bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevation of Prostate-Specific Markers After Cardiopulmonary Resuscitation
Authors: Koller-Strametz Jeanette , Fritzer Monika , Gwechenberger Marianne , Geppert Alexander , Heinz Gottfried , Haumer Markus , Koreny Maria , Maurer Gerald , Siostrzonek Peter
Published: June 2012

Background
—Prostate-specific antigen (PSA), acid phosphatase (AP), and prostatic acid phosphatase (PAP) are serum markers for adenocarcinoma of the prostate gland. Previous studies indicated that prostatic ischemia may also produce elevations of PSA. Cardiopulmonary resuscitation (CPR) is frequently associated with profound tissue hypoperfusion. The present study investigated whether PSA, AP, and PAP are influenced by prolonged CPR.

Methods and Results
—PSA, AP, and PAP were assessed immediately, 12 hours, 24 hours, 2 days, 3 days, 5 days, and 7 days after prolonged CPR (>5 minutes) in 14 male and 5 female patients. No changes were noted in women. In men, serum levels increased significantly after CPR and gradually decreased to near baseline values after 7 days. PSA, AP, and PAP values above the normal range were observed in 63%, 71%, and 64% of all patients, respectively. Compared with survivors, nonsurvivors exhibited higher peak serum levels of PSA (98.6±14.3 versus 1.1±2.2 μg/L;
P
<0.03), AP (57.0±71 versus 8.6±8.8 U/L;
P
<0.05), and PAP (47.0±62 versus 5.7±8.0 U/L;
P
=NS). Patients with poor neurological outcome exhibited higher peak serum levels of PSA (86.4±135.5 versus 12.0±23.8 μg/L;
P
<0.05), AP (50.9±68.1 versus 8.7±9.6 U/L;
P
=NS), and PAP (41.6±59.5 versus 5.8±8.8 U/L;
P
=NS) than patients with good neurological outcome.

Conclusions
—Prolonged CPR is frequently associated with increases of PSA, AP, and PAP serum levels. Therefore, PSA cannot be used for diagnosis of adenocarcinoma of the prostate during the first weeks after CPR. Further evaluation of these parameters as additional prognostic markers after CPR is warranted.
Reduced Ventricular Response Irregularity Is Associated With Increased Mortality in Patients With Chronic Atrial Fibrillation
Authors: Yamada Akira , Hayano Junichiro , Sakata Seiichiro , Okada Akiyoshi , Mukai Seiji , Ohte Nobuyuki , Kimura Genjiro
Published: June 2012

Background
—Variations in the ventricular response interval (VRI) during atrial fibrillation (AF) may be reduced in patients with adverse clinical outcomes. The properties of VRI dynamics associated with prognosis remain undetermined.

Methods and Results
—In 107 patients with chronic AF (age, 64±9 years), we analyzed a 24-hour ambulatory ECG for VRI variability (SD, SD of successive differences, and SD of 5-minute averages) and VRI irregularity (Shannon entropy of histogram, symbolic dynamics, and approximate entropy of beat-to-beat and minute-to-minute fluctuations [ApEn
b-b
and ApEn
m-m
]). During a follow-up period of 33±16 months, 18 patients died (17%), 9 from cardiac causes, 7 from fatal strokes, and 2 from malignancies. Reductions in all VRI variability and irregularity measures were associated with an increased risk for cardiac death but not for fatal stroke. A significant association with cardiac death was also found for ejection fraction (relative risk, 1.10; 95% confidence interval [CI], 1.04 to 1.17, per 1% decrement) and ischemic AF (relative risk, 6.52; 95% CI, 1.62 to 26.3). After adjustment for these clinical variables, all irregularity measures except symbolic dynamics had predictive value (relative risks [95% CIs] per 1SD decrement: Shannon entropy of histogram, 2.03 [1.14 to 3.61]; ApEn
b-b
, 1.72 [1.14 to 2.60]; and ApEn
m-m
, 1.90 [1.03 to 3.52]); however, the predictive power of variability measures was no longer significant. When the patients were stratified with the 33rd and 67th percentile values of ApEn
b-b
(1.83 and 1.94, respectively), the 5-year cardiac mortality rates for the upper, middle, and lower tertiles were 0%, 13%, and 43%, respectively (log-rank test,
P
=0.04).

Conclusions
—Reduced VRI irregularity in a 24-hour ambulatory ECG has an independent prognostic value for cardiac mortality during long-term follow-up in patients with chronic AF.
Improvement of Endothelial Function by Chronic Angiotensin-Converting Enzyme Inhibition in Heart Failure
Authors: Varin Rémi , Mulder Paul , Tamion Fabienne , Richard Vincent , Henry Jean-Paul , Lallemand Françoise , Lerebours Guy , Thuillez Christian
Published: June 2012

Background
—Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved.

Methods and Results
—FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg · kg
−1
· day
−1
for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N
W
-nitro-
l
-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor–treated CHF rats was abolished by N
W
-nitro-
l
-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor–treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF.

Conclusions
—In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.
Body Composition and Prevalence of Left Ventricular Hypertrophy
Authors: Kuch Bernhard , Hense Hans-Werner , Gneiting Birgit , Döring Angela , Muscholl Michael , Bröckel Ulrich , Schunkert Heribert
Published: June 2012

Background
—Fat-free mass (FFM) has been proposed as an optimal normalization of left ventricular (LV) mass to body size. We sought to evaluate the novel FFM-based criteria of LV hypertrophy (LVH).

Methods and Results
—A population sample of 1371 men and women aged 25 to 74 years was examined by echocardiography and bioelectrical impedance analysis. Internal partition values for LVH were generated in a healthy population subgroup on the basis of LV mass divided by FFM and by the traditional indexations to body height, height
2.7
, and body surface area. In contrast to the sex-specific criteria required by traditional indexations, the value of LV mass/FFM that divided individuals with and without LVH was identical for men and women (4.1 g/kg). Estimates of LVH prevalence varied significantly by type of indexation used, internally or externally derived cut points, and by population subgroups. Differences were pronounced among hypertensives and the obese. Thus, the application of LV mass/FFM more than halved the risk of LVH in obese versus nonobese women (odds ratio, 2.5; 95% confidence interval, 1.6 to 4.0) compared with criteria based on LV mass/height
2.7
(odds ratio, 5.5; 95% confidence interval, 3.6 to 8.3). Implications among hypertensives were less marked.

Conclusions
—Indexation of LV mass to FFM eliminates sex-specific LVH criteria. The proportion of individuals defined as having LVH using the new criteria deviate markedly from traditional indexations. Prospective investigations will be needed to identify the prognostic implications of different indexations, especially in subgroups such as the obese.
Localization of the Slow Conduction Zone During Reentrant Ventricular Tachycardia
Authors: Ciaccio Edward J.
Published: June 2012

Background
—Reentrant ventricular tachycardia is sometimes difficult to treat effectively because localizing the slow conduction zone (SCZ) for catheter ablation may be problematic. It was hypothesized that a linear relationship exists between activating wave-front acceleration and deceleration in the SCZ and, respectively, contractions and expansions of the far-field extracellular signal, which could be used for SCZ localization.

Methods and Results
—To test the hypothesis, a model was developed to approximate SCZ location on the basis of the time interval between activation at the recording site and shifts in electrogram far-field deflections. Electrograms were recorded during reentry from 196 to 312 epicardial sites (canine model, 8 episodes). Activation maps of reentry were constructed to determine wave-front velocity, and piecewise linear adaptive template matching (PLATM) measured time shifts in far-field electrogram deflections. Linear trends of cycle length change often occurred during tachycardia (mean trend, +15 ms/96.8 cardiac cycles;
r
2
=0.92). Alteration in the time interval for activation through the SCZ approximated the change in tachycardia cycle length (mean correspondence, 75.7%). The beginning and end times of far-field extracellular waveform time shifts measured by PLATM predicted the time from recording site activation to activation at the SCZ proximal and distal edges, respectively (mean absolute error with respect to activation mapping, 20.3 ms).

Conclusions
—During reentry, PLATM estimates the time interval from activation at any recording site near the circuit to SCZ activation. PLATM time intervals are convertible to arc lengths along the circuit for potentially more rapid and accurate update of a hand-held probe toward the SCZ for catheter ablation.
Race, Sex, Poverty, and the Medical Treatment of Acute Myocardial Infarction in the Elderly
Authors: Rathore Saif S. , Berger Alan K. , Weinfurt Kevin P. , Feinleib Manning , Oetgen William J. , Gersh Bernard J. , Schulman Kevin A.
Published: June 2012

Background
—Race, sex, and poverty are associated with the use of diagnostic cardiac catheterization and coronary revascularization during treatment of acute myocardial infarction (AMI). However, the association of sociodemographic characteristics with the use of less costly, more readily available medical therapies remains poorly characterized.

Methods and Results
—We evaluated 169 079 Medicare beneficiaries ≥65 years of age treated for AMI between January 1994 and February 1996 to determine the association of patient race, sex, and poverty with the use of medical therapy. Multivariable regression models were constructed to evaluate the unadjusted and adjusted influence of sociodemographic characteristics on the use of 2 admission (aspirin, reperfusion) and 2 discharge therapies (aspirin, β-blockers) indicated during the treatment of AMI. Therapy use varied by patient race, sex, and poverty status. Black patients were less likely to undergo reperfusion (RR 0.84, 95% CI 0.78, 0.91) or receive aspirin on admission (RR 0.97, 95% CI 0.96, 0.99) and β-blockers (RR 0.94, 95% CI 0.88, 1.00) at discharge. Female patients were less likely to receive aspirin on admission (RR 0.98, 95% CI 0.97, 0.99) and discharge (RR 0.98, 95% CI 0.96, 0.99). Poor patients were less likely to receive aspirin (RR 0.97, 95% CI 0.96, 0.98) or reperfusion (RR 0.97, 95% CI 0.93, 1.00) on admission and aspirin (RR 0.98, 95% CI 0.96, 1.00), or β-blockers (RR 0.95, 95% CI 0.91, 0.99) on discharge.

Conclusions
—Medical therapies are currently underused in the treatment of black, female, and poor patients with AMI.
Visualization and Temporal/Spatial Characterization of Cardiac Radiofrequency Ablation Lesions Using Magnetic Resonance Imaging
Authors: Lardo Albert C. , McVeigh Elliot R. , Jumrussirikul Pitayadet , Berger Ronald D. , Calkins Hugh , Lima João , Halperin Henry R.
Published: June 2012

Background
—The purpose of this study was to describe a system and method for creating, visualizing, and monitoring cardiac radiofrequency ablation (RFA) therapy during magnetic resonance imaging (MRI).

Methods and Results
—RFA was performed in the right ventricular apex of 6 healthy mongrel dogs with a custom 7F nonmagnetic ablation catheter (4-mm electrode) in a newly developed real-time interactive cardiac MRI system. Catheters were positioned to intracardiac targets by use of an MRI fluoroscopy sequence, and ablated tissue was imaged with T2-weighted fast spin-echo and contrast-enhanced T1-weighted gradient-echo sequences. Lesion size by MRI was determined and compared with measurements at gross and histopathological examination. Ablated areas of myocardium appeared as hyperintense regions directly adjacent to the catheter tip and could be detected 2 minutes after RF delivery. Lesions reached maximum size ≈5 minutes after ablation, whereas lesion signal intensity increased linearly with time but then reached a plateau at 12.2±2.1 minutes. Lesion size by MR correlated well with actual postmortem lesion size and histological necrosis area (55.4±7.2 versus 49.7±5.9 mm
2
,
r
=0.958,
P
<0.05).

Conclusions
—RFA can be performed in vivo in a new real-time interactive cardiac MRI system. The spatial and temporal extent of cardiac lesions can be visualized and monitored by T2- and T1-weighted imaging, and MRI lesion size agrees well with actual postmortem lesion size. MRI-guided RFA may be a useful approach to help facilitate anatomic lesion placement and to provide insight into the biophysical effects of new ablation techniques and technologies.
Dose-Finding, Safety, and Tolerability Study of an Oral Platelet Glycoprotein IIb/IIIa Inhibitor, Lotrafiban, in Patients With Coronary or Cerebral Atherosclerotic Disease
Authors: Harrington Robert A. , Armstrong Paul W. , Graffagnino Carmelo , Van de Werf Frans , Kereiakes Dean J. , Sigmon Kristina N. , Card Tracy , Joseph Diane M. , Samuels Robert , Granett Jeffrey , Chan Robert , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
—Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease.

Methods and Results
—Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/μL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/μL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%.

Conclusions
—Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.
Randomized, Double-Blind Trial of Simultaneous Right and Left Atrial Epicardial Pacing for Prevention of Post–Open Heart Surgery Atrial Fibrillation
Authors: Daoud Emile G. , Dabir Reza , Archambeau Michelle , Morady Fred , Strickberger S. Adam
Published: June 2012

Background
—The purpose of this study was to assess simultaneous right and left atrial pacing as prophylaxis for postoperative atrial fibrillation.

Methods and Results
—In a double-blind, randomized fashion, 118 patients who underwent open heart surgery were assigned to right atrial pacing at 45 bpm (RA-AAI; n=39), right atrial triggered pacing at a rate of ≥85 bpm (RA-AAT; n=38), or simultaneous right and left atrial triggered pacing at a rate of ≥85 bpm (Bi-AAT; n=41). Holter monitoring was performed for 4.8±1.4 days after surgery to assess for episodes of atrial fibrillation lasting >5 minutes. The prevalence of postoperative atrial fibrillation was significantly less in the patients randomized to biatrial AAT pacing when compared with the other 2 pacing regimens (
P
=0.02). An episode of atrial fibrillation occurred in 4 (10%) of 41 patients in the Bi-AAT group compared with 11 (28%) of 39 patients in the RA-AAI group (
P
=0.03 versus Bi-AAT) and 12 (32%) of 38 patients in the RA-AAT group (
P
=0.01 versus Bi-AAT). There was no difference in the occurrence of atrial fibrillation between the right atrial AAI and AAT groups (
P
=0.8). There was no significant difference among the 3 groups with regard to the number of postoperative hospital days (7.3±4.2 days), morbidity (5.1%), or mortality rate (2.5%).

Conclusions
—Simultaneous right and left atrial triggered pacing is well tolerated and significantly reduces the prevalence of post–open heart surgery atrial fibrillation.
Overexpression of G Protein–Coupled Receptor Kinase-2 in Smooth Muscle Cells Attenuates Mitogenic Signaling via G Protein–Coupled and Platelet-Derived Growth Factor Receptors
Authors: Peppel Karsten , Jacobson Anne , Huang Xuewei , Murray John P. , Oppermann Martin , Freedman Neil J.
Published: June 2012

Background
—Neointimal hyperplasia involves activation of smooth muscle cells (SMCs) by several G protein–coupled receptor (GPCR) agonists, including endothelin-1, angiotensin II, thrombin, and thromboxane A
2
. Signaling of many GPCRs is diminished by GPCR kinase-2 (GRK2). We therefore tested whether overexpression of GRK2 in SMCs could diminish mitogenic signaling elicited by agonists implicated in the pathogenesis of neointimal hyperplasia.

Methods and Results
—Overexpression of GRK2 was achieved in primary rabbit aortic SMCs with a recombinant adenovirus. Control SMCs were infected with an empty vector adenovirus. Inositol phosphate responses to endothelin-1, angiotensin II, thrombin agonist peptide, and platelet-derived growth factor (PDGF) were attenuated by 37% to 72% in GRK2-overexpressing cells (
P
<0.01), but the response to the thromboxane A
2
analogue U46619 was unaffected. GRK2 also inhibited SMC [
3
H]thymidine incorporation stimulated not only by these agonists (by 30% to 60%,
P
<0.01) but also by 10% FBS (by 35%,
P
<0.05). However, GRK2 overexpression had no effect on epidermal growth factor–induced [
3
H]thymidine incorporation. Agonist-induced tyrosine phosphorylation of the PDGF-β receptor, but not the epidermal growth factor receptor, was reduced in GRK2-overexpressing SMCs. GRK2 overexpression also reduced SMC proliferation in response to endothelin-1, PDGF, and 10% FBS by 62%, 51%, and 29%, respectively (
P
<0.01), without any effect on SMC apoptosis.

Conclusions
—GRK2 overexpression diminishes SMC mitogenic signaling and proliferation stimulated by PDGF or agonists for several GPCRs. Gene transfer of GRK2 may therefore be therapeutically useful for neointimal hyperplasia.
Increased Activity of Nuclear Factor-κB Participates in Cardiovascular Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats
Authors: Kitamoto Shiro , Egashira Kensuke , Kataoka Chu , Koyanagi Masamichi , Katoh Makoto , Shimokawa Hiroaki , Morishita Ryuichi , Kaneda Yasufumi , Sueishi Katsuo , Takeshita Akira
Published: June 2012

Background
—Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) to rats induces early vascular inflammatory changes [monocyte infiltration into coronary vessels, nuclear factor-κB (NF-κB) activation, and monocyte chemoattractant protein-1 expression] as well as subsequent arteriosclerosis (medial thickening and perivascular fibrosis) and cardiac fibrosis. However, no direct evidence for the importance of NF-κB in this process is known.

Methods and Results
—We examined the effect of a
cis
element decoy strategy to address the functional importance of NF-κB in the pathogenesis of cardiovascular remodeling. We found here that in vivo transfection of
cis
element decoy oligodeoxynucleotides against NF-κB to hearts prevented the L-NAME–induced early inflammation and subsequent coronary vascular medial thickening. In contrast, NF-κB decoy oligodeoxynucleotide transfection did not decrease the development of fibrosis, the expression of transforming growth factor-β
1
mRNA, or systolic pressure overload induced by L-NAME administration.

Conclusions
—The NF-κB system participates importantly in the development of early vascular inflammation and subsequent medial thickening but not in fibrogenesis in this model. The present study may provide a new aspect of how endothelium-derived NO contributes to anti-inflammatory and/or antiarteriosclerotic properties of the vascular endothelium in vivo.
Oxidant Stress and Aspirin-Insensitive Thromboxane Biosynthesis in Severe Unstable Angina
Authors: Cipollone Francesco , Ciabattoni Giovanni , Patrignani Paola , Pasquale Massimo , Di Gregorio Domenico , Bucciarelli Tonino , Davı̀ Giovanni , Cuccurullo Franco , Patrono Carlo
Published: June 2012

Background
—Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F
2
-isoprostane 8-iso-prostaglandin (PG)F
2α
, a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis.

Methods and Results
—Urine samples were obtained from patients with unstable angina (n=32), stable angina (n=32), or variant angina (n=4) and from 40 healthy subjects for the measurement of immunoreactive 8-iso-PGF
2α
and 11-dehydro-TXB
2
. 8-Iso-PGF
2α
excretion was significantly higher in patients with unstable angina (339±122 pg/mg creatinine) than in matched patients with stable angina (236±83 pg/mg creatinine,
P
=0.001) and control subjects (192±71 pg/mg creatinine,
P
<0.0001). In patients with unstable angina, 8-iso-PGF
2α
was linearly correlated with 11-dehydro-TXB
2
excretion (ρ=0.721,
P
<0.0001) and inversely correlated with plasma vitamin E (ρ=−0.710,
P
=0.004). Spontaneous myocardial ischemia in patients with variant angina or ischemia elicited by a stress test in patients with stable angina was not accompanied by any change in 8-iso-PGF
2α
excretion, thus excluding a role of ischemia per se in the induction of increased F
2
-isoprostane production.

Conclusions
—These findings establish a putative biochemical link between increased oxidant stress and aspirin-insensitive TX biosynthesis in patients with unstable angina and provide a rationale for dose-finding studies of antioxidants in this setting.
Biventricular Pacing Decreases Sympathetic Activity Compared With Right Ventricular Pacing in Patients With Depressed Ejection Fraction
Authors: Hamdan Mohamed H. , Zagrodzky Jason D. , Joglar Jose A. , Sheehan Clifford J. , Ramaswamy Karthik , Erdner Jeffrey F. , Page Richard L. , Smith Michael L.
Published: June 2012

Background
—Although there have been few studies in which the hemodynamic effects of right ventricular (RV) and left ventricular (LV) pacing were compared with those of biventricular (BV) pacing, the autonomic changes during these different pacing modes remain unknown. We hypothesized that BV pacing results in improved hemodynamics and a decrease in sympathetic nerve activity (SNA) compared with single-site pacing.

Methods and Results
—Thirteen men with a mean ejection fraction of 0.28±0.7 were enrolled in the study. Arterial blood pressure (BP), central venous pressure (CVP), and SNA were recorded during 3 minutes of right atrial (RA)-RV, RA-LV, and RA-BV pacing at a rate 10 beats faster than sinus rhythm. BP was greater during LV (151±7/85±3 mm Hg) and BV (151±6/85±3 mm Hg) pacing than during RV pacing (146±7/82±3 mm Hg) (
P
<0.05). There were no differences in CVP among all pacing modes (
P
=0.27). SNA was significantly less (
P
<0.02) during both LV (606±35 U) and BV (582±41 U) pacing compared with RV pacing (685±32 U) (
P
<0.02). Although not statistically significant (
P
=0.08 to 0.14), there was a trend for patients with a narrow QRS to have a lower mean BP and higher SNA during LV pacing than during BV pacing (
r
=0.42 to 0.49).

Conclusions
—LV-based pacing results in improved hemodynamics and a decrease in SNA compared with RV pacing in patients with LV dysfunction regardless of the QRS duration.
Microtubule Depolymerization Normalizes In Vivo Myocardial Contractile Function in Dogs With Pressure-Overload Left Ventricular Hypertrophy
Authors: Koide Masaaki , Hamawaki Masayoshi , Narishige Takahiro , Sato Hiroshi , Nemoto Shintaro , DeFreyte Gilberto , Zile Michael R. , Cooper George , Carabello Blase A.
Published: June 2012

Background
—Because initially compensatory myocardial hypertrophy in response to pressure overloading may eventually decompensate to myocardial failure, mechanisms responsible for this transition have long been sought. One such mechanism established in vitro is densification of the cellular microtubule network, which imposes a viscous load that inhibits cardiocyte contraction.

Methods and Results
—In the present study, we extended this in vitro finding to the in vivo level and tested the hypothesis that this cytoskeletal abnormality is important in the in vivo contractile dysfunction that occurs in experimental aortic stenosis in the adult dog. In 8 dogs in which gradual stenosis of the ascending aorta had caused severe left ventricular (LV) pressure overloading (gradient, 152±16 mm Hg) with contractile dysfunction, LV function was measured at baseline and 1 hour after the intravenous administration of colchicine. Cardiocytes obtained by biopsy before and after in vivo colchicine administration were examined in tandem. Microtubule depolymerization restored LV contractile function both in vivo and in vitro.

Conclusions
—These and additional corroborative data show that increased cardiocyte microtubule network density is an important mechanism for the ventricular contractile dysfunction that develops in large mammals with adult-onset pressure-overload–induced cardiac hypertrophy.
Physical Activity and Coronary Heart Disease Risk in Men
Authors: Lee I-Min , Sesso Howard D. , Paffenbarger Ralph S.
Published: June 2012

Background
—Physical activity is associated with a decreased risk of coronary heart disease (CHD). However, it is unclear whether the duration of exercise episodes is important: Are accumulated shorter sessions as predictive of decreased risk as longer sessions if the same amount of energy is expended?

Methods and Results
—In the Harvard Alumni Health Study, we prospectively followed 7307 Harvard University alumni (mean age 66.1 years) from 1988 through 1993. At baseline, men reported their walking, stair climbing, and participation in sports or recreational activities. For each of the latter activities, they also reported the frequency and average duration per episode. During follow-up, 482 men developed CHD. In age-adjusted analysis, a longer duration of exercise episodes predicted lower CHD risk (
P
trend=0.04). However, after total energy expended on physical activity and potential confounders was accounted for, duration no longer had an independent effect on CHD risk (
P
trend=0.25); that is, longer sessions of exercise did not have a different effect on risk compared with shorter sessions, as long as the total energy expended was similar. In contrast, higher levels of total energy expenditure significantly predicted decreased CHD risk in both age-adjusted (
P
trend=0.009) and multivariate (
P
trend=0.046) analyses.

Conclusions
—These data clearly indicate that physical activity is associated with decreased CHD risk. Furthermore, they lend some support to recent recommendations that allow for the accumulation of shorter sessions of physical activity, as opposed to requiring 1 longer, continuous session of exercise. This may provide some impetus for those sedentary to become more active.
Radioactive Stents Delay but Do Not Prevent In-Stent Neointimal Hyperplasia
Authors: Kay I. Patrick , Wardeh Alexander J. , Kozuma Ken , Foley David P. , Knook A. H. Marco , Thury Attila , Sianos George , van der Giessen Willem J. , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—Restenosis after conventional stenting is almost exclusively caused by neointimal hyperplasia. β-Particle–emitting radioactive stents decrease in-stent neointimal hyperplasia at 6-month follow-up. The purpose of this study was to evaluate the 1-year outcome of
32
P radioactive stents with an initial activity of 6 to 12 μCi using serial quantitative coronary angiography and volumetric ECG-gated 3D intravascular ultrasound (IVUS).

Methods and Results
—Of 40 patients undergoing initial stent implantation, 26 were event-free after the 6-month follow-up period and 22 underwent repeat catheterization and IVUS at 1 year; they comprised half of the study population. Significant luminal deterioration was observed within the stents between 6 months and 1 year, as evidenced by a decrease in the angiographic minimum lumen diameter (−0.43±0.56 mm;
P
=0.028) and in the mean lumen diameter in the stent (−0.55±0.63 mm;
P
=0.001); a significant increase in in-stent neointimal hyperplasia by IVUS (18.16±12.59 mm
3
at 6 months to 27.75±11.99 mm
3
at 1 year;
P
=0.001) was also observed. Target vessel revascularization was performed in 5 patients (23%). No patient experienced late occlusion, myocardial infarction, or death. By 1 year, 21 of the initial 40 patients (65%) remained event-free.

Conclusions
—Neointimal proliferation is delayed rather than prevented by radioactive stent implantation. Clinical outcome 1 year after the implantation of stents with an initial activity of 6 to 12 μCi is not favorable when compared with conventional stenting.
Exercise Training in Coronary Artery Disease and Coronary Vasomotion
Authors: Gielen S. , Schuler G. , Hambrecht R.
Published: June 2012

Abstract
—Exercise training has assumed a major role in cardiac rehabilitation, mostly because of its positive effects on myocardial perfusion in patients with coronary artery disease. The mechanisms involved in mediating this key effect have long been debated: both regression of coronary artery stenosis and improvement of collateralization have been suggested as potential adaptations. However, the comparatively minute changes in luminal diameter and myocardial contrast staining do not fully explain the significant changes in myocardial perfusion. During the last decade, endothelial dysfunction was identified as a trigger of myocardial ischemia. The impaired production of endothelium-derived nitric oxide (NO) in response to acetylcholine and flow leads to paradoxic vasoconstriction and exercise-induced ischemia. Recently, it was confirmed in humans that training attenuates paradoxic vasoconstriction in coronary artery disease and increases coronary blood flow in response to acetylcholine. Data from cell-culture and animal experiments suggest that shear stress acts as a stimulus for the endothelium to increase the transport capacity for L-arginine (the precursor molecule for NO), to enhance NO synthase activity and expression, and to increase the production of extracellular superoxide dismutase, which prevents premature breakdown of NO. Exercise also affects the microcirculation, where it sensitizes resistance arteries for the vasodilatory effects of adenosine. These novel findings provide a pathophysiological framework to explain the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Because endothelial dysfunction has been identified as a predictor of coronary events, exercise may contribute to the long-term reduction of cardiovascular morbidity and mortality.
Thrombomodulin Ala455Val Polymorphism and Risk of Coronary Heart Disease
Authors: Wu Kenneth K. , Aleksic Nena , Ahn Chul , Boerwinkle Eric , Folsom Aaron R. , Juneja Harinder
Published: June 2012

Background
—Thrombomodulin (TM) is expressed on the endothelial surface and plays an important role in vasoprotection. A common polymorphism of TM at amino acid position 455 with an alanine (A) to valine (V) transition was previously reported to be associated cross-sectionally with acute myocardial infarction. Whether this single nucleotide polymorphism predicts risk of developing coronary heart disease (CHD) is unclear.

Methods and Results
—Within a large cohort study, we identified 467 incident CHD cases during an average of 5 years of follow-up. We determined TM-455 genotypes on 376 CHD cases (23% black, 77% white) and a reference sample of 461. The AA genotype was significantly more prevalent in noncases than in cases (
P
=0.016). The prevalences of the AA genotype in noncase blacks and whites were 93% and 67%, respectively. The AA genotype frequency was significantly reduced in black cases versus noncases (
P
=0.018). It was also lower in white cases than in noncases, but the difference was not statistically significant (
P
=0.066). Weighted proportional hazards regression analysis after adjustment for age, sex, and other CHD risk factors showed that having the V allele increased risk of CHD by 6.1-fold (risk ratio 6.1, 95% CI 1.7 to 22.9) in blacks but did not significantly increase the risk in whites.

Conclusions
—The TM A455V polymorphism predicts risk of developing CHD in blacks.
Cost-Effectiveness of the Implantable Cardioverter-Defibrillator
Authors: O’Brien Bernie J. , Connolly Stuart J. , Goeree Ron , Blackhouse Gordon , Willan Andrew , Yee Raymond , Roberts Robin S. , Gent Michael
Published: June 2012

Background
—In the Canadian Implantable Defibrillator Study (CIDS), we assessed the cost-effectiveness of the implantable cardioverter-defibrillator (ICD) in reducing the risk of death in survivors of previous ventricular tachycardia (VT) or fibrillation (VF).

Methods and Results
—Healthcare resource use was collected prospectively on the first 430 patients enrolled in CIDS (n=212 ICD, n=218 amiodarone). Mean cost per patient, adjusted for censoring, was computed for each group based on initial therapy assignment. Incremental cost-effectiveness of ICD therapy was computed as the ratio of the difference in cost (ICD minus amiodarone) to the difference in life expectancy (both discounted at 3% per year). All costs are in 1999 Canadian dollars (C$1 ≈ US$0.65). Over 6.3 years, mean cost per patient in the ICD group was C$87 715 versus C$38 600 in the amiodarone group (difference C$49 115; 95% CI C$25 502 to C$69 508). Life expectancy for the ICD group was 4.58 years versus 4.35 years for amiodarone (difference 0.23, 95% CI −0.09 to 0.55), for incremental cost-effectiveness of ICD therapy of C$213 543 per life-year gained. ICD benefit was greater in patients with low left ventricular ejection fraction (<35%), and cost-effectiveness in this group was more attractive (C$108 484). Alternative extrapolations of survival benefit and costs to 12 years indicated cost-effectiveness in the range of C$100 000 to C$150 000 per life-year gained.

Conclusions
—At C$213 543, the value for the money offered by ICD therapy is not attractive by currently accepted standards. Further research is warranted to identify the indications and patient subgroups for whom ICDs are a cost-effective use of resources.
Cardiac Overexpression of a G
q
Inhibitor Blocks Induction of Extracellular Signal–Regulated Kinase and c-Jun NH
2
-Terminal Kinase Activity in In Vivo Pressure Overload
Authors: Esposito Giovanni , Prasad Sathyamangla V. Naga , Rapacciuolo Antonio , Mao Lan , Koch Walter J. , Rockman Howard A.
Published: June 2012

Background
—Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal–regulated kinases (ERKs), c-Jun NH
2
-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function.

Methods and Results
—To determine the mechanism of activation of MAPK pathways during the development of cardiac hypertrophy, we evaluated the induction of MAPK activity after aortic constriction in wild-type and in 2 types of cardiac gene-targeted mice: one overexpressing a carboxyl-terminal peptide of Gα
q
that inhibits G
q
-mediated signaling (TG GqI mouse) and another overexpressing a carboxyl-terminal peptide of β-adrenergic receptor kinase-1 that inhibits Gβγ signaling (TG βARKct mouse). Wild-type mice with pressure overload showed an acute induction of JNK, followed by the induction of p38/p38β at 3 days and ERK at 7 days. Both JNK and p38 activity remained elevated at 7 days after banding. In TG GqI mice, hypertrophy was significantly attenuated, and induction of ERK and JNK activity was abolished, whereas the induction of p38 and p38β was robust, but delayed. By contrast, all 3 MAPK pathways were activated by aortic constriction in the TG βARKct hearts, suggesting a role for Gα
q
, but not Gβγ.

Conclusions
—Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of G
q
-coupled receptors and that non–G
q
-mediated pathways are recruited to activate p38 and p38β.
Ascorbate Restores Endothelium-Dependent Vasodilation Impaired by Acute Hyperglycemia in Humans
Authors: Beckman Joshua A. , Goldfine Allison B. , Gordon Mary Beth , Creager Mark A.
Published: June 2012

Background
—Endothelium-dependent vasodilation is impaired in patients with insulin-dependent and non–insulin-dependent diabetes mellitus and restored by vitamin C administration, implicating a causative role for oxidant stress. Hyperglycemia per se attenuates endothelium-dependent vasodilation in healthy subjects. Accordingly, this study investigated whether impaired endothelium-dependent vasodilation caused by hyperglycemia in nondiabetic humans is restored by administration of the antioxidant vitamin C.

Methods and Results
—Endothelium-dependent vasodilation was measured by incremental brachial artery administration of methacholine chloride (0.3 to 10 μg/min) during euglycemia, after 6 hours of hyperglycemia (300 mg/dL) created by dextrose (50%) intra-arterial infusion, and with coadministration of vitamin C (24 mg/min) during hyperglycemia. Endothelium-dependent vasodilation was significantly diminished by hyperglycemia (
P
=0.02 by ANOVA) and restored by vitamin C (
P
=0.04). In contrast, endothelium-dependent vasodilation was not affected by equimolar infusions of mannitol, with and without vitamin C coinfusion (
P
=NS). Endothelium-independent vasodilation was measured by incremental infusion of verapamil chloride (10 to 300 μg/min) without and with coadministration of
N
G
-monomethyl-
l
-arginine (L-NMMA). In the absence of L-NMMA, endothelium-independent vasodilation was not significantly altered during hyperglycemia (
P
=NS) but was augmented by vitamin C (
P
=0.04). The coadministration of L-NMMA eliminated the vitamin C–related augmentation in verapamil-mediated vasodilation.

Conclusions
—Vitamin C administration restores endothelium-dependent vasodilation impaired by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia may contribute in part to impaired vascular function through production of superoxide anion.
Ischemic Preconditioning Prevents Endothelial Injury and Systemic Neutrophil Activation During Ischemia-Reperfusion in Humans In Vivo
Authors: Kharbanda Rajesh K. , Peters Mark , Walton Benjamin , Kattenhorn Mia , Mullen Michael , Klein Nigel , Vallance Patrick , Deanfield John , MacAllister Raymond
Published: June 2012

Background
—Endothelial dysfunction leading to neutrophil infiltration of tissues has been implicated in tissue injury caused by ischemia-reperfusion (IR). Tissue injury during IR can be reduced by prior ischemic preconditioning (IPC). In humans, it is unclear whether endothelial dysfunction occurs during IR or whether IPC offers protection against endothelial dysfunction and inflammatory cell activation. We studied the effects of experimental IR on endothelial and neutrophil function in the human forearm in vivo and examined the protection afforded by IPC.

Method and Results
—The forearm was made ischemic for 20 minutes by inflating a blood pressure cuff to 200 mm Hg. We assessed endothelial function of conduit (radial artery flow–mediated dilation) and resistance vessels (blood flow responses to intra-arterial infusion of the endothelium-dependent dilator acetylcholine) in healthy volunteers before and after IR. IR reduced flow-mediated dilation of the radial artery at 15 minutes of reperfusion (7.7±1.5% to 3.5±0.9%) and the dilator response of resistance vessels to acetylcholine at 15, 30, and 60 minutes of reperfusion. IR did not reduce the dilator response of the radial artery to glyceryltrinitrate and only caused a small reduction of glyceryltrinitrate-induced dilation of resistance vessels at 60 minutes of reperfusion. IR caused an increase in neutrophil CD11b expression and platelet-neutrophil complexes in the circulating blood. IPC (three 5-minute episodes of ischemia) before IR prevented endothelial dysfunction and neutrophil activation.

Conclusions
—A clinically relevant period of ischemia-reperfusion causes profound and sustained endothelial dysfunction and systemic neutrophil activation. IPC attenuates both of these effects in humans.
Scaling Exponent Predicts Defibrillation Success for Out-of-Hospital Ventricular Fibrillation Cardiac Arrest
Authors: Callaway Clifton W. , Sherman Lawrence D. , Mosesso Vincent N. , Dietrich Thomas J. , Holt Eric , Clarkson M. Christopher
Published: June 2012

Background
—Defibrillator shocks often fail to terminate ventricular fibrillation (VF) in out-of-hospital cardiac arrest (OOHCA), and repeated failed shocks can worsen the subsequent response to therapy. Because the VF waveform changes with increasing duration of VF, it is possible that ECG analyses could estimate the preshock likelihood of defibrillation success. This study examined whether an amplitude-independent measure of preshock VF waveform morphology predicts outcome after defibrillation.

Methods and Results
—Clinical data and ECG recordings from an automated external defibrillator were obtained for 75 subjects with OOHCA in a suburban community with police first responders and a paramedic-based emergency medical system. An estimate of the fractal self-similarity dimension, the scaling exponent, was calculated off-line for the VF waveform preceding shocks. Success of the first shock was determined from the recordings. Return of pulses and survival were determined by chart review. The first shock resulted in an organized rhythm in 43% of cases, and 17% of cases survived to hospital discharge. A lower mean value of the scaling exponent was observed for cases in which the first defibrillation resulted in an organized rhythm (
P
=0.004), for cases with return of pulses (
P
=0.049), and for cases surviving to hospital discharge (
P
<0.001). Receiver operator curves revealed the utility of the scaling exponent for predicting the probability of restoring an organized rhythm (area under the curve=0.70) and of survival (area under the curve=0.84).

Conclusions
—The VF waveform in OOHCA can be quantified with the scaling exponent, which predicts the probability of first-shock defibrillation and survival to hospital discharge.
Red Wine Does Not Reduce Mature Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Bentzon Jacob F. , Skovenborg Erik , Hansen Carsten , Møller Jan , de Gaulejac Nathalie Saint-Cricq , Proch John , Falk Erling
Published: June 2012

Background
—Red wine polyphenols and ethanol reduce fatty streak formation (early atherosclerosis) in various animal models. These experimental results support the observation that alcoholic beverages protect against myocardial infarction in humans. However, fatty streaks may not reflect the pathology of mature and clinically relevant atherosclerosis. The present study examined the effects of red wine polyphenols and ethanol on mature atherosclerosis in apolipoprotein E–deficient mice.

Methods and Results
—Eighty-four 7-week-old mice were randomized to receive water, red wine (diluted to 6% ethanol v/v), 6% ethanol v/v, or red wine powder in water. All mice were fed a normal chow diet. At 26 weeks of age, the mice were killed. HDL cholesterol was raised 12.0% (95% CI, 4.0% to 20.0%) and 9.2% (95% CI, 1.5% to 16.9%) by red wine and ethanol, respectively. At the end of study, all mice exhibited advanced atherosclerosis in the aortic bulb, whereas less mature atherosclerosis predominated in the brachiocephalic trunk. The amount of atherosclerosis in the aortic bulb and the brachiocephalic trunk were similar in all groups (
P
=0.92 and
P
=0.14, respectively). To evaluate whether ethanol or red wine polyphenols were protective by stabilizing atherosclerotic plaques rather than reducing their size, we measured the percentage of collagen-poor areas in left coronary sinus plaques as a morphological criterion of plaque stability. The percentage of collagen-poor areas did not differ between groups (
P
=0.71).

Conclusions
—Neither ethanol nor red wine polyphenols reduced mature atherosclerosis or changed the content of collagen in plaques in apolipoprotein E–deficient mice.
Acyl-CoA:Cholesterol Acyltransferase Inhibitor Avasimibe Reduces Atherosclerosis in Addition to Its Cholesterol-Lowering Effect in ApoE*3-Leiden Mice
Authors: Delsing Dianne J. M. , Offerman Erik H. , van Duyvenvoorde Wim , van der Boom Hans , de Wit Elly C. M. , Gijbels Marion J. J. , van der Laarse Arnoud , Jukema J. Wouter , Havekes Louis M. , Princen Hans M. G.
Published: June 2012

Background
—The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice.

Methods and Results
—Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (HC) diet; 1 group received 0.01% (wt/wt) avasimibe mixed into the diet. The HC diet resulted in a plasma cholesterol concentration of 18.7±2.6 mmol/L. Addition of avasimibe lowered plasma cholesterol by 56% to 8.1±1.2 mmol/L, caused mainly by a reduction of and composition change in VLDL and LDL. In a separate low-cholesterol (LC) control group, plasma cholesterol was titrated to a level comparable to that of the avasimibe group (10.3±1.4 mmol/L) by lowering the amount of dietary cholesterol. After 22 weeks of intervention, atherosclerosis in the aortic root area was quantified. Treatment with avasimibe resulted in a 92% reduction of lesion area compared with the HC control group. Compared with the LC control, avasimibe reduced lesion area by 78%. After correction for the slight difference in cholesterol exposure between the LC control and avasimibe groups, the effect of avasimibe on lesion area (73% reduction) remained highly significant. In addition, monocyte adherence to the endothelium, free cholesterol accumulation, and lesion severity were reduced by avasimibe treatment.

Conclusions
—Treatment with avasimibe potently lowered plasma cholesterol levels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adherence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefore a reduced risk of plaque rupture.