bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelin in human congestive heart failure.
Authors: Wei C M , Lerman A , Rodeheffer R J , McGregor C G , Brandt R R , Wright S , Heublein D M , Kao P C , Edwards W D , Burnett J C 
Published: June 2012

BACKGROUND
Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction.

METHODS AND RESULTS
The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts.

CONCLUSIONS
The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.
Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.
Authors: Drexler H , Fischell T A , Pinto F J , Chenzbraun A , Botas J , Cooke J P , Alderman E L 
Published: June 2012

BACKGROUND
Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis.

METHODS AND RESULTS
Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002).

CONCLUSIONS
The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.
Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators.
Authors: Bristow M R , O'Connell J B , Gilbert E M , French W J , Leatherman G , Kantrowitz N E , Orie J , Smucker M L , Marshall G , Kelly P 
Published: June 2012

BACKGROUND
Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy (IDC). The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy (ISCD).

METHODS AND RESULTS
Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties. One hundred forty-one subjects with class II or III heart failure, left ventricular ejection fraction (LVEF) < or = 0.40, and background therapy of angiotensin-converting enzyme inhibitors, digoxin, and diuretics were given an initial challenge dose of bucindolol 12.5 mg. One hundred thirty-nine subjects (99 with IDC, 40 with ISCDC) tolerated challenge and were randomized to treatment with placebo or bucindolol 12.5 mg/d (low dose), 50 mg/d (medium dose), or 200 mg/d (high dose). At the end of 12 weeks, left ventricular function and other parameters were measured and compared with baseline values. There was a dose-related improvement in left ventricular function in bucindolol-treated subjects. In the high-dose bucindolol group, radionuclide-measured LVEF improved by 7.8 EF units (%) compared with 1.8 units in the placebo group (P < .05), and compared with the placebo group, a greater percentage of subjects had an increase in LVEF by > or = 5 units. In contrast, all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units.

CONCLUSIONS
In heart failure from systolic dysfunction, beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function.
Detection of myocardial ischemia by 31P magnetic resonance spectroscopy during handgrip exercise.
Authors: Yabe T , Mitsunami K , Okada M , Morikawa S , Inubushi T , Kinoshita M 
Published: June 2012

BACKGROUND
The metabolic changes of myocardial ischemia in patients with coronary artery disease assessed by 31P magnetic resonance spectroscopy (MRS) have been reported previously. A significant decrease in the ratio of phosphocreatine (PCr) to ATP during handgrip exercise in a group of patients with severe coronary artery disease has been demonstrated. However, there are no reports at present that directly compare cardiac 31P MRS data with exercise 201Tl myocardial scintigraphy, now established as one of the most important clinical methods to assess myocardial ischemia. The purpose of this study was to investigate whether 31P MRS with handgrip exercise testing is able to detect myocardial ischemia, demonstrated by exercise 201Tl scintigraphy.

METHODS AND RESULTS
Twenty-seven patients with severe stenosis of the left anterior descending coronary artery (> or = 75%) and 11 normal control subjects composed the present study. Patients were divided into two groups on the basis of exercise 201Tl scintigraphy: a reversible 201Tl defect group (RD[+]) who demonstrated redistribution at the late image and a fixed 201Tl defect group (RD[-]). While lying supine within the magnet, subjects performed handgrip exercise at 30% of maximal force once in every two cardiac cycles. 31P MR spectra were collected before and during handgrip exercise. Data were corrected for the saturation factor. ANOVA revealed significant differences among the three groups with respect to the mean +/- SD PCr/ATP ratio at rest (control, 1.85 +/- 0.28 > RD(+), 1.60 +/- 0.19 > RD(-), 1.24 +/- 0.30; P < .05). The PCr/ATP ratio decreased significantly from 1.60 +/- 0.19 at rest to 0.96 +/- 0.28 during exercise (P < .001) in the RD(+) group (n = 15). However, in the RD(-) group (n = 12), the ratio did not change significantly during handgrip exercise (1.24 +/- 0.30 at rest versus 1.19 +/- 0.28 during exercise). Similarly, the ratio did not change in the control group (n = 11) (1.85 +/- 0.28 at rest versus 1.90 +/- 0.23 during exercise).

CONCLUSIONS
Contrary to normal subjects or patients with fixed thallium defects, the PCr/ATP ratio was significantly altered by exercise in patients with reversible thallium defects. These results suggest that 31P MRS with handgrip exercise testing is a sensitive method for detecting myocardial ischemia.
Liposome-bound prostaglandin E1 often prevents cyclic flow variations in stenosed and endothelium-injured canine coronary arteries.
Authors: Willerson J T , Yao S K , McNatt J , Cui K , Anderson H V , Swensen C , Ostro M , Buja L M 
Published: June 2012

BACKGROUND
Prostaglandin E1 is a potent vasodilator with anti-inflammatory and antiplatelet effects. We tested the hypothesis that prostaglandin E1 attenuates or prevents platelet aggregation-associated cyclic flow variations (CFVs) in severely stenosed and endothelium-injured coronary arteries.

METHODS AND RESULTS
We induced CFVs in 21 dogs by placing an external constrictor around the left anterior descending coronary artery at the site where the endothelium had been mechanically injured. The blood flow velocity in the artery was monitored by a pulsed Doppler flow probe. Sixty minutes after CFVs were established, liposome-bound prostaglandin E1, a stable formulation, was administered intravenously to 12 dogs at incremental doses of 0.25, 0.5, 1, and 2 micrograms/kg body wt; it abolished CFVs in 8 of the 12 dogs (67%). After CFVs were eliminated, epinephrine was infused intravenously, and at a dose of 6.6 +/- 1.6 micrograms/min, it restored CFVs in 7 of 7 dogs. Control dogs (n = 9) were treated with free prostaglandin E1, which did not abolish CFVs in any dog.

CONCLUSIONS
Liposome-bound but not free prostaglandin E1 effectively diminishes CFVs in severely stenosed and endothelium-injured canine coronary arteries.
Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion.
Authors: Horwitz L D , Fennessey P V , Shikes R H , Kong Y 
Published: June 2012

BACKGROUND
There has been controversy about whether early reperfusion of myocardial infarcts causes further necrosis mediated by reactive oxygen species or other mechanisms. Unequivocal evidence that therapeutic agents given only during reperfusion can prevent, rather than delay or modify, injury has been sparse. Failure to account for variables, such as collateral blood flow, that influence infarct size independently and attempts to measure infarct size too early in reperfusion may have limited the sensitivity and specificity of some previous studies.

METHODS AND RESULTS
After 90 minutes of coronary occlusion and 48 hours of reperfusion in a canine model, we examined the effect on infarct size of intravenous infusion of N-(2-mercaptopropionyl)-glycine (MPG), a diffusible antioxidant. Infarct size and region at risk were measured by post-mortem dual perfusion with triphenyl tetrazolium chloride and Evans blue dyes, and regional myocardial blood flow was measured with radioactive microspheres. Infusion of MPG 100 mg.kg-1.h-1, beginning either 15 minutes before the onset of reperfusion or 30 minutes after the onset of reperfusion and continued until 4 hours of reperfusion and followed by an intramuscular dose, reduced infarct size, normalized for both region at risk and the level of collateral blood flow, by 60% and 45%, respectively. When infusion of MPG was limited to the last 15 minutes of ischemia and the first hour of reperfusion only, the normalized infarct size was reduced by 26%. Heart rate, blood pressure, and their product did not differ among the four groups studied. The plasma half-time of MPG was < 10 minutes. In in vitro experiments MPG was a scavenger of hydrogen peroxide but not of superoxide radical.

CONCLUSIONS
After 90 minutes of coronary ligation, infusion of the diffusible hydrogen peroxide scavenger, MPG, for several hours, beginning as late as 30 minutes after the onset of reperfusion, substantially reduced infarct size measured 48 hours later. In this model, necrosis caused by processes during reperfusion may be more extensive than necrosis caused by ischemia alone. Since infusion of this agent for only the first hour of reperfusion was considerably less effective, it appears that most of the oxidant injury leading to necrosis occurred after the first 60 minutes but within the first 4 hours of reperfusion.
In vivo assessment of left atrial contractile performance in normal and pathological conditions using a time-varying elastance model.
Authors: Hoit B D , Shao Y , Gabel M , Walsh R A 
Published: June 2012

BACKGROUND
Contractile function of the ex vivo, isolated left atrium (LA) has been described by a time-varying elastance, but this atrial chamber property has not been shown in vivo.

METHODS AND RESULTS
Instantaneous LA pressure-volume (P-V) relations were studied in 12 anesthetized, autonomically blocked, atrially paced dogs. LA volume was calculated from orthogonal sonomicrometer pairs using a cast-validated formula. Data were collected during increases in LA pressure produced by a phenylephrine bolus (200 to 400 micrograms IV). Isochronal P-V points from 5 beats, representing a wide range of atrial pressures, were fitted by linear regression analysis (range of R2, .92 to .99). There were significant time-dependent increases in the slopes [E(t)] and small but statistically insignificant decreases in the volume axis intercepts [VO(t)] of the instantaneous LA P-V relations during atrial contraction; maximal elastance (Emax) occurred 29 +/- 16 milliseconds before atrial end systole (minimal LA volume). Emax was not significantly different than the slopes of either the nonisochronal end-systolic P-V relation (Ees) or the nonisochronal maximal P-to-V relation (EmaxPV): 5.5 +/- 2.8, 4.3 +/- 1.5, and 5.4 +/- 4.2 mm Hg/mL, respectively. In 7 dogs, data were collected both before and after a rapid infusion of calcium gluconate (1 to 2 g IV). Emax increased significantly with a calcium-induced increase in inotropic state (4.5 +/- 1.6 to 5.7 +/- 1.8 mm Hg/mL, P < .01), but the volume axis intercept was unchanged (3.6 +/- 0.7 versus 3.4 +/- 1.9, P = NS). In 4 additional dogs with heart failure (mean LA pressure, 26 +/- 6 mm Hg) produced by 3 weeks of rapid right ventricular pacing, LA stroke volume was significantly greater than and elastance determinations were similar to those of normal dogs. However, the effects of calcium infusion on LA function were attenuated in these animals.

CONCLUSIONS
We conclude that (1) in the intact heart, LA contraction may be approximated by time-varying elastance with time-dependent changes in E(t) and that (2) LA systolic P-V relations using either the nonisochronal maximum P-to-V ratio or end systole may be useful as an estimate of Emax, are highly linear and sensitive to calcium-induced changes in inotropic state, and may be useful in identifying LA chamber adaptation to chronic hemodynamic loads.
Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction.
Authors: Flaherty J T , Pitt B , Gruber J W , Heuser R R , Rothbaum D A , Burwell L R , George B S , Kereiakes D J , Deitchman D , Gustafson N 
Published: June 2012

BACKGROUND
Animal studies have demonstrated a burst of oxygen free radical generation after reperfusion of ischemic myocardium that could be blocked by administration of the free radical scavenger recombinant human superoxide dismutase (h-SOD). A multicenter, randomized, placebo-controlled clinical trial was designed to test the hypothesis that free radical-mediated reperfusion injury could be reduced by intravenous administration of h-SOD begun before percutaneous transluminal coronary angioplasty (PTCA) in patients with acute transmural myocardial infarction.

METHODS AND RESULTS
One hundred twenty patients were randomized to receive placebo (n = 59) or h-SOD (n = 61) given as a 10-mg/kg intravenous bolus followed by a 60-minute infusion of 0.2 mg.kg-1.min-1. Left ventricular function was analyzed via paired contrast left ventriculograms performed before PTCA and after 6 to 10 days and paired radionuclide ventriculograms performed within 24 hours of PTCA and after 4 to 6 weeks. Both h-SOD- and placebo-treated patients showed improvement in global and regional left ventricular function after successful reperfusion. Compared with the placebo group, no additional improvement was observed in the patients treated with h-SOD.

CONCLUSIONS
The results of this clinical trial failed to demonstrate a beneficial effect of h-SOD on global or regional left ventricular function in patients who underwent successful PTCA for treatment of acute myocardial infarction.
Prospective study of phobic anxiety and risk of coronary heart disease in men.
Authors: Kawachi I , Colditz G A , Ascherio A , Rimm E B , Giovannucci E , Stampfer M J , Willett W C 
Published: June 2012

BACKGROUND
To examine prospectively the association between self-reported symptoms of phobic anxiety and subsequent risk of coronary heart disease, a 2-year follow-up study was conducted of a cohort of 33,999 US male health professionals, aged 42 to 77 years in 1988, who were free of diagnosed cardiovascular disease at baseline. Levels of phobic anxiety were assessed using the Crown-Crisp index, a short, diagnostic self-rating scale used for common phobias. Main outcomes were incidents of coronary heart disease consisting of nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD).

METHODS AND RESULTS
One hundred sixty-eight incident cases of CHD occurred during 2 years of follow-up (128 cases of nonfatal MI and 40 cases of fatal CHD). The age-adjusted relative risk of fatal CHD among men with highest levels of phobic anxiety (scoring 4 or higher on the Crown-Crisp index) was 3.01 (95% confidence interval, 1.31 to 6.90) compared with men with the lowest levels of anxiety (scoring 0 or 1 on the phobia index). Risk of fatal CHD increased with levels of phobic anxiety (P trend = .002). When fatal CHD was further categorized into sudden and nonsudden coronary death, the excess risk was confined to sudden death (relative risk among men scoring 3 or higher on the phobia index was 6.08; 95% confidence interval, 2.35 to 15.73). No association was found between phobic anxiety and risk of nonfatal MI. These findings remained essentially unchanged after adjusting for a broad range of cardiovascular risk factors.

CONCLUSIONS
The specificity, strength, and dose-response gradient of the association, together with the consistency and biological plausibility of the experimental and epidemiologic evidence, support a strong causal association between phobic anxiety and fatal CHD.
Efficient repopulation of denuded rabbit arteries with autologous genetically modified endothelial cells.
Authors: Conte M S , Birinyi L K , Miyata T , Fallon J T , Gold H K , Whittemore A D , Mulligan R C 
Published: June 2012

BACKGROUND
In an effort to determine whether specific genetic modifications of cells of the vascular system might improve the efficacy of existing clinical procedures such as endarterectomy, atherectomy, and percutaneous angioplasty, we investigated the utility of gene transfer to rapidly and efficiently repopulate injured arteries with genetically modified cells in an animal model.

METHODS AND RESULTS
The method involves the harvest of autologous venous-derived endothelial cells, the efficient genetic modification of the cells through the use of recombinant retroviruses, and the subsequent implantation of the genetically modified cells on the surface of balloon-denuded arterial segments. With a rabbit model, freshly isolated endothelial cells were transduced with a recombinant retrovirus encoding the bacterial enzyme beta-galactosidase. The autologous transduced cells were then implanted on the surface of balloon-denuded ileofemoral arterial segments at different cell densities; after 1 to 14 days, the animals were killed, and the vessel segments were examined. Cells expressing the bacterial gene product, as determined by in situ staining for beta-galactosidase, were found to be present on the surface of 28 of the 32 arteries seeded with genetically modified cells. Vessels examined at 4 to 7 days after seeding displayed 40% to 90% coverage with transduced cells, even when seeded at subconfluent density, and an intact endothelial cell monolayer, as evidenced by scanning electron microscopy studies. Vessels examined at 14 days after seeding revealed more variable staining for beta-galactosidase yet, again, in most cases, an intact endothelial cell monolayer.

CONCLUSIONS
These studies indicate the feasibility of generating segments of arterial vessels containing genetically modified cells in a rapid and efficient fashion. Further studies are now necessary to determine whether the local expression of specific polypeptides within a region of vessel for a finite period of time will be clinically useful.