bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective Randomized Study of Ablation and Pacing Versus Medical Therapy for Paroxysmal Atrial Fibrillation
Authors: Marshall Howard J. , Harris Zoë I. , Griffith Michael J. , Holder Roger L. , Gammage Michael D.
Published: June 2012

Background
—Atrioventricular (AV) node ablation and pacing has become accepted therapy for drug-refractory paroxysmal atrial fibrillation (PAF). However, few data demonstrate its superiority over continued medical therapy. The influence of pacing mode and mode-switch algorithm has not been investigated.

Methods and Results
—Symptomatic patients who had tried ≥2 drugs for PAF were randomized to continue medical therapy (n=19) or AV junction ablation and implantation of dual-chamber mode-switching (DDDR/MS) pacemakers (slow algorithm [n=19] or fast algorithm [n=18]). Follow-up over 18 weeks was at 6-week intervals and used quality-of-life questionnaires (Psychological General Well Being [PGWB], McMaster Health Index [MHI], cardiac symptom score), exercise testing, echocardiography, and Holter monitoring. Paced patients were randomized to DDDR/MS or VVIR and subsequently crossed over. Ablation and DDDR/MS pacing produced better scores than drug therapy for overall symptoms (−41%,
P
<0.01), palpitations (−58%,
P
=0.0001), and dyspnea (−37%,
P
<0.05). Changes in score from baseline were better with ablation and DDDR/MS pacing for overall symptoms (−48% versus −4%,
P
<0.005), palpitation (−62% versus −5%,
P
<0.001), dyspnea (−44% versus −3%,
P
<0.005), and PGWB (+12% versus +0.5%,
P
<0.05). DDDR/MS was better than VVIR pacing for overall symptoms (−21%,
P
<0.05), dyspnea (−30%,
P
<0.005), and MHI (+5%,
P
<0.03). There were no differences between algorithms. More patients developed persistent AF with ablation and pacing than with drugs at 6 weeks (12 of 37 versus 0 of 19,
P
<0.01).

Conclusions
—Ablation and DDDR/MS pacing produces more symptomatic benefit than medical therapy or ablation and VVIR pacing but may result in early development of persistent AF.
Pulmonary Capillary Endothelium-Bound Angiotensin-Converting Enzyme Activity in Humans
Authors: Orfanos Stylianos E. , Langleben David , Khoury Joseph , Schlesinger Robert D. , Dragatakis Leonidas , Roussos Charis , Ryan James W. , Catravas John D.
Published: June 2012

Background
—Pulmonary endothelium has metabolic functions including the conversion of angiotensin I to angiotensin II by angiotensin-converting ectoenzyme (ACE). In this study, we have validated an indicator-dilution technique that provides estimations of dynamically perfused capillary surface area (DPCSA) in humans, and we have characterized pulmonary endothelial ACE in vivo.

Methods and Results
—In 12 adults, single-pass transpulmonary (one or both lungs) hydrolysis of the specific ACE substrate
3
H-benzoyl-Phe-Ala-Pro (
3
H-BPAP) was measured and expressed as % metabolism (%M) and v=−ln(1−M). We also calculated A
max
/K
m
, an index of DPCSA. %M (70.1±3.2 vs 67.9±3.1) and v (1.29±0.14 vs 1.20±0.12) were similar in both lungs and the right lung, respectively, whereas A
max
/K
m/
/body surface area decreased from 2460±193 to 1318±115 mL/min per square meter.

Conclusions
—Pulmonary endothelial ACE activity can be assessed in humans at the bedside by means of indicator-dilution techniques. Our data suggest homogeneous pulmonary capillary ACE concentrations and capillary transit times (t
c
) in both human lungs, and similar t
c
within the normal range of cardiac index. A
max
/K
m
in the right lung is 54% of total A
max
/K
m
in both lungs, suggesting that A
max
/K
m
is a reliable and quantifiable index of DPCSA in humans.
Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia
Authors: Best Patricia J. M. , McKenna Charles J. , Hasdai David , Holmes David R. , Lerman Amir
Published: June 2012

Background
—Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.

Methods and Results
—Acetylcholine (10
−6
to 10
−4
mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: −41.6%±10.7%, group 2: −4.7%±11.9%, group 3: 11.4%±7.4%).

Conclusions
—Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.
Trends in Antihypertensive Drug Advertising, 1985–1996
Authors: Wang Thomas J. , Ausiello John C. , Stafford Randall S.
Published: June 2012

Background
—Over the past decade, calcium channel blockers (CCBs) and ACE inhibitors have been used increasingly in the treatment of hypertension. In contrast, β-blocker and diuretic use has decreased. It has been suggested that pharmaceutical marketing has influenced these prescribing patterns. No objective analysis of advertising for antihypertensive therapies exists, however.

Methods and Results
—We reviewed the January, April, July, and October issues of the
New England Journal of Medicine
from 1985 to 1996 (210 issues). The intensity of drug promotion was measured as the proportion of advertising pages used to promote a given medication. Statistical analyses used the χ
2
test for trend. Advertising for CCBs increased from 4.6% of advertising pages in 1985 to 26.9% in 1996, while advertising for β-blockers (12.4% in 1985 to 0% in 1996) and diuretics (4.2% to 0%) decreased (all
P
<0.0001). A nonsignificant increase was observed in advertising for ACE inhibitors (3.5% to 4.3%,
P
=0.17). Although the total number of drug advertising pages per issue decreased from 60 pages in 1985 to 42 pages in 1996 (
P
<0.001), the number of pages devoted to calcium channel blocker advertisements nearly quadrupled.

Conclusions
—Increasing promotion of CCBs has mirrored trends in physician prescribing. An association between advertising and prescribing patterns could explain why CCBs have supplanted better-substantiated therapies for hypertension.
Novel Mechanism Associated With an Inherited Cardiac Arrhythmia
Authors: Furutani Michiko , Trudeau Matthew C. , Hagiwara Nobuhisa , Seki Akiko , Gong Qiuming , Zhou Zhengfeng , Imamura Shin-ichiro , Nagashima Hirotaka , Kasanuki Hiroshi , Takao Atsuyoshi , Momma Kazuo , January Craig T. , Robertson Gail A. , Matsuoka Rumiko
Published: June 2012

Background
—The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go–related gene (
HERG
), which encodes the rapidly activating component of the delayed rectifier current (I
Kr
), cause chromosome 7–linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of
HERG
(G601S) in an LQTS family that we have characterized in the present work.

Methods and Results
—To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and
Xenopus
oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane.

Conclusions
—-Our results from both the
Xenopus
oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.
Relation Between Coronary “Steal” and Contractile Function at Rest in Collateral-Dependent Myocardium of Humans With Ischemic Heart Disease
Authors: Holmvang Gotfred , Fry Stefanie , Skopicki Hal A. , Abraham Stephen A. , Alpert Nathaniel M. , Fischman Alan J. , Picard Michael H. , Gewirtz Henry
Published: June 2012

Background
—We tested the hypothesis that rest asynergy in collateral-dependent myocardium correlates with coronary steal.

Methods and Results
—PET with [
13
N]ammonia measured myocardial blood flow and flow reserve in 15 patients with symptomatic chronic ischemic heart disease. Coronary angiography assessed stenosis severity and collateral blood supply. Echocardiography or contrast ventriculography evaluated regional wall motion. Collateral-dependent segments with normal flow at rest and supplied by coronary vessels having ≤50% diameter stenosis were studied. Steal was defined as a decline in myocardial blood flow with adenosine ≥0.15 mL · min
−1
· g
−1
versus rest. Blood flow at rest in asynergic, collateral-dependent segments with steal (1.15±0.35 mL · min
−1
· g
−1
) exceeded (
P
<0.0001) that of asynergic segments without steal (0.81±0.24) and those with normal contraction (0.77±0.18). Although the flow reserve ratio of segments with normal contraction (1.8±0.8) exceeded that of asynergic ones with (0.6±0.1) or without (1.3±0.4) steal, overlap was great. Correlation between basal contraction and flow reserve ratio in collateral-dependent myocardium was significant but weak (
r
=0.45,
P
<0.001). However, segments demonstrating “steal” with adenosine manifested asynergy in 22 of 23 collateral-dependent segments versus 24 of 39 nonsteal segments (χ
2
=7.10,
P
<0.01).

Conclusions
—Although myocardial flow reserve in collateral-dependent segments with normal contraction exceeded that of asynergic segments, overlap was great. However, in patients with angina or congestive heart failure, left ventricular segments demonstrating steal with adenosine almost always exhibit asynergy at rest. Thus, coronary steal may play an important role in the pathogenesis of chronic contractile impairment at rest, whereas simple reduction of flow reserve may be less important in selected patients.
Protease-Activated Receptor-2 Involvement in Hypotension in Normal and Endotoxemic Rats In Vivo
Authors: Cicala Carla , Pinto Aldo , Bucci Mariarosaria , Sorrentino Raffaella , Walker Brian , Harriot Patrick , Cruchley Alan , Kapas Supriya , Howells Gareth L. , Cirino Giuseppe
Published: June 2012

Background
—The protease-activated receptor-2 (PAR-2) is expressed by vascular endothelial cells and upregulated by lipopolysaccharide (LPS) in vitro. PAR-2 is activated by a tethered ligand created after proteolytic cleavage by trypsin or experimentally by a synthetic agonist peptide (PAR-2AP) corresponding to the new amino terminus of the tethered ligand.

Methods and Results
—Intravenous administration of PAR-2AP (0.1, 0.3, and 1 mg/kg) to rats caused a dose-dependent hypotension. A scrambled peptide was without effect. A specific trypsin inhibitor, biotin–SGKR-chloromethylketone, inhibited trypsin-induced hypotension but not that stimulated by PAR-2AP. In animals treated with LPS 20 hours earlier, we found an increased sensitivity to trypsin and PAR-2AP in the hypotensive response. In particular, PAR-2AP caused hypotension at a low concentration of 30 ng/kg. Moreover, PAR-2 was immunolocalized to endothelial and smooth muscle cells in aorta and jugular vein in LPS-treated rats, and increased levels of PAR-2 mRNA were shown by reverse transcription–polymerase chain reaction analysis.

Conclusions
—Our findings suggest that PAR-2 is important in the regulation of blood pressure in vivo. A functional upregulation of PAR-2 by LPS was demonstrated by the activity of concentrations of PAR-2AP that were inactive in normal animals. We conclude that PAR-2 may play an important role in the hypotension associated with endotoxic shock and may represent a new therapeutic target.
Reduction of Stroke Incidence After Myocardial Infarction With Pravastatin
Authors: Plehn Jonathan F. , Davis Barry R. , Sacks Frank M. , Rouleau Jean L. , Pfeffer Marc A. , Bernstein Victoria , Cuddy T. Edward , Moyé Lemuel A. , Piller Linda B. , Rutherford John , Simpson Lara M. , Braunwald Eugene
Published: June 2012

Background
—The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease.

Methods and Results
—To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%,
P
=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%,
P
=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively).

Conclusions
—Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.
Treatment of Acute Myocardial Infarction by Primary Coronary Angioplasty or Intravenous Thrombolysis in the “Real World”
Authors: Danchin Nicolas , Vaur Laurent , Genès Nathalie , Etienne Sylvie , Angioï Michaël , Ferrières Jean , Cambou Jean-Pierre
Published: June 2012

Background
—Recent randomized trials comparing primary coronary angioplasty and intravenous thrombolysis at the acute stage of myocardial infarction have shown a limited but definite advantage for primary angioplasty. The aim of this study was to document 1-year outcome in patients receiving either thrombolysis or primary angioplasty for acute myocardial infarction in the “real world.”

Methods and Results
—We used a nationwide prospective registry of all patients admitted for acute myocardial infarction in French intensive care units in November 1995. Of the 721 patients who received reperfusion therapy, 152 were treated with primary angioplasty and 569 received intravenous thrombolysis. The two groups were remarkably similar with respect to all baseline descriptors, except that a higher proportion of patients in the angioplasty group had a history of cerebrovascular accident (10% versus 2%,
P
<0.01). In-hospital outcome was not different in the 2 groups. One-year survival was 85.5% in the angioplasty group and 89.5% in the thrombolysis group (
P
=0.18). Multivariate analysis showed that older age, anterior location of infarction, female sex, and history of heart failure were related to 1-year mortality. In patients alive on day 5, the use of primary angioplasty and higher Killip class were additional adverse prognostic indicators.

Conclusions
—The results of this large registry of real-world practice indicate no survival benefit for patients treated with primary angioplasty compared with those who received thrombolytic therapy.
Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Organic Nitrates in Patients With Chronic Heart Failure Treated With Angiotensin-Converting Enzyme Inhibition
Authors: Elkayam Uri , Johnson Janet V. , Shotan Avraham , Bokhari Syed , Solodky Alejandro , Canetti Menahem , Wani Omar Rashid , Karaalp Ilyas Somer
Published: June 2012

Background
—Organic nitrates are widely used in the treatment of chronic heart failure (CHF). No information, however, is available regarding their effect in patients already treated with ACE inhibitors.

Methods and Results
—In a randomized, double-blind, crossover design, we studied the effects of high-dose (50 to 100 mg) transdermal nitroglycerin (NTG) and placebo given daily for 12 hours in 29 patients with CHF (NYHA functional classes II to III). Exercise time (4 hours after patch application) showed a progressive improvement during NTG administration, with an increase of 38±35 seconds (9±7%) at the end of the first month (
P
=NS), 76±28 seconds (16±6%) at the end of the second month (
P
=0.01), and 117±34 seconds (27±6%) at the end of the third month (
P
=0.003). No significant change was seen during placebo administration (12±20, 5±26, and 19±28 seconds, all
P
=NS). Exercise time 8 hours after NTG application measured at 3 months was also significantly longer, with a difference of 87±28 seconds (
P
=0.006), but not with placebo (23±36 seconds,
P
=0.53). Assessment of quality of life and need for additional diuretics or hospitalizations for CHF failed to demonstrate a significant difference between the 2 treatment periods. In contrast, NTG decreased left ventricular end-diastolic (−2.1±0.1%,
P
<0.05) and end-systolic (−3.2±1.3%,
P
<0.05) dimensions and augmented LV fractional shortening (24.7±10.5%,
P
<0.03). The effect of placebo on these parameters was not statistically significant.

Conclusion
—High-dose nitrate therapy significantly improves exercise tolerance and left ventricular size and systolic function in patients with chronic, mild to moderate CHF already treated with ACE inhibitors. These findings support the role of organic nitrates as an adjunctive therapy to ACE inhibitors in patients with chronic CHF.
Establishment of a Simple and Practical Procedure Applicable to Therapeutic Angiogenesis
Authors: Kanno Shinichi , Oda Nobuyuki , Abe Mayumi , Saito Sachiko , Hori Katsuyoshi , Handa Yasunobu , Tabayashi Koichi , Sato Yasufumi
Published: June 2012

Background
—Therapeutic angiogenesis is thought to be beneficial for serious ischemic diseases. This investigation was designed to establish a simple and practical procedure applicable to therapeutic angiogenesis.

Methods and Results
—When cultured skeletal muscle cells were electrically stimulated at a voltage that did not cause their contraction, vascular endothelial growth factor (VEGF) mRNA was augmented at an optimal-frequency stimulation. This increase of VEGF mRNA was derived primarily from transcriptional activation. Electrical stimulation increased the secretion of VEGF protein into the medium. This conditioned medium then augmented the growth of endothelial cells. The effect of electrical stimulation was further confirmed in a rat model of hindlimb ischemia. The tibialis anterior muscle in the ischemic limb was electrically stimulated. The frequency of stimulation was 50 Hz and strength was 0.1 V, which was far below the threshold for muscle contraction. After a 5-day stimulation, there was a significant increase in blood flow within the muscle. Immunohistochemical analysis revealed that VEGF protein was synthesized and capillary density was significantly increased in the stimulated muscle. Rats tolerated this procedure very well, and there was no muscle contraction, muscle injury, or restriction in movement.

Conclusions
—We propose this procedure as a simple and practical method of therapeutic angiogenesis.
Triggering of Myocardial Infarction by Cocaine
Authors: Mittleman Murray A. , Mintzer David , Maclure Malcolm , Tofler Geoffrey H. , Sherwood Jane B. , Muller James E.
Published: June 2012

Background
—Cocaine has been implicated as a trigger of acute myocardial infarction in patients with and those without underlying coronary atherosclerosis. However, the magnitude of the increase in risk of acute myocardial infarction immediately after cocaine use remains unknown.

Methods and Results
—In the Determinants of Myocardial Infarction Onset Study, we interviewed 3946 patients (1282 women) with acute myocardial infarction an average of 4 days after infarction onset. Data were collected on the use of cocaine and other potential triggers of myocardial infarction. We compared the reported use of cocaine in the hour preceding the onset of myocardial infarction symptoms with its expected frequency by using self-matched control data based on the case-crossover study design. Of the 3946 patients interviewed, 38 (1%) reported cocaine use in the prior year and 9 reported use within the 60 minutes preceding the onset of infarction symptoms. Compared with nonusers, cocaine users were more likely to be male (87% vs 67%,
P
=0.01), current cigarette smokers (84% vs 32%,
P
<0.001), younger (44±8 vs 61±13 years,
P
<0.001), and minority group members (63% vs 11%,
P
<0.001). The risk of myocardial infarction onset was elevated 23.7 times over baseline (95% CI 8.5 to 66.3) in the 60 minutes after cocaine use. The elevated risk rapidly decreased thereafter.

Conclusions
—Cocaine use is associated with a large abrupt and transient increase in the risk of acute myocardial infarction in patients who are otherwise at relatively low risk. This finding suggests that studying the pathophysiological changes produced by cocaine may provide insights into the mechanisms by which myocardial infarction is triggered by other stressors.
HLA Class II Associations With Rheumatic Heart Disease Are More Evident and Consistent Among Clinically Homogeneous Patients
Authors: Guédez Yajaira , Kotby Alyaa , El-Demellawy Maha , Galal Ashraf , Thomson Glenys , Zaher Salah , Kassem Samir , Kotb Malak
Published: June 2012

Background
—Discrepancies in reported HLA class II associations with rheumatic heart disease (RHD) may have been due to inaccuracies of serological typing reagents and/or lack of defined clinical classification of patients analyzed. The molecular association between HLA and RHD was investigated in patients with defined clinical outcome.

Methods and Results
—Class II allele/haplotype distribution was determined in 2 groups of RHD patients (n=88) and a control group (n=59). Patients were divided into the mitral valve disease (MVD) category (ie, those with mitral regurgitation with or without mitral stenosis) and the multivalvular lesions (MVL) category, with impairment of aortic and/or tricuspid valves in addition to mitral valve damage. The MVD category (n=65) accounted for 74% of patients and included significantly fewer recurrent RF episodes compared with MVL patients (
P
=0.002).

Conclusions
—Significant increases in DRB1*0701 and DQA1*0201 alleles and DRB1*0701-DQA1*0201 haplotypes were found in patients. Removal of the MVL patients from analysis increased the strength of HLA associations among the MVD sample. The frequency of DQA1*0103 allele was decreased and the DQB1*0603 allele was absent from the patient group, suggesting that these alleles may confer protective effects against RHD. DQ alleles in linkage disequilibrium with DR alleles appear to influence risk/protection effect: whereas the DRB1*13–DQA1*0501-3–DQB1*0301 haplotype showed a trend toward risk, the DRB1*13-DQA1*0103-DQB1*0603 haplotype was absent in the RHD sample. Our data indicate that certain class II alleles/haplotypes are associated with risk or protection from RHD and that these associations appear to be stronger and more consistent when analyzed in patients with relatively more homogeneous clinical manifestations.
Clinical Significance of Thrombocytopenia During a Non–ST-Elevation Acute Coronary Syndrome
Authors: McClure Matthew W. , Berkowitz Scott D. , Sparapani Rodney , Tuttle Robert , Kleiman Neal S. , Berdan Lisa G. , Lincoff A. Michael , Deckers Jaap , Diaz Rafael , Karsch Karl R. , Gretler Daniel , Kitt Michael , Simoons Maarten , Topol Eric. J. , Califf Robert M. , Harrington Robert A.
Published: June 2012

Background
—The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non–ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes.

Methods and Results
—Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100×10
9
/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (
P
<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk.

Conclusions
—Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.
Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure
Authors: Varin Rémi , Mulder Paul , Richard Vincent , Tamion Fabienne , Devaux Corinne , Henry Jean-Paul , Lallemand Françoise , Lerebours Guy , Thuillez Christian
Published: June 2012

Background
—Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown.

Methods and Results
—FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 μL/min flow: sham, 42±5%; CHF, −4±3%;
P
<0.05). Exercise partially restored FMD (18±3%;
P
<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide–synthase inhibitor
N
ω
-nitro-
l
-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise.

Conclusions
—CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.
Expression of Tissue Inhibitor of Matrix Metalloproteinases 1 by Use of an Adenoviral Vector Inhibits Smooth Muscle Cell Migration and Reduces Neointimal Hyperplasia in the Rat Model of Vascular Balloon Injury
Authors: Dollery Clare M. , Humphries Steven E. , McClelland Alan , Latchman David S. , McEwan Jean R.
Published: June 2012

Background
—Cell migration is a major contributor to injury-induced neointimal hyperplasia and depends on alteration of the proteolytic balance within the arterial wall toward matrix breakdown. This is partly mediated by the matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).

Methods and Results
—An increase in expression of biologically active and immunoreactive TIMP-1 was seen in vitro after infection of rat smooth muscle cells (SMCs) with Av1.TIMP1 (an adenoviral vector containing the human TIMP1 cDNA). Infection of rat SMCs with Av1.TIMP1 reduced migration in vitro by 27% compared with control virus–infected cells (37.6±4.34 versus 51±5.01 cells per high-power field,
P
<0.05). The adenoviral vector was delivered to the injured rat carotid artery, and 4 days later, immunoreactive protein was identified and migration of SMCs reduced by 60% (5.2±0.5 versus 12.8±1.5 cells per section,
P
<0.05, n=5). Neointimal area 14 days after injury showed a 30% reduction in the animals receiving the Av1.TIMP1 virus compared with controls (0.09±0.01 versus 0.14±0.01 mm
2
,
P
=0.02, n=14).

Conclusions
—The response to arterial balloon injury involves MMP-dependent SMC migration and can be attenuated in vivo by the transmural expression of TIMP-1 by adenoviral gene transfer.
Interleukin-8 Mediates Downregulation of Tissue Inhibitor of Metalloproteinase-1 Expression in Cholesterol-Loaded Human Macrophages
Authors: Moreau Martine , Brocheriou Isabelle , Petit Laure , Ninio Ewa , Chapman M. John , Rouis Mustapha
Published: June 2012

Background
—The accumulation of macrophage-derived foam cells in atherosclerotic lesions correlates with increased local release of matrix-degrading metalloproteinases (MMPs) and a thin fibrous cap. The activity of these enzymes is controlled by specific tissue inhibitors of metalloproteinases (TIMPs).

Methods and Results
—Because oxidized low-density lipoprotein (OxLDL) modulates gene expression, we investigated the effect of these particles on the levels of MMP-1, MMP-3, MMP-9, TIMP-1, and TIMP-2 in the culture media of human monocyte-derived macrophages. OxLDL but not native LDL or high-density lipoprotein reduced the level of TIMP-1 in a dose-dependent manner with maximal effect (60% of control) at ≈100 μg protein/mL. In addition, Northern blotting revealed marked reduction in the abundance of TIMP-1 mRNA in OxLDL-treated cells. Evaluation of the effect of oxysterol components of OxLDL on TIMP-1 production revealed that 25-hydroxycholesterol (1 μg/mL) was the most potent inhibitor (≈30% of control). Such inhibition was partially mediated by interleukin (IL)-8. Indeed, IL-8 (2.5 ng/mL) induced maximal inhibition of TIMP-1 accumulation (30% of control) in 4 of 6 cell preparations. In addition, the inhibitory effect of OxLDL-treated cells in the presence of an anti–IL-8 neutralizing antibody was partially reversed.

Conclusions
—Immunohistochemical analyses of human atherosclerotic plaques revealed the expression of TIMP-1 in some but not all macrophage-rich and IL-8–rich areas. Therefore, IL-8 may play a potential atherogenic role by inhibiting local TIMP-1 expression, thereby leading to an imbalance between MMPs and TIMPs at focal sites in the atherosclerotic plaque.
Delayed Response of Myocardial Flow Reserve to Lipid-Lowering Therapy With Fluvastatin
Authors: Guethlin Martin , Kasel Albert Markus , Coppenrath Klaus , Ziegler Sibylle , Delius Wolfram , Schwaiger Markus
Published: June 2012

Background
—Lipid-lowering therapy can improve endothelial function in patients with coronary artery disease (CAD) and hypercholesterolemia. Little is known about induced changes in myocardial microcirculation. This study prospectively investigated the temporal effects of lipid-lowering therapy with fluvastatin on coronary flow and flow reserve (CFR) in patients with CAD assessed by PET.

Methods and Results
—In an open clinical trial, CFR was studied in 15 patients with angiographically documented multivessel CAD and hypercholesterolemia (LDL >160 mg/dL). Dynamic
13
N-labeled ammonia PET imaging in conjunction with adenosine was used to assess regional and global CFR at baseline as well as at 2 and 6 months during treatment with fluvastatin (60 to 80 mg/d). Despite a rapid decrease in total cholesterol (29±6%) and LDL (37±9%), myocardial blood flow at rest and during stress was unchanged after 2 months of treatment (2.7±0.9 versus 2.5±0.6 mL · g
−1
· min
−1
). At 6 months, stress blood flow as well as CFR increased significantly (3.4±1.0 mL · g
−1
· min
−1
). No change in hemodynamic parameters was noted during the entire study. Nine of 15 patients increased CFR by >20%. All responders demonstrated improvement in anginal symptoms, whereas nonresponders stated no change (n=4) or worsening of symptoms (n=2). The improvement in CFR was not related to the amount of lipid lowering and was independent of the severity of stenoses.

Conclusions
—Improvement in stress blood flow and CFR is delayed compared with the lipid-lowering effect of fluvastatin, suggesting a slow recovery of the vasodilatory response to adenosine.
Relationship Between Na
+
-Ca
2+
–Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium
Authors: Hasenfuss Gerd , Schillinger Wolfgang , Lehnart Stephan E. , Preuss Michael , Pieske Burkert , Maier Lars S. , Prestle Jürgen , Minami Kazutomo , Just Hanjörg
Published: June 2012

Background
—In the failing human heart, sarcoplasmic reticulum (SR) calcium handling is impaired, and therefore, calcium elimination and diastolic function may depend on the expression of sarcolemmal Na
+
-Ca
2+
exchanger.

Methods and Results
—Force-frequency relations were studied in ventricular muscle strip preparations from failing human hearts (n=29). Protein levels of Na
+
-Ca
2+
exchanger and SR Ca
2+
-ATPase were measured in the same hearts. Hearts were divided into 3 groups by discriminant analysis according to the behavior of diastolic function when stimulation rate of muscle strips was increased from 30 to 180 min
−1
. At 180 compared with 30 min
−1
, diastolic force was increased by 160%, maximum rate of force decline was decreased by 46%, and relaxation time was unchanged in group III. In contrast, in group I, diastolic force and maximum rate of force decline did not change, and relaxation time decreased by 20%. Na
+
-Ca
2+
exchanger was 66% higher in group I than in group III. Na
+
-Ca
2+
exchanger was inversely correlated with the frequency-dependent rise of diastolic force when stimulation rate was increased (
r
=−0.74;
P
<0.001). Compared with nonfailing human hearts (n=6), SR Ca
2+
-ATPase was decreased and Na
+
-Ca
2+
exchanger unchanged in group III, whereas Na
+
-Ca
2+
exchanger was increased and SR Ca
2+
-ATPase unchanged in group I. Results with group II hearts were between those of group I and group III hearts.

Conclusions
—By discriminating failing human hearts according to their diastolic function, we identified different phenotypes. Disturbed diastolic function occurs in hearts with decreased SR Ca
2+
-ATPase and unchanged Na
+
-Ca
2+
exchanger, whereas increased expression of the Na
+
-Ca
2+
exchanger is associated with preserved diastolic function.
Familial Dilated Cardiomyopathy Locus Maps to Chromosome 2q31
Authors: Siu Benjamin L. , Niimura Hideshi , Osborne John A. , Fatkin Diane , MacRae Calum , Solomon Scott , Benson D. Woodrow , Seidman J. G. , Seidman Christine E.
Published: June 2012

Background
—Inherited gene defects are an important cause of dilated cardiomyopathy. Although the chromosome locations of some defects and 1 disease gene (actin) have been identified, the genetic etiologies of most cases of familial dilated cardiomyopathy remain unknown.

Methods and Results
—We clinically evaluated 3 generations of a kindred with autosomal dominant transmission of dilated cardiomyopathy. Nine surviving and affected individuals had early-onset disease (ventricular chamber dilation during the teenage years and congestive heart failure during the third decade of life). The disease was nonpenetrant in 2 obligate carriers. To identify the causal gene defect, linkage studies were performed. A new dilated cardiomyopathy locus was identified on chromosome 2 between loci
GCG
and
D2S72
(maximum logarithm of odds [LOD] score=4.86 at θ=0). Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, sequences encoding 900 amino acid residues of the cardiac-specific (N2-B) domain were analyzed. Five sequence variants were identified, but none segregated with disease in this family.

Conclusions
—A dilated cardiomyopathy locus (designated
CMD1G
) is located on chromosome 2q31 and causes early-onset congestive heart failure. Although titin remains an intriguing candidate gene for this disorder, a disease-causing mutation is not present in its cardiac-specific N2-B domain.
Sex, Age, Cardiovascular Risk Factors, and Coronary Heart Disease
Authors: Jousilahti Pekka , Vartiainen Erkki , Tuomilehto Jaakko , Puska Pekka
Published: June 2012

Background
—Coronary heart disease (CHD) is markedly more common in men than in women. In both sexes, CHD risk increases with age, but the increase is sharper in women. We analyzed the extent to which major cardiovascular risk factors can explain the sex difference and the age-related increase in CHD risk.

Methods and Results
—The study cohort consists of 14 786 Finnish men and women 25 to 64 years old at baseline. The following cardiovascular risk factors were determined: smoking, serum total cholesterol, HDL cholesterol, blood pressure, body mass index, and diabetes. Risk factor measurements were done in 1982 or 1987, and the cohorts were followed up until the end of 1994. The Cox proportional hazards model was used to assess the relation between risk factors and CHD risk. CHD incidence in men compared with women was ≈3 times higher and mortality was ≈5 times higher. Most of the risk factors were more favorable in women, but the sex difference in risk factor levels diminished with increasing age. Differences in risk factors between sexes, particularly in HDL cholesterol and smoking, explained nearly half of the difference in CHD risk between men and women. Differences in serum total cholesterol level, blood pressure, body mass index, and diabetes prevalence explained about one-third of the age-related increase in CHD risk among men and 50% to 60% among women.

Conclusions
—Differences in major cardiovascular risk factors explained a substantial part of the sex difference in CHD risk. An increase in risk factor levels was associated with the age-related increase in CHD incidence and mortality in both sexes but to a larger extent in women.
The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat.
Authors: Crofton J T , Share L , Shade R E , Lee-Kwon W J , Manning M , Sawyer W H
Published: June 2012

Experiments were performed to determine the role of vasopressin in deoxycorticosterone (DOC)-salt hypertension. In order to determine if vasopressin is necessary for the development of DOC-salt hypertension, rats with hereditary diabetes insipidus (DI) and normal Long-Evans rats (LE) were unilaterally nephrectomized, treated with DOC Pivalate (30 mg/kg . week) and given saline to drink for 8 weeks. A second group of DI rats were unilaterally nephrectomized, but received no treatment. Systolic blood pressure (SBP) increased 40 mm Hg in the LE group (p less than 0.01) but failed to increase significantly in either DI group. Urinary excretion of vasopressin (UADHV) and SBP were measured in unilaterally nephrectomized LE rats treated with DOC and salt (DOC-LE), salt alone (NaCl-LE) and untreated rats (H2O-LE). The UADHV was elevated in DOC-LE (p less than 0.01) and NaCl-LE (p less than 0.05), but only the DOC-LE rats became hypertensive. Finally, the I.V. injection of analogs of vasopressin, which block its pressor but not antidiuretic activity, lowered mean arterial blood pressure 27 +/- 5 mm Hg in 11 conscious DOC-salt hypertensive rats. It is concluded that vasopressin plays a major role as a pressor agent in both the onset and maintenance of DOC-salt hypertension.
A quantitative study of muscle nerve sympathetic activity in resting normotensive and hypertensive subjects.
Authors: Wallin B G , Sundlöf G
Published: June 2012

Recordings of multi-unit sympathetic activity were made from muscle branches of the peroneal or median nerves in 33 healthy and 12 hypertensive subjects resting in the recumbent position. Simultaneous recordings of intra-arterial blood pressure were made on 17 normotensive and all hypertensive subjects. The neural activity, quantified by counting the number of sympathetic pulse-synchronous impulse bursts in the mean voltage neurogram (burst incidence) was plotted against the age and the arterial blood pressure level of the subjects. Between different subjects there were marked differences in mean burst incidence, from less than 10 to more than 90 bursts/100 heart beats and there was a tendency for increasing values with increasing age. Taking the age differences into account there was no significant correlation between the amount of activity and the blood pressure level. The effect of spontaneous temporary blood pressure fluctuations was studied by correlation different pressure parameters of individual heart beats to the probability of occurrence of a sympathetic burst and to the mean voltage amplitude of the occurring burst. Irrespective of the mean burst incidence, the occurrence of the bursts and their mean voltage amplitudes were determined mainly by fluctuations of the diastolic blood pressure. The diastolic pressure threshold for sympathetic outflow was found to be reset to higher blood pressure values in the hypertensive subjects and the variability of their thresholds was also greater than for the normotensive controls. At a given diastolic blood pressure, more sympathetic activity occurred if diastolic blood pressure was falling than if it was rising, and this directional dependence was more pronounced in the hypertensive subjects. We suggest that the increased directional dependence accounts for the greater variability of the blood pressure threshold for sympathetic outflow in the hypertensive subjects. The differences can be expalined on the basis of findings in animals with experimental hypertension, and it appears that they are secondary to the hypertension.
Pathophysiology of hypertension in blacks and whites. A review of the basis of racial blood pressure differences.
Authors: Gillum R F
Published: June 2012

Differences in blood pressure between blacks and whites in the United States are now well documented. The causes of these differences remain speculative. Genetic factors, personal characteristics, renal physiology, endocrine factors, autonomic nervous system function, cardiac function and various environmental factors are examined in the present review as potential determinants of racial blood pressure differences. Racial differences in renal physiology and environmental influences such as socioeconomic status seem to be likely candidates for important contributions to blood pressure differences. Further research aimed specifically at black-white blood pressure differences is of great importance to a fundamental understanding of the etiology and prevention of essential hypertension.
Regulated systemic activation of rat plasma prorenin.
Authors: Hare G M , Ioannou P , Dubiski S , Osmond D H
Published: June 2012

Nephrectomized rats have above-normal plasma prorenin levels, presumably of extra-renal origin, but essentially no renin, suggesting a lack of "convertase" for prorenin activation. Adrenalectomized rats have low plasma prorenin levels accompanied by high renin activity, suggesting enhanced prorenin activation by the action of a stimulated "convertase" mechanism. Cross-circulation between adrenalectomized and nephrectomized rats for 15 or 30 minutes, dramatically lowered prorenin and raised renin levels in both types of rats, suggesting extensive activation of prorenin to renin. Similarly, in vitro mixing of these bloods (without cross-circulation) raised renin activity over five times the expected calculated level, while prorenin essentially disappeared. In both cases, prorenin from nephrectomized rat plasma apparently was activated to renin by the enhanced action of "convertase" in the adrenalectomized rat plasma. This newly generated renin activity was, like normal plasma renin, almost completely inhibited by a monoclonal antibody against hog renin and generated an immunoreactive angiotensin I. In contrast, cross-circulation or in vitro mixing of blood from normal control and nephrectomized rats produced little detectable activation of prorenin and only modest increments of renin, suggesting relative inactivity of the "convertase" mechanism in normal plasma. Our data suggest that activation of plasma prorenin is a significant regulated pathway for renin production, as it is greatly stimulated after adrenalectomy and deficient after nephrectomy, thereby implicating the kidney as an important contributor to the "convertase" mechanism operating within the circulation.