymphocytes have been associated with acute vascular rejection and early cardiac allograft failure. However, the effect of preformed anti-HLA antibodies directed against allogeneic major histocompatibility complex (MHC) class I or II antigens of a donor panel on heart transplantation outcome has not been extensively studied.

Methods and Results
—The study group consisted of 68 patients who received cardiac transplants between 1989 and 1996 and who were at high risk for developing anti-HLA antibodies before transplantation. The effect of preformed antibodies against allogeneic MHC class I or class II antigens on the development of early high-grade cellular rejection and on cumulative annual rejection frequency was determined. Both patients with left ventricular assist devices and retransplantation candidates had a similar increase in the frequency of IgG anti-MHC class II antibodies (IgG anti-II) compared with control subjects (
P
<0.0001), whereas the frequency of IgG anti-MHC class I antibodies (IgG anti-I) was elevated only in patients with left ventricular assist devices. Pretransplantation IgG anti-II predicted early development of high-grade cellular rejection (
P
=0.006) and higher cumulative annual rejection frequency (
P
<0.001) in both of these sensitized patient groups. Among retransplantation recipients, a match between donors 1 and 2 at HLA-A additionally predicted an earlier time to a high-grade cellular rejection.

Conclusions
—These results emphasize the importance of specifically screening heart transplantation candidates for the presence of IgG antibodies directed against MHC class II molecules and suggest that strategies aimed at their reduction may have an impact on the onset and frequency of high-grade cellular rejections after transplantation.