bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Abciximab on the Architecture of Platelet-Rich Clots in Patients With Acute Myocardial Infarction Undergoing Primary Coronary Intervention
Authors: Collet J. P. , Montalescot G. , Lesty C. , Mishal Z. , Soria J. , Choussat R. , Drobinski G. , Soria C. , Pinton P. , Barragan P. , Thomas D.
Published: June 2012

Background
—Abciximab plus aspirin improves the TIMI 3 flow rate of the infarct-related artery in patients treated with either percutaneous coronary intervention or thrombolysis. The present study investigated whether the reperfusion efficacy of abciximab relates to modifications of clot architecture in patients admitted for acute myocardial infarction (AMI).

Methods and Results
—A total of 23 AMI patients in the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long term follow-up (ADMIRAL) trial received, in a double-blind fashion, either abciximab (n=13) or placebo (n=10) before primary stenting. Viscoelastic (G′ in dyne/cm
2
) and morphological (mean platelet aggregate surface area [SAG] in μm
2
) indexes of ex vivo platelet-rich clots (PRC) were assessed in a double-blind fashion before and after the bolus administration of abciximab or placebo. G′ and SAG reflect the mechanical and morphological impact of activated platelets on the PRC fibrin network, respectively. Abciximab administration reduced G′ by 63% (
P
=0.0001) and SAG by 65% (
P
=0.0007), and no effect was seen in the placebo group. These abciximab-related changes increased fibrin exposure as a consequence of the platelet-aggregate surface reduction and may have improved endogenous fibrinolysis. These effects were identified in all patients, independent of previous heparin administration.

Conclusions
—Abciximab dramatically reduces platelet aggregate size and increases the fibrin accessibility of ex vivo PRC in AMI patients. These modifications could participate in the better coronary artery patency observed with abciximab.
Abnormal Coronary Flow Velocity Reserve After Coronary Intervention Is Associated With Cardiac Marker Elevation
Authors: Herrmann Joerg , Haude Michael , Lerman Amir , Schulz Rainer , Volbracht Lothar , Ge Junbo , Schmermund Axel , Wieneke Heinrich , von Birgelen Clemens , Eggebrecht Holger , Baumgart Dietrich , Heusch Gerd , Erbel Raimund
Published: June 2012

Background
—Residual reduction of relative coronary flow velocity reserve (rCVR) after successful coronary intervention has been related to microvascular impairment. However, the incidence of cardiac enzyme elevation as a surrogate marker of an underlying embolic myocardial injury in these cases has not been studied.

Methods and Results
—A series of 55 consecutive patients with successful coronary stenting, periprocedural intracoronary Doppler analysis, and determination of creatine kinase (CK; upper limit of normal [ULN] for women 70 IU/L, for men 80 IU/L) and cardiac troponin T (cTnT; bedside test, threshold 0.1 ng/mL) before and 6, 12, and 24 hours after intervention were studied. Postprocedural rCVR was the only intracoronary Doppler parameter that independently correlated with cTnT (
r
=−0.498,
P
<0.001) and CK outcome (
r
=−0.406,
P
=0.002). Receiver operating characteristic analysis identified a postprocedural rCVR of 0.78 as the best discriminating value, with a sensitivity of 83.3% and 69.2% and a specificity of 79.1% and 76.2% for detection of cTnT and CK elevation, respectively. Stratified according to this cutoff value, the incidence of cTnT elevation was 52.6% in patients with (n=19) and 5.6% in patients without (n=36) a postprocedural rCVR <0.78 (
P
<0.001), associated with a CK elevation >1 times the ULN in 36.8% and 5.6% (
P
=0.005) of patients, respectively.

Conclusions
—Cardiac marker elevation can frequently be found after coronary procedures that are associated with a persistent reduction of rCVR, indicating procedural embolization of atherothrombotic debris with microvascular impairment and myocardial injury as a potential underlying mechanism.
Sudden Cardiac Death, Genes, and Arrhythmogenesis
Authors: Spooner Peter M. , Albert Christine , Benjamin Emelia J. , Boineau Robin , Elston Robert C. , George Alfred L. , Jouven Xavier , Kuller Lewis H. , MacCluer Jean W. , Marbán Eduardo , Muller James E. , Schwartz Peter J. , Siscovick David S. , Tracy Russell P. , Zareba Wojciech , Zipes Douglas P.
Published: June 2012

Abstract
—Malignant ventricular arrhythmias are the leading mechanism of death in patients with acute and chronic cardiac pathologies. The extent to which inherited mutations and polymorphic variation in genes determining arrhythmogenic mechanisms affect these patients remains unknown, but based on recent population studies, this risk appears significant, deserving much greater investigation. This report summarizes a National Heart, Lung, and Blood Institute workshop that considered sources of genetic variation that may contribute to sudden cardiac death in common cardiac diseases. Evidence on arrhythmogenic mechanisms in recent population studies suggests a significant portion of the risk of sudden cardiac death in such broad populations may be unrelated to traditional risk factors for predisposing conditions such as atherosclerosis, hypertension, and diabetes and instead may involve unrecognized genetic and environmental interactions that influence arrhythmic susceptibility more directly. Additional population and genetic studies directed at discovering the sources of inherited molecular risk that are most directly linked to arrhythmia initiation and propagation, in addition to studies on previously well-described risk factors, would appear to have considerable potential for reducing premature cardiovascular mortality.
Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism
Authors: Myerson Saul G. , Montgomery Hugh E. , Whittingham Martin , Jubb Mick , World Michael J. , Humphries Steve E. , Pennell Dudley J.
Published: June 2012

Background
—Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT
1
) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype–associated exertional LV growth and to clarify the role of the AT
1
receptor in this association.

Methods and Results
—One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT
1
receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g,
P
<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb,
P
=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (
P
=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (−0.022 versus 0.131 g/kg, respectively;
P
=0.0009).

Conclusions
—ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT
1
receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.
Treatment With a Growth Hormone Secretagogue in a Model of Developing Heart Failure
Authors: King Mary K. , Gay David M. , Pan Lydia C. , McElmurray James H. , Hendrick Jennifer W. , Pirie Christine , Morrison Allison , Ding Connie , Mukherjee Rupak , Spinale Francis G.
Published: June 2012

{abs}Background
—Exogenous administration of growth hormone (GH) and subsequently increased production of insulin-like growth factor-1 can influence left ventricular (LV) myocardial growth and geometry in the setting of congestive heart failure (CHF). This study determined the effects of an orally active GH secretagogue (GHS) treatment that causes a release of endogenous GH on LV function and myocyte contractility in a model of developing CHF.

Methods and Results
—Pigs were randomly assigned to the following treatment groups: (1) chronic rapid pacing at 240 bpm for 3 weeks (n=11); (2) chronic rapid pacing and GHS (CP-424,391 at 10 mg·kg
−1
·d
−1
, n=9); and (3) sham controls (n=8). In the untreated pacing CHF group, LV fractional shortening was reduced (21±2% versus 47±2%) and peak wall stress increased (364±21 versus 141±5 g/cm
2
) from normal control values (
P
<0.05). In the GHS group, LV fractional shortening was higher (29±2%) and LV peak wall stress lower (187±126 g/cm
2
) than untreated CHF values (
P
<0.05). With GHS treatment, the ratio of LV mass to body weight increased by 44% from untreated values. Steady-state myocyte velocity of shortening was reduced with pacing CHF compared with controls (38±1 versus 78±1 μm/s,
P
<0.05) and was increased from pacing CHF values with GHS treatment (55±7 μm/s,
P
<0.05).

Conclusions
—The improved LV pump function that occurred with GHS treatment in this model of CHF was most likely a result of favorable effects on LV myocardial remodeling and contractile processes. On the basis of these results, further studies are warranted to determine the potential role of GH secretagogues in the treatment of CHF.
Myocardial Fibrosis in DOCA-Salt Hypertensive Rats
Authors: Ammarguellat Fatima , Larouche Isabelle , Schiffrin Ernesto L.
Published: June 2012

Background
—To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate–salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ET
A
-selective endothelin receptor antagonist A-127722 were evaluated.

Methods and Results
—A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103±1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202±3.2 mm Hg in DOCA-salt rats (
P
<0.01 versus Uni-Nx), and 182±3.1 mm Hg in ET
A
antagonist–treated DOCA-salt rats (
P
<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold,
P
<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ET
A
antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ET
A
antagonist treatment. TGF-β
1
mRNA and TGF-β
1
protein increased at 1 week in DOCA-salt rats and were lowered in ET
A
antagonist–treated rats.

Conclusions
—ET
A
receptor–mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-β
1
. These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.
Does Reduced Vascular Stiffening Fully Explain Preserved Cardiovagal Baroreflex Function in Older, Physically Active Men?
Authors: Hunt Brian E. , Farquhar William B. , Taylor J. Andrew
Published: June 2012

Background
—We measured cardiovagal baroreflex gain and its vascular mechanical and neural components during dynamic baroreflex engagement in 10 young untrained men, 6 older untrained men, and 12 older, physically active men.

Methods and Results
—Our newly developed assessment of beat-to-beat carotid diameters during baroreflex engagement estimates the mechanical transduction of pressure into barosensory stretch (Δdiameter/Δpressure), the neural transduction of stretch into vagal outflow (ΔR-R interval/Δdiameter), and conventional integrated cardiovagal baroreflex gain (ΔR-R interval/Δpressure). Integrated gain was lower in older untrained men than in young untrained men (6.8±1.2 versus 15.7±1.8 ms/mm Hg) due to both lower mechanical (9.1±1.0 versus 17.1±2.4 mm Hg/μm) and lower neural (0.57±0.10 versus 0.90±0.10 ms/μm) transduction. Integrated gain in older active men (13.3±2.7 ms/mm Hg) was comparable to that in young untrained men. This was achieved through mechanical transduction (12.1±1.4 mm Hg/μm) that was modestly higher than that in older untrained men and neural transduction (1.00±0.20 ms/μm) comparable to that in young untrained men. Across groups, both mechanical and neural components were related to integrated gain; however, the neural component carried greater predictive weight (β=0.789 versus 0.588).

Conclusions
—Both vascular and neural deficits contribute to age-related declines in cardiovagal baroreflex gain; however, long-term physical activity attenuates this decline by maintaining neural vagal control.
Detection of Coronary Artery Stenoses by Contrast-Enhanced, Retrospectively Electrocardiographically-Gated, Multislice Spiral Computed Tomography
Authors: Achenbach Stephan , Giesler Tom , Ropers Dieter , Ulzheimer Stefan , Derlien Hans , Schulte Christoph , Wenkel Evelyn , Moshage Werner , Bautz Werner , Daniel Werner G. , Kalender Willi A. , Baum Ulrich
Published: June 2012

Background
—Multislice spiral computed tomography (MSCT) with retrospectively ECG-gated image reconstruction permits coronary artery visualization. We investigated the method’s ability to identify high-grade coronary artery stenoses and occlusions.

Methods and Results
—A total of 64 consecutive patients were studied by MSCT (4×1 mm cross-sections, 500-ms rotation, table feed 1.5 mm/rotation, intravenous contrast agent, retrospectively ECG-gated image reconstruction). All coronary arteries and side branches with a luminal diameter ≥2.0 mm were assessed concerning evaluability and the presence of high-grade stenoses (>70% diameter stenosis) or occlusions. Results were compared with quantitative coronary angiography. Of 256 coronary arteries (left main, left anterior descending, left circumflex and right coronary artery, including their respective side branches), 174 could be evaluated (68%). In 19 patients (30%), all arteries were evaluable. Artifacts caused by coronary motion were the most frequent reason for unevaluable arteries. Overall, 32 of 58 high-grade stenoses and occlusions were detected by MSCT (58%). In evaluable arteries, 32 of 35 lesions were detected, and the absence of stenosis was correctly identified in 117 of 139 arteries (sensitivity, 91%; specificity, 84%). If analysis was extended to all stenoses with >50% diameter reduction, sensitivity was 85% (40 of 47) and specificity was 76% (96 of 127).

Conclusions
—MSCT with retrospective ECG gating permits the detection of coronary artery stenoses with high accuracy if image quality is sufficient, but its clinical use may presently be limited due to degraded image quality in a substantial number of cases, mainly due to rapid coronary motion.
Combination Therapy With Abciximab Reduces Angiographically Evident Thrombus in Acute Myocardial Infarction
Authors: Gibson C. Michael , de Lemos James A. , Murphy Sabina A. , Marble Susan J. , McCabe Carolyn H. , Cannon Christopher P. , Antman Elliott M. , Braunwald Eugene
Published: June 2012

Background
—Use of abciximab in combination with administration of thrombolytics has been shown to improve epicardial and microvascular coronary blood flow in acute myocardial infarction (AMI). As a potential mechanism, we hypothesized that combination therapy would reduce angiographically evident thrombus (AET) and would increase lumen diameter compared with thrombolytic monotherapy.

Methods and Results
—Patients who received combination therapy in TIMI 14 (low-dose thrombolytic plus abciximab, n=732) were compared with patients who received thrombolytic monotherapy without abciximab in the TIMI 4, 10A, 10B, and 14 trials (n=1662). Thrombus burden was assessed 90 minutes after treatment, and quantitative angiography was performed in an angiographic core laboratory by investigators blinded to treatment assignment. The frequency of AET was reduced in patients who received abciximab combination therapy compared with thrombolytic monotherapy (26.6% versus 35.4%,
P
<0.001). Similar findings were observed when the analysis was restricted to patients with patent arteries (14.7% versus 20.8%,
P
=0.001). Residual percent diameter stenosis at 90 minutes was also improved in the abciximab therapy group both in patent arteries (64.6±16.6 versus 68.3±14.8,
P
<0.001) and between patent and occluded arteries (69.3±19.5 versus 73.8±17.9,
P
<0.001). The absence of AET was associated with an increased frequency of >70% ST-segment resolution by 90 minutes (37.2%, 110/296 versus 18.9%, 54/286,
P
<0.001).

Conclusions
—Compared with thrombolytic monotherapy, combination therapy with abciximab reduces AET, which in turn is associated with reduced residual stenosis and improved ST-segment resolution in AMI. These data provide a pathophysiological link between platelet inhibition, reduced thrombus, and improvements in both epicardial and microvascular perfusion in AMI.
Ability of Recombinant Factor VIIa to Generate Thrombin During Inhibition of Tissue Factor in Human Subjects
Authors: Friederich Philip W. , Levi Marcel , Bauer Kenneth A. , Vlasuk George P. , Rote William E. , Breederveld Daan , Keller Tijmen , Spataro Marco , Barzegar Samad , Büller Harry R.
Published: June 2012

Background
—In view of the central role of the tissue factor–factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor–factor VIIa complex, in a double-blind randomized crossover study.

Methods and Results
—Administration of nematode anticoagulant protein c2 (3.5 μg/kg) caused a prolongation of the prothrombin time from 13.7±0.6 to 16.9±1.2 seconds. The subsequent injection of rVIIa (90 μg/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75±0.64 to 3.29±6.3 nmol/L and from 2.4±0.6 to 10.7±3.9 μg/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2.

Conclusions
—During treatment with an inhibitor of the tissue factor–factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.
Alleviation of Myocardial Ischemia After Kawasaki Disease by Heparin and Exercise Therapy
Authors: Tateno Shigeru , Terai Masaru , Niwa Koichiro , Jibiki Toshiaki , Hamada Hiromichi , Yasukawa Kumi , Honda Takafumi , Oana Shinji , Kohno Yoichi
Published: June 2012

Background
—Heparin promotes angiogenesis. We evaluated the effects of combined treatment with heparin and exercise on myocardial ischemia in the chronic stage of Kawasaki disease.

Methods and Results
—This study was conducted in 7 patients (aged 6 to 19 years) who had a totally occluded coronary artery and stress-induced myocardial ischemia in the collateral-dependent areas. Twice-daily exercise using a bicycle ergometer was performed with increments of 0.5 W/kg every 3 minutes up to maximal exertion for 10 days. Heparin, which immediately increased circulating hepatocyte growth factor, was given intravenously 10 minutes before each exercise period. Newly developed myocardial infarction, ventricular tachyarrhythmia, anginal attack, or hemorrhagic complication was not observed in any patient. Dipyridamole-loading single photon emission computed tomography documented improved myocardial perfusion in the collateral-dependent areas and a significant reduction in total defect scores in all patients after the completion of 20 sessions (
P
=0.01). In control patients who did not receive the heparin-exercise therapy, however, stress defect scores remained unchanged (n=1) or increased (n=2) during follow-up. Computerized quantitative coronary angiography provided evidence that the heparin-exercise therapy increased the diameter of the occluded artery to which collaterals terminated (
P
=0.001) but not that of the reference artery with which collaterals were not connected (
P
=0.96).

Conclusions
—The findings suggest that a series of heparin and exercise treatments over 10 days may have a dramatic effect on the alleviation of myocardial ischemia in collateral-dependent regions. This may be a safe, noninvasive revascularization therapy for patients with coronary artery occlusion in the chronic stage of Kawasaki disease.
Increased Particulate Air Pollution and the Triggering of Myocardial Infarction
Authors: Peters Annette , Dockery Douglas W. , Muller James E. , Mittleman Murray A.
Published: June 2012

Background
—Elevated concentrations of ambient particulate air pollution have been associated with increased hospital admissions for cardiovascular disease. Whether high concentrations of ambient particles can trigger the onset of acute myocardial infarction (MI), however, remains unknown.

Methods and Results
—We interviewed 772 patients with MI in the greater Boston area between January 1995 and May 1996 as part of the Determinants of Myocardial Infarction Onset Study. Hourly concentrations of particle mass <2.5 μm (PM
2.5
), carbon black, and gaseous air pollutants were measured. A case-crossover approach was used to analyze the data for evidence of triggering. The risk of MI onset increased in association with elevated concentrations of fine particles in the previous 2-hour period. In addition, a delayed response associated with 24-hour average exposure 1 day before the onset of symptoms was observed. Multivariate analyses considering both time windows jointly revealed an estimated odds ratio of 1.48 associated with an increase of 25 μg/m
3
PM
2.5
during a 2-hour period before the onset and an odds ratio of 1.69 for an increase of 20 μg/m
3
PM
2.5
in the 24-hour period 1 day before the onset (95% CIs 1.09, 2.02 and 1.13, 2.34, respectively).

Conclusions
—The present study suggests that elevated concentrations of fine particles in the air may transiently elevate the risk of MIs within a few hours and 1 day after exposure. Further studies in other locations are needed to clarify the importance of this potentially preventable trigger of MI.
Benefit of Glycoprotein IIb/IIIa Inhibition in Patients With Acute Coronary Syndromes and Troponin T–Positive Status
Authors: Newby L. Kristin , Ohman E. Magnus , Christenson Robert H. , Moliterno David J. , Harrington Robert A. , White Harvey D. , Armstrong Paul W. , Van de Werf Frans , Pfisterer Matthias , Hasselblad Vic , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
—Troponin T (TnT) is valuable for short- and long-term risk stratification of patients with acute coronary syndromes (ACS). It also may predict which ACS patients will benefit from glycoprotein (GP) IIb/IIIa blockade.

Methods and Results
—We prospectively studied 1160 patients with non–ST-segment elevation ACS randomized in PARAGON-B to receive lamifiban, an intravenous GP IIb/IIIa antagonist, or placebo. TnT levels were obtained before study treatment began and 24 to 72 hours later; assays were performed by a blinded core laboratory. At baseline, 40.2% of patients were TnT-positive (≥0.1 ng/mL); these patients were older and more often male or smokers. Patients positive at baseline had a significantly higher rate of the primary end point (composite of death, myocardial [re]infarction, or severe recurrent ischemia at 30 days; odds ratio, 1.5; 95% CI, 1.1 to 2.1) than those who were TnT-negative. Lamifiban was associated with significant reduction in the primary end point (from 19.4% to 11.0%,
P
=0.01) among TnT-positive patients but not among TnT-negative patients (11.2% for placebo versus 10.8% for lamifiban,
P
=0.86;
P
=0.08 for test of interaction between TnT status and treatment assignment). This pattern held for the end points of death alone and death or myocardial (re)infarction at 30 days. Peak TnT level at 48 hours did not differ with lamifiban treatment.

Conclusions
—TnT predicts poor short-term outcomes in non–ST-segment elevation ACS. Treatment benefit with lamifiban is limited almost exclusively to TnT-positive patients, reducing 30-day adverse outcomes to a rate nearly identical to that of negative patients.
Estrogen Replacement Therapy Improves Baroreflex Regulation of Vascular Sympathetic Outflow in Postmenopausal Women
Authors: Hunt Brian E. , Taylor J. Andrew , Hamner Jason W. , Gagnon Margaret , Lipsitz Lewis A.
Published: June 2012

Background
—Menopausal estrogen loss has been associated with increased cardiovascular disease in postmenopausal women. However, the link between estrogen and cardiovascular disease remains unclear. Some data suggest estrogen mediates its effect through changes in arterial pressure and its regulation. However, the data available in older women are equivocal regarding estrogen’s ability to reduce resting arterial pressure or to improve its regulation.

Methods and Results
—We studied 11 healthy, postmenopausal women before and after 6 months of estrogen administration. Arterial pressure was measured by brachial auscultation and finger photoplethysmography. Vascular sympathetic nerve activity was measured in the peroneal nerve by microneurography, and the slope of the relations between changes in heart period, sympathetic activity, and arterial pressure caused by bolus infusions of nitroprusside and phenylephrine were used as an index of baroreflex gain. Estrogen therapy did not change systolic pressure (128±2 versus 123±2 mm Hg) or cardiac-vagal baroreflex gain (6.6±0.9 versus 6.7±0.7 ms/mm Hg). However, vascular sympathetic baroreflex gain was increased (−4.6±0.6 versus −7.4±1.0 arbitrary integrated units/mm Hg;
P
=0.02).

Conclusion
—These findings suggest long-term estrogen replacement therapy has effects on cardiovascular regulation that may not be reflected in resting arterial pressures.
Delayed Preconditioning-Mimetic Action of Nitroglycerin in Patients Undergoing Coronary Angioplasty
Authors: Leesar Massoud A. , Stoddard Marcus F. , Dawn Buddhadeb , Jasti Venu G. , Masden Ronald , Bolli Roberto
Published: June 2012

Background
—Experimental studies suggest that the cardioprotective effects of the late phase of ischemic preconditioning (PC) can be mimicked pharmacologically. However, to date, no drug has been tested with respect to its ability to elicit a late PC effect in humans. As a consequence, clinical exploitation of the powerful anti-stunning and anti-infarct actions of late PC has been elusive thus far.

Methods and Results
—A total of 66 patients were randomized to receive a 4-hour intravenous infusion of nitroglycerin (NTG) or normal saline; on the following day, they underwent percutaneous transluminal coronary angioplasty (three 2-minute balloon inflations 5 minutes apart). Measurements of ST-segment shifts (intracoronary and surface ECGs), regional wall motion (quantitative 2D echocardiography), and chest pain score indicated that the infusion of NTG 24 hours before angioplasty rendered the myocardium relatively resistant to ischemia and that the degree of this cardioprotective effect was comparable to that afforded by the ischemia associated with the first balloon inflation in control subjects (early phase of ischemic PC). Collateral flow (estimated from a pressure-derived index) did not differ between control and NTG-pretreated patients, indicating that the enhanced tolerance to ischemia in NTG-pretreated patients cannot be accounted for by baseline differences in collateral function.

Conclusions
—NTG protects human myocardium against ischemia 24 hours after its administration. To the best of our knowledge, this is the first report that a late PC effect can be recruited pharmacologically in humans. The results suggest that prophylactic administration of nitrates could be a novel approach to the protection of the ischemic myocardium in patients.
Dispersion of Ventricular Depolarization-Repolarization
Authors: Turrini Pietro , Corrado Domenico , Basso Cristina , Nava Andrea , Bauce Barbara , Thiene Gaetano
Published: June 2012

Background
—We retrospectively investigated the value of clinical and ECG findings as well as QT-QRS dispersion in predicting the risk of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).

Methods and Results
—Duration and interlead variability of the QT interval and QRS complex were measured manually from standard ECGs in 20 sudden death victims with ARVC diagnosed at autopsy (group I), in 20 living ARVC patients with sustained ventricular tachycardia (group II), in 20 living ARVC patients with ≤3 consecutive premature ventricular beats (group III), and in 20 control subjects (group IV). QT and QRS dispersions were greater in group I (77.5±10.6 ms for QT and 45.7±8.1 ms for QRS) compared with group II (64.5±13.9 ms for QT [
P
=0.001] and 33.5±8.7 ms for QRS [
P
=0.0004]) and in group II compared with group III (48±8.9 ms for QT [
P
<0.0001] and 28±5.2 ms for QRS [
P
<0.0001]) and group IV (33.5±4.8 ms for QT [
P
<0.0001] and 18.5±3.6 ms for QRS [
P
<0.0001]). Negative T wave beyond V
1
and syncope were statistically more frequent in group I (
P
=0.02 and
P
=0.007, respectively). On multivariate analysis, QRS dispersion remained an independent predictor of sudden death (
P
<0.0001), followed by syncope (
P
=0.09). In assessing risk of sudden death, QRS dispersion ≥40 ms had a sensitivity and specificity of 90% and 77%, respectively; QT dispersion >65 ms, 85% and 75%, respectively; negative T wave beyond V
1
, 85% and 42%, respectively; and syncope, 40% and 90%, respectively.

Conclusions
—QRS dispersion (≥40 ms) was the strongest independent predictor of sudden death in ARVC. Syncope, QT dispersion >65 ms, and negative T wave beyond V
1
refined arrhythmic risk stratification in these patients.
Relationship Between Pacemaker Dependency and the Effect of Pacing Mode on Cardiovascular Outcomes
Authors: Tang Anthony S.L. , Roberts Robin S. , Kerr Charles , Gillis Anne M. , Green Martin S. , Talajic Mario , Yusuf Salim , Abdollah Hoshiar , Gent Michael , Connolly Stuart J.
Published: June 2012

Background
—A recently completed trial, the Canadian Trial of Physiological Pacing (CTOPP), showed that physiological pacing did not significantly reduce mortality, stroke, or heart failure hospitalization, but it did show that atrial fibrillation occurred less frequently in patients with physiological pacing. Many pacemaker patients experience only transient bradyarrhythmias with an adequate unpaced heart rate (UHR) and are not pacemaker-dependent. The purpose of the present analysis was to determine if pacemaker-dependent patients have an increased benefit from physiological pacing compared with non–pacemaker-dependent patients.

Methods and Results
—Of 2568 patients included in the CTOPP trial, 2244 patients had a pacemaker dependency test performed at the first follow-up visit. The yearly event rate of cardiovascular death or stroke steadily increased with decreasing UHR in the ventricular pacing group, but it remained constant in the physiological pacing group. When the patients were subdivided to UHR ≤60 bpm or >60 bpm, there was an interaction between pacing mode treatment and UHR subgroup. The Kaplan-Meier plot confirmed a physiological pacing advantage only in the UHR ≤60 bpm subgroup. This differential effect was also present for the outcomes of cardiovascular death and total mortality.

Conclusions
—This study demonstrated that UHR at first follow-up has an important influence on how pacing mode selection affects cardiovascular death and total mortality. Pacemaker-dependent patients with low UHR will probably be paced frequently and will likely benefit from physiological pacing. In contrast, non–pacemaker-dependent patients will likely be paced infrequently and may not benefit from physiological pacing.
Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11β-Hydroxysteroid Dehydrogenase Inhibition
Authors: Ruschitzka Frank , Quaschning Thomas , Noll Georg , deGottardi Andrea , Rossier Michel F. , Enseleit Frank , Hürlimann David , Lüscher Thomas F. , Shaw Sidney G.
Published: June 2012

Background
—The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11β-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11β-HSD in the regulation of vascular tone remains to be determined.

Methods and Results
—Glycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11β-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls;
P
<0.01). After 11β-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all
P
<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (
P
<0.05 versus controls). Chronic ET
A
receptor blockade with LU135252 (50 mg · kg
−1
· d
−1
) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (
P
<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11β-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids.

Conclusions
—Chronic ET
A
receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11β-HSD inhibitor–induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11β-HSD activity.
Coronary Artery Stenosis After Radiofrequency Catheter Ablation of Accessory Atrioventricular Pathways in Children With Ebstein’s Malformation
Authors: Bertram Harald , Bökenkamp Regina , Peuster Matthias , Hausdorf Gerd , Paul Thomas
Published: June 2012

Background
—Complications concerning the coronary arteries that are directly related to radiofrequency catheter ablation procedures have not been reported in children. Coronary artery lesions, however, have been demonstrated after the endocardial application of radiofrequency current in young animals.

Methods and Results
—Two boys with Ebstein’s anomaly of the tricuspid valve developed clinically asymptomatic coronary artery stenosis after radiofrequency catheter ablation of right-sided accessory atrioventricular pathways with standard catheter technology.

Conclusions
—The complication of coronary artery stenosis demonstrates a substantial risk after right atrial free wall radiofrequency current application in children. The risk of late coronary alterations should be considered when the use of catheter ablation procedures to young patients is proposed.
Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction
Authors: Negoro Shinji , Oh Hidemasa , Tone Eiroh , Kunisada Keita , Fujio Yasushi , Walsh Kenneth , Kishimoto Tadamitsu , Yamauchi-Takihara Keiko
Published: June 2012

Background
—We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown.

Methods and Results
—We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation.

Conclusions
—Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.
Gradient Model Versus Mosaic Model of the Sinoatrial Node
Authors: Zhang H. , Holden A. V. , Boyett M. R.
Published: June 2012

Background
—A radical reinterpretation (mosaic model) of the makeup of the sinoatrial (SA) node has been proposed to explain the characteristic regional differences in electrical activity between the periphery and center of the SA node. According to the mosaic model, the differences result from a change in the mix of atrial cells and uniform SA node cells from periphery to center, whereas according to the alternative gradient model, there are no atrial cells within the functional SA node, and the differences result from a change in the intrinsic properties of SA node cells from periphery to center.

Methods and Results
—A mosaic model of peripheral and central tissue has been constructed computationally by use of a coupled ordinary differential equation network (CODE) in a 2D lattice (20×20), with each node of the lattice designated randomly as an atrial cell or SA node cell (in correct proportions for periphery and center). The mosaic model fails to predict the characteristic differences in action potential rate and shape between the periphery and center, whereas the existing gradient model can do so.

Conclusions
—The mosaic model of the SA node is untenable, and the SA node is adequately described by the gradient model.
Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease
Authors: Hornig Burkhard , Landmesser Ulf , Kohler Christoph , Ahlersmann Dorothe , Spiekermann Stephan , Christoph Annemarie , Tatge Helma , Drexler Helmut
Published: June 2012

Background
—Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT
1
-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity.

Methods and Results
—Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT
1
-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial
N
-monomethyl-
l
-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and losartan (each group
P
<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group
P
<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4±1.1 versus 3.8±0.9 and AT
1
-A, 13.5±1.0 versus 3.9±0.9 U · mL
−1
· min
−1
; each
P
<0.01).

Conclusions
—Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.
Mechanisms of Neointima Formation and Remodeling in the Porcine Coronary Artery
Authors: Christen Thomas , Verin Vitali , Bochaton-Piallat Marie-Luce , Popowski Youri , Ramaekers Frans , Debruyne Philippe , Camenzind Edoardo , van Eys Guillaume , Gabbiani Giulio
Published: June 2012

Background
—To characterize the cells responsible for neointima formation after porcine coronary artery wall injury, we studied the expression of smooth muscle cell (SMC) differentiation markers in 2 models: (1) self-expanding stent implantation resulting in no or little interruption of internal elastic lamina and (2) percutaneous transluminal coronary angioplasty (PTCA) resulting in complete medial rupture and exposure of adventitia to blood components.

Methods and Results
—The expression of α-smooth muscle (SM) actin, SM myosin heavy chain isoforms 1 and 2, desmin, and smoothelin was investigated by means of immunohistochemistry and Western blots in tissues of the arterial wall collected at different time points and in cell populations cultured from these tissues. The expression of smoothelin, a marker of late SMC differentiation, was used to discriminate between SMCs and myofibroblasts. Both stent- and PTCA-induced neointimal tissues and their cultured cell populations expressed all 4 markers. The adventitial tissue underlying PTCA-induced lesions temporarily expressed α-SM actin, desmin, and SM myosin heavy chain isoforms, but not smoothelin. When placed in culture, adventitial cells expressed only α-SM actin.

Conclusions
—Our results suggest that SMCs are the main components of coronary artery neointima after both self-expanding stent implantation and PTCA. The adventitial reaction observed after PTCA evolves with a chronology independent of that of neointima formation and probably corresponds to a myofibroblastic reaction.
Interactions Between Phospholamban and β-Adrenergic Drive May Lead to Cardiomyopathy and Early Mortality
Authors: Dash Rajesh , Kadambi Vivek J. , Schmidt Albrecht G. , Tepe Nicole M. , Biniakiewicz Danuta , Gerst Michael J. , Canning Amy M. , Abraham William T. , Hoit Brian D. , Liggett Stephen B. , Lorenz John N. , Dorn Gerald W. , Kranias Evangelia G.
Published: June 2012

Background
—Relieving the inhibition of sarcoplasmic reticular function by phospholamban is a major target of β-adrenergic stimulation. Chronic β-adrenergic receptor activity has been suggested to be detrimental, on the basis of transgenic overexpression of the receptor or its signaling effectors. However, it is not known whether physiological levels of sympathetic tone, in the absence of preexisting heart failure, are similarly detrimental.

Methods and Results
—Transgenic mice overexpressing phospholamban at 4-fold normal levels were generated, and at 3 months, they exhibited mildly depressed ventricular contractility without heart failure. As expected, transgenic cardiomyocyte mechanics and calcium kinetics were depressed, but isoproterenol reversed the inhibitory effects of phospholamban on these parameters. In vivo cardiac function was substantially depressed by propranolol administration, suggesting enhanced sympathetic tone. Indeed, plasma norepinephrine levels and the phosphorylation status of phospholamban were elevated, reflecting increased adrenergic drive in transgenic hearts. On aging, the chronic enhancement of adrenergic tone was associated with a desensitization of adenylyl cyclase (which intensified the inhibitory effects of phospholamban), the development of overt heart failure, and a premature mortality.

Conclusions
—The unique interaction between phospholamban and increased adrenergic drive, elucidated herein, provides the first evidence that compensatory increases in catecholamine stimulation can, even in the absence of preexisting heart failure, be a primary causative factor in the development of cardiomyopathy and early mortality.
The Impact of Calcification on the Biomechanical Stability of Atherosclerotic Plaques
Authors: Huang Hayden , Virmani Renu , Younis Hesham , Burke Allen P. , Kamm Roger D. , Lee Richard T.
Published: June 2012

Background
—Increased biomechanical stresses in the fibrous cap of atherosclerotic plaques contribute to plaque rupture and, consequently, to thrombosis and myocardial infarction. Thin fibrous caps and large lipid pools are important determinants of increased plaque stresses. Although coronary calcification is associated with worse cardiovascular prognosis, the relationship between atheroma calcification and stresses is incompletely described.

Methods and Results
—To test the hypothesis that calcification impacts biomechanical stresses in human atherosclerotic lesions, we studied 20 human coronary lesions with techniques that have previously been shown to predict plaque rupture locations accurately. Ten ruptured and 10 stable lesions derived from post mortem coronary arteries were studied using large-strain finite element analysis. Maximum stress was not correlated with percentage of calcification, but it was positively correlated with the percentage of lipid (
P
=0.024). When calcification was eliminated and replaced with fibrous plaque, stress changed insignificantly; the median increase in stress for all specimens was 0.1% (range, 0% to 8%;
P
=0.85). In contrast, stress decreased by a median of 26% (range, 1% to 78%;
P
=0.02) when lipid was replaced with fibrous plaque.

Conclusions
—Calcification does not increase fibrous cap stress in typical ruptured or stable human coronary atherosclerotic lesions. In contrast to lipid pools, which dramatically increase stresses, calcification does not seem to decrease the mechanical stability of the coronary atheroma.